Depression and the Risk of Myocardial Infarction and Coronary Death: A Meta-Analysis of Prospective Cohort Studies.
Findings regarding the association between depression and risk of coronary heart disease are inconsistent. We aimed to assess the association between depression and risk of myocardial infarction (MI) and coronary death through a meta-analysis.We performed an electronic literature search of MEDLINE, EMBASE, PsycINFO, ISI Web of Science, and Scopus databases through August 1, 2015, and manual search of the references of the eligible papers and related review articles. Two investigators independently conducted study selection and data abstraction. Disagreement was resolved by consensus. Confounder-adjusted hazard ratios (HRs) were pooled using a random-effects model. Heterogeneity was evaluated using the Cochran Q statistic and Higgins index. Publication bias was assessed by funnel plot and Egger test. Study quality was appraised with the Newcastle-Ottawa Scale.Among 19 eligible cohort studies including 323,709 participants, 8447 cases of MI and coronary death were reported during follow-up ranging from 4 to 37 years. The pooled adjusted HRs for patients with depression (vs those without) were 1.22 (95% CI, 1.13-1.32) for combined MI and coronary death, 1.31 (95% CI, 1.09-1.57) for MI alone (9 studies), and 1.36 (95% CI, 1.14-1.63) for coronary death alone (8 studies). The increased risk of MI and coronary death associated with depression was consistent using modified inclusion criteria, across most subgroups, and after adjusting for possible publication bias.Depression is associated with a significantly increased risk of MI and coronary death. Effective prevention and treatment of depression may decrease such risk.


Endovascular model of rabbit hindlimb ischemia: a platform to evaluate therapeutic angiogenesis.
Current animal hindlimb ischemia models involve surgical ligation of the femoral artery and delivery of therapeutic angiogenic agents into the adductor compartment. The authors hypothesize that an endovascular model of hindlimb ischemia would be a more appropriate platform, closely resembling atherosclerosis by occluding the vessel from within, causing less inflammation, wound healing and subsequent collateralization. The left superficial femoral artery in 17 rabbits was occluded by endovascular coil embolization (n=9) or surgical ligation (n=8). Animals (n=3; in each group) were sacrificed on day 3 to determine the arteriolar luminal area, number of arterioles, microsphere determined perfusion, and degree of inflammation. On day 28, the remaining animals underwent calf blood pressure measurements and angiography to determine the number of collaterals and diameter of vessels supplying the hindlimb. Immediate postprocedure (day 0) and presacrifice (day 3 or 28) occlusion rates were 89% (eight of nine rabbits) and 100% for the endovascular model; 100% and 100% for the surgical model, respectively. Hindlimb paralysis and muscle atrophy was found in one surgical animal. On day 3, there was an increase in hindlimb perfusion (surgery, 0.04+/-0.01; endovascular, 0.02+/-0.01; P=.02), an increase in arteriolar luminal area (surgery, 481 microm+/-240; endovascular, 345 microm+/-151; P=.04), and a trend toward more inflammation (surgery, 5.5+/-3.8; endovascular, 2.5+/-3.0; P=.08) in the surgical group. There was no difference in number of vessels between both groups. On day 28 there was no difference in the calf blood pressure ratios or in the number of collaterals. However, there was enlargement of the distal profunda femoris artery, the vessel closest to the surgical incision, in the surgical group (L/R ratio: immediate post-occlusion, 1.06+/-0.11; day 28, 1.27+/-0.08; P=.02). The endovascular model was efficacious in providing occlusion of the superficial femoral artery, and induced less of an arteriogenic response compared with the surgical model. The authors believe that this endovascular model is a superior platform for studying therapeutic angiogenic agents.


Listeria monocytogenes multidrug resistance transporters and cyclic di-AMP, which contribute to type I interferon induction, play a role in cell wall stress.
The intracellular bacterial pathogen Listeria monocytogenes activates a robust type I interferon response upon infection. This response is partially dependent on the multidrug resistance (MDR) transporter MdrM and relies on cyclic-di-AMP (c-di-AMP) secretion, yet the functions of MdrM and cyclic-di-AMP that lead to this response are unknown. Here we report that it is not MdrM alone but a cohort of MDR transporters that together contribute to type I interferon induction during infection. In a search for a physiological function of these transporters, we revealed that they play a role in cell wall stress responses. A mutant with deletion of four transporter genes (ΔmdrMTAC) was found to be sensitive to sublethal concentrations of vancomycin due to an inability to produce and shed peptidoglycan under this stress. Remarkably, c-di-AMP is involved in this phenotype, as overexpression of the c-di-AMP phosphodiesterase (PdeA) resulted in increased susceptibility of the ΔmdrMTAC mutant to vancomycin, whereas overexpression of the c-di-AMP diadenylate cyclase (DacA) reduced susceptibility to this drug. These observations suggest a physiological association between c-di-AMP and the MDR transporters and support the model that MDR transporters mediate c-di-AMP secretion to regulate peptidoglycan synthesis in response to cell wall stress.


Prevention of skin carcinogenesis by the β-blocker carvedilol.
The stress-related catecholamine hormones and the α- and β-adrenergic receptors (α- and β-AR) may affect carcinogenesis. The β-AR GRK/β-arrestin biased agonist carvedilol can induce β-AR-mediated transactivation of the EGFR. The initial purpose of this study was to determine whether carvedilol, through activation of EGFR, can promote cancer. Carvedilol failed to promote anchorage-independent growth of JB6 P(+) cells, a skin cell model used to study tumor promotion. However, at nontoxic concentrations, carvedilol dose dependently inhibited EGF-induced malignant transformation of JB6 P(+) cells, suggesting that carvedilol has chemopreventive activity against skin cancer. Such effect was not observed for the β-AR agonist isoproterenol and the β-AR antagonist atenolol. Gene expression, receptor binding, and functional studies indicate that JB6 P(+) cells only express β2-ARs. Carvedilol, but not atenolol, inhibited EGF-mediated activator protein-1 (AP-1) activation. A topical 7,12-dimethylbenz(α)anthracene (DMBA)-induced skin hyperplasia model in SENCAR mice was utilized to determine the in vivo cancer preventative activity of carvedilol. Both topical and oral carvedilol treatment inhibited DMBA-induced epidermal hyperplasia (P < 0.05) and reduced H-ras mutations; topical treatment being the most potent. However, in models of established cancer, carvedilol had modest to no inhibitory effect on tumor growth of human lung cancer A549 cells in vitro and in vivo. In conclusion, these results suggest that the cardiovascular drug carvedilol may be repurposed for skin cancer chemoprevention, but may not be an effective treatment of established tumors. More broadly, this study suggests that β-ARs may serve as a novel target for cancer prevention.


The Search for Antifungal Prophylaxis After Artificial Corneal Surgery-An In Vitro Study.
To evaluate the antifungal properties of topical antibiotics (already being used successfully to prevent bacterial endophthalmitis) and some promising antiseptics for antifungal prophylaxis in the setting of artificial corneal implantation. Several commonly used antibiotics for antimicrobial prophylaxis after artificial corneal implantation, in addition to antiseptics [benzalkonium chloride (BAK), povidone-iodine (PI), and some ionic liquids (ILs)], were tested in vitro against Candida albicans, Fusarium solani, and Aspergillus fumigatus. The time-kill activity was determined. Toxicity was assayed in vitro on human corneal epithelial cultures using trypan blue. Adhesion and tissue invasion experiments were also carried out on porcine corneas and commonly used contact lenses, with or without gamma irradiation, and by analysis with fluorescence microscopy. Polymyxin B (PMB)/trimethoprim/BAK (Polytrim), PMB alone, gatifloxacin with BAK (Zymaxid), and same-concentration BAK alone exhibited antifungal activity in vitro. Moxifloxacin (MOX) or gatifloxacin without BAK-as well as trimethoprim, vancomycin, and chloramphenicol-had no effect. 1% PI and ILs had the highest efficacy/toxicity ratios (>1), and Polytrim was species dependent. Subfungicidal concentrations of Polytrim reduced adhesion of C. albicans to Kontur contact lenses. Gamma-irradiated corneas showed enhanced resistance to fungal invasion. Of antibiotic preparations already in use for bacterial prophylaxis after KPro surgery, Polytrim is a commonly used antibiotic with antifungal effects mediated by both PMB and BAK and may be sufficient for prophylaxis. PI as a 1% solution seems to be promising as a long-term antifungal agent. Choline-undecanoate IL is effective and virtually nontoxic and warrants further development.


Optimal design of nanoplasmonic materials using genetic algorithms as a multiparameter optimization tool.
An optimal control approach based on multiple parameter genetic algorithms is applied to the design of plasmonic nanoconstructs with predetermined optical properties and functionalities. We first develop nanoscale metallic lenses that focus an incident plane wave onto a prespecified, spatially confined spot. Our results illustrate the mechanism of energy flow through wires and cavities. Next we design a periodic array of silver particles to modify the polarization of an incident, linearly polarized plane wave in a desired fashion while localizing the light in space. The results provide insight into the structural features that determine the birefringence properties of metal nanoparticles and their arrays. Of the variety of potential applications that may be envisioned, we note the design of nanoscale light sources with controllable coherence and polarization properties that could serve for coherent control of molecular, electronic, or electromechanical dynamics in the nanoscale.


Comparative distribution of quinolone antibiotics in cerebrospinal fluid and brain in rats and dogs.
The distribution of the quinolone antibiotics, norfloxacin (NFLX), AM-1155, fleroxacin (FLRX), ofloxacin, sparfloxacin (SPFX) and pefloxacin (PFLX), in the central nervous system (CNS) was investigated in dogs and rats. In dogs, the steady-state cerebrospinal fluid (CSF) to unbound serum concentration ratio (Kp,uCSF) differed widely ranging from 0.11 (NFLX) to 1.0 (PFLX). About a 10-fold difference between compounds was also observed in the Kp,uCSF in rats; however, these values were 25 to 50% smaller than those in dogs. Similarly, the brain to unbound serum concentration ratio (Kp,uBrain) of quinolones differed widely ranging from 0.15 (NFLX) to 1.5 (SPFX) in dogs and 0.04 (NFLX) to 0.33 (FLRX) in rats. The steady-state concentration ratio between CSF and brain tissue exhibited a 3-fold difference among quinolones (0.5 for PFLX to 1.6 for SPFX) in dogs, whereas, these values were all close to unity in rats. Kp,uBrain and Kp,uCSF all increased as the lipophilicity of the compound increased (except the Kp,uBrain in dogs). We also found that the quinolones inhibited the saturable accumulation of [14C]FLRX (Km 660 microM) by the isolated rat choroid plexus. About a 20-fold difference among the apparent IC50 values for FLRX transport was observed between NFLX (6000 microM) and PFLX (300 microM). The absence of a negative correlation between the affinity of the quinolones for this transport system, which in turn represents the efflux clearance from the CSF, and their in vivo distribution in rat CNS (Kp,uBrain or Kp,uCSF) suggests a minor contribution of this efflux system to the CNS distribution of quinolones.


Critical learning period for speech acquisition and screening techniques in early detection of hearing impairment.
In order to develop verbal communication skills, an infant nervous system needs sound stimuli, especially human speech, in the early and critical learning period of life. The maturation of hearing and language learning abilities of an infant is considered to be complete within the first two to three years of life. Therefore, detection of hearing impairment before the end of the critical language learning period is considered crucial if a child is expected to acquire his/her native language properly. Parents or caregivers may suspect the presence of a delay in language acquisition; however, relying only on parental awareness could cause a delay in detection of the hearing impairment. Even mild hearing loss may interfere with normal development of speech and language in infants, therefore, universal screening of infants for hearing loss as early as possible should be the goal. The purpose of this paper is to discuss the concept of the critical language learning period and its relevance to language acquisition. Furthermore, it is the aim of the paper to evaluate the available techniques for early identification of hearing impairment in general and the feasibility of the various techniques in Turkey.


Altered retinoblastoma and p53 protein status in non-small cell carcinoma of the lung: potential synergistic effects on prognosis.
Routinely processed pathological specimens from 119 patients with stage I and II adenocarcinomas or squamous cell carcinomas were examined by immunohistochemical analysis for altered retinoblastoma (RB) and/or p53 protein expression. Absent RB nuclear staining (RB-) indicating loss of RB function occurred in 19 (16%) of the cases studied, whereas expression of a putative mutant p53 nuclear protein (p53(+)) was found in 54 (45%) of the tumors. The median survival was 39 versus 12 months for patients with RB+ and RB- tumors, respectively (P = 0.05 by log rank analysis). Similarly, the median survival was 41 months for patients whose tumors had no expression of mutant p53 (p53(-)) compared with 24 months for individuals with p53 (+) tumors (P = 0.01). These differences in survival, however, were not statistically significant by multivariate analysis. Nevertheless, individuals with RB-/p53(+) tumors had a significantly shorter median survival (12 months) than those with RB+/p53(-) tumors (41 months), as determined by both log rank and multivariate analyses (P = 0.005 and 0.03, respectively). In addition, 66 large cell carcinomas from all stages were examined. Again, a more significant difference in survival (48 versus 8 months) was found between patients with RB+/p53(-) versus RB-/p53(+) tumors (P = 0. 006). These results suggest that RB and p53 status might be used synergistically as prognostic factors in a subset of non-small cell lung carcinomas.


Examining Cultural Competency and Sexual Abuse Training Needs Among Service Providers Working with Black and Latino Sexual Minority Men.
Black and Latino sexual minority men (SMM) with a history of childhood sexual abuse (CSA) may be reluctant to disclose such experiences or may appraise them as consensual because of cultural norms. Anticipated stigma, medical mistrust, and concerns that providers lack training in sexuality may complicate their efforts to obtain treatment for long-term health consequences of CSA. It is important to examine the training needs of service providers working with SMM who may disclose sexual abuse. Qualitative interviews were conducted with 35 substance use disorder (SUD) treatment and allied health service providers across the New York City area. Themes included the importance of training in cultural competence, trauma-informed care, and assessment of-and counseling for-CSA. Further education in these areas can enable providers to recognize indicators of abuse in their clients' sexual histories and to more effectively and safely respond to this information. Future studies are encouraged to test a trauma-informed approach to screening for CSA history with Black and Latino SMM who present to SUD treatment and allied health service providers. This research should consider provider perspectives in developing such an approach and will likely involve training and evaluation to ensure adequate preparedness and effective service delivery.


Simulation of Na/Ca exchange activity during ischemia.
Simulation of sodium-calcium exchange activity during the rise of intracellular sodium that occurs during ischemia suggests that the exchanger may not reverse direction except transiently during calcium oscillations. This conclusion depends on the presence of a small resting leak of calcium into the cell, consistent with radioactive calcium flux measurements. The conditions for intracellular calcium to rise to around 3 microM were explored. A combination of extracellular potassium accumulation and extracellular sodium depletion is sufficient to explain this result. The computations also show a counterintuitive result concerning the role of the exchanger in the mechanism of calcium oscillations. Reducing its activity would be expected to enhance these oscillations, whereas increasing it can reduce or suppress oscillations. If such oscillations play a role in acute ischemic arrhythmias, then block of Na/Ca exchange may not be therapeutic.


Quantification of UV-B flux through time using UV-B-absorbing compounds contained in fossil Pinus sporopollenin.
UV-B radiation currently represents c. 1.5% of incoming solar radiation. However, significant changes are known to have occurred in the amount of incoming radiation both on recent and on geological timescales. Until now it has not been possible to reconstruct a detailed measure of UV-B radiation beyond c. 150 yr ago. Here, we studied the suitability of fossil Pinus spp. pollen to record variations in UV-B flux through time. In view of the large size of the grain and its long fossil history, we hypothesized that this grain could provide a good proxy for recording past variations in UV-B flux. Two key objectives were addressed: to determine whether there was, similar to other studied species, a clear relationship between UV-B-absorbing compounds in the sporopollenin of extant pollen and the magnitude of UV-B radiation to which it had been exposed; and to determine whether these compounds could be extracted from a small enough sample size of fossil pollen to make reconstruction of a continuous record through time a realistic prospect. Preliminary results indicate the excellent potential of this species for providing a quantitative record of UV-B through time. Using this technique, we present the first record of UV-B flux during the last 9500 yr from a site near Bergen, Norway.


A review of state regulations to promote infant physical activity in child care.
The purpose of this study was to review state regulations promoting increased physical activity and decreased sedentary behaviors in infants in child care and to assess consistency with recent Institute of Medicine (IOM) recommendations. We compared existing state and territory licensing and administrative regulations to recent IOM recommendations to promote physical activity and decrease sedentary time in very young children attending out-of-home child care (both child care centers and family child care homes). Three independent reviewers searched two sources (a publicly available website and WestlawNext™) and compared regulations with five IOM recommendations: 1) providing daily opportunities for infants to move, 2) engaging with infants on the ground, 3) providing daily tummy time for infants less than six months of age, 4) using cribs, car seats and high chairs for their primary purpose, and 5) limiting the use of restrictive equipment for holding infants while they are awake. We used Pearson chi-square tests to assess associations between geographic region, year of last update, and number of state regulations consistent with the IOM recommendations. The mean (SD) number of regulations for states was 1.9 (1.3) for centers and 1.6 (1.2) for homes out of a possible 5.0. Two states had regulations for all five recommendations, Arizona for centers and Virginia for homes. Six states and territories had zero regulations for child care centers and seven states and territories had zero regulations for family child care homes. There were no significant associations between geographic region and number of regulations consistent with IOM recommendations. Out-of-home child care settings are important targets for optimal early child health interventions. While most states had some regulations related to the promotion of physical activity among infants, few states had regulations for more than three of the five IOM recommendations. Enhancing state regulations in child care facilities could aid in early childhood obesity prevention efforts.


Effect of molecular hydrogen saturated alkaline electrolyzed water on disuse muscle atrophy in gastrocnemius muscle.
The objectives of this paper were to determine the level of oxidative stress in atrophied gastrocnemius, and to verify the effect of molecular hydrogen (H2) saturated alkaline electrolyzed water (HSW) on gastrocnemius atrophy by modifying the redox status, indicated by 8-hydroxy-2'-deoxyguanosine (8-OHdG), malondialdehyde (MDA), and superoxide dismutase (SOD)-like activity. Female Wistar rats were divided into four groups: (1) the control (CONT); (2) the Hindlimb unloading (HU, for 3 weeks) given purified normal water (HU-NW); (3) the HU given alkaline electrolyzed reduced water (HU-AEW); and (4) the HU given HSW (HU-HSW). We showed that 8-OHdG, but not MDA, significantly increased by 149% and 145% in HU-NW and HU-AEW, respectively, when compared with CONT. In contrast, there was a trend toward suppression in 8-OHdG levels (increased by 95% compared with CONT) by treatment of HSW, though this effect was not prominent. Additionally, SOD-like activity significantly increased in both HU-NW (184%) and HU-AEW (199%) when compared with CONT. This result suggests the elevation of O2-· in the atrophied gastrocnemius. However, upregulation of SOD-like activity in the HU-HSW was increased by only 169% compared with CONT, though this difference is too small to detect statistical significance. HU led to 13% and 15% reduction of gastrocnemius wet weights in HU-NW and HU-AEW, respectively, compared with CONT. And the reduction of gastrocnemius wet weights in HU-HSW was attenuated by 7% compared with CONT. The gastrocnemius wet weights in the HU-HSW group were significantly greater than those in the HU-AEW, but not statistically significant with HU-NW. These results indicate that HU causes an increase in oxidative stress, but, in this experimental protocol, continuous consumption of HSW during HU does not demonstrate successful attenuation of oxidative stress and HU-mediated gastrocnemius atrophy.


A pilot study of edrecolomab (Panorex, 17-1A antibody) and capecitabine in patients with advanced or metastatic adenocarcinoma.
Edrecolomab (Panorex) is a monoclonal antibody directed against the 17-1A antigen located on the cell surfaces of carcinomas. Clinical activity has been seen in colon and breast cancer. This trial investigated the feasibility of combining edrecolomab with the oral fluoropyrimidine capecitabine (Xeloda). Patients received a loading dose of edrecolomab 500 mg intravenously (i.v.) on day--14, followed 2 weeks later by 100 mg i.v. every 28 days (day 1). Capecitabine was administered to single-patient cohorts at escalating doses of 1500, 2000, and 2500 mg/m2/day in two equally divided doses for 14 of 21 days, beginning on day 1. Additional patients were enrolled at the 2500 mg/m2/day dose level to better define the toxicities of combination therapy. Toxicity assessment was the primary endpoint. Twenty seven patients with advanced or metastatic adenocarcinoma were enrolled on this study: 20 were evaluable for toxicity and 18 for response. The most common toxicities were elevated liver enzymes, diarrhea, and hand-foot syndrome. In cycle 1, grade 3 hand-foot syndrome was seen in two patients, and grade 3 diarrhea in one patient. Grade 2 toxicities included diarrhea, hand-foot syndrome, anemia, leukopenia, and transaminitis. Cumulative hand-foot syndrome was observed in four patients treated beyond two cycles. Three patients had edrecolomab infusion reactions during the course of treatment. One complete response and two partial responses were seen. Nine patients had disease stabilization lasting a median of 17.5 weeks (range 14.5-28+). Edrecolomab and capecitabine may be safely given in combination to patients with advanced or metastatic adenocarcinoma. Clinical activity is seen in this heavily pretreated patient population.


A Systematic Review and Meta-Analysis of the Efficacy of Anti-Toxoplasma gondii Medicines in Humans.
No effective drug and definitive "gold standard" treatment for Toxoplasma gondii (T. gondii) infection has been available so far, though some medicines have been commonly used in the treatment of T. gondii infection, such as spiramycin, azithromycin, traditional Chinese medicine (TCM), pyrimethamine- sulfadiazine (P-S), trimethoprim-sulfamethoxazole (TMP-SMX), and pyrimethamine-clindamycin (P-C). A systematic review and meta-analysis were performed to compare the efficacies of these conventional medicines in the treatment. Cohort studies for the treatment of acute T. gondii infection were searched from PubMed, Google Scholar, ect. All the cases number for different group extracted from each included literature were input to meta-analysis 3.13 software to calculate the pooled negative conversion rate (NCR), cure rate (CR) or vertical transmission rate based on their sample size and weight. The pooled NCR with 95% confidence intervals (CI) was used to evaluate the overall rate of a diagnosis positive result conversion to a negative result after treatment, which of spiramycin, azithromycin and TCM were 83.4% (95%CI, 72.1%-90.8%), 82.5% (95%CI, 75.9%-87.6%), and 85.5% (95%CI, 71.3%-93.3%) respectively, with no statistical difference between them. The pooled CR with 95% CI was used to evaluate the overall rate of complete disappearance of clinical symptoms for toxoplasmic encephalitis after therapy, which of P-S, TMP-SMX, and P-C were 49.8% (95%CI, 38. 8% -60.8%), 59.9% (95%CI, 48.9%-70.0%), and 47.6% (95%CI, 24.8%-71.4%) respectively, with no statistical difference between them. Primary T. gondii infection in pregnancy was treated mainly with spiramycin alone or combined with other drugs, and the pooled rate of vertical transmission was about 9.9% (95%CI, 5.9%-16.2%) after therapy. Toxoplasmic encephalitis in AIDS patients was usually treated with sulfonamides combined with other drugs and the pooled CR was 49.4% (95%CI, 37.9%-60.9%).


Prospective study of serum 25-hydroxyvitamin D concentration and mortality in a Chinese population.
Prospective epidemiologic data on the association between vitamin D and mortality are limited, particularly in Asian populations. Among subjects in Linxian, China, the authors aimed to test whether baseline serum 25-hydroxyvitamin D (25(OH)D) concentrations in a prospective cohort were associated with all-cause mortality and cause-specific mortality rates over 24 years of follow-up (1986-2010). Serum 25(OH)D concentrations were measured in 1,101 subjects using an immunoassay. Hazard ratios and 95% confidence intervals were calculated using Cox regression models that were adjusted for age, sex, tobacco smoking, alcohol drinking, and hypertension. The 25th, 50th, and 75th percentile concentrations of 25(OH)D were 19.6, 31.9, and 48.4 nmol/L, respectively. During follow-up, 793 subjects died, including 279 who died of cerebrovascular accident, 217 who died of cancer, and 200 cardiovascular disease deaths. All-cause mortality was not associated with 25(OH)D concentrations using continuous models (for every 15 nmol/L, hazard ratio = 1.01, 95% confidence interval: 0.97, 1.05) or quartile models (fourth vs. first quartiles, hazard ratio = 1.06, 95% confidence interval: 0.87, 1.30; P for trend = 0.731). The authors also found no association with the cause-specific mortality outcomes. Results were similar for men and women. This study showed that prediagnostic serum 25(OH)D concentrations were not associated with all-cause or cause-specific mortality rates in this Chinese population who had low levels of vitamin D.


No role for initial severity on the efficacy of antidepressants: results of a multi-meta-analysis.
During the last decade, a number of meta-analyses questioned the clinically relevant efficacy of antidepressants. Part of the debate concerned the method used in each of these meta-analyses as well as the quality of the data set. The Kirsch data set was analysed with a number of different methods, and eight key questions were tackled. We fit random effects models in both Bayesian and frequentist statistical frameworks using raw mean difference and standardised mean difference scales. We also compare between-study heterogeneity estimates and produce treatment rank probabilities for all antidepressants. The role of the initial severity is further examined using meta-regression methods. The results suggest that antidepressants have a standardised effect size equal to 0.34 which is lower but comparable to the effect of antipsychotics in schizophrenia and acute mania. The raw HDRS difference from placebo is 2.82 with the value of 3 included in the confidence interval (2.21-3.44). No role of initial severity was found after partially controlling for the effect of structural (mathematical) coupling. Although data are not definite, even after controlling for baseline severity, there is a strong possibility that venlafaxine is superior to fluoxetine, with the other two agents positioned in the middle. The decrease in the difference between the agent and placebo in more recent studies in comparison to older ones is attributed to baseline severity alone. The results reported here conclude the debate on the efficacy of antidepressants and suggest that antidepressants are clearly superior to placebo. They also suggest that baseline severity cannot be utilized to dictate whether the treatment should include medication or not. Suggestions like this, proposed by guidelines or institutions (e.g. the NICE), should be considered mistaken.


The effects of compression garments on intermittent exercise performance and recovery on consecutive days.
The aim of this study was to determine whether compression garments improve intermittent-sprint performance and aid performance or self-reported recovery from high-intensity efforts on consecutive days. Following familiarization, 14 male rugby players performed two randomized testing conditions (with or without garments) involving consecutive days of a simulated team sport exercise protocol, separated by 24 h of recovery within each condition and 2 weeks between conditions. Each day involved an 80-min high-intensity exercise circuit, with exercise performance determined by repeated 20-m sprints and peak power on a cart dynamometer (single-man scrum machine). Measures of nude mass, heart rate, skin and tympanic temperature, and blood lactate (La-) were recorded throughout each day; also, creatine kinase (CK) and muscle soreness were recorded each day and 48 h following exercise. No differences (P=.20 to 0.40) were present between conditions on either day of the exercise protocol for repeated 20-m sprint efforts or peak power on a cart dynamometer. Heart rate, tympanic temperature, and body mass did not significantly differ between conditions; however, skin temperature was higher under the compression garments. Although no differences (P=.50) in La- or CK were present, participants felt reduced levels of perceived muscle soreness in the ensuing 48 h postexercise when wearing the garments (2.5+/-1.7 vs 3.5+/-2.1 for garment and control; P=.01). The use of compression garments did not improve or hamper simulated team-sport activity on consecutive days. Despite benefits of reduced self-reported muscle soreness when wearing garments during and following exercise each day, no improvements in performance or recovery were apparent.


Assisted reproduction for postmenopausal women.
With increasing longevity, an ageing population and advances in assisted reproductive technologies (ART), a greater number of women are deciding to have a child and become a mother in their later years. With this social and demographic change, an important social and ethical debate has emerged over whether single and/or married postmenopausal women should have access to ARTs. The aim of this paper is to address this question and review critically the arguments that have been advanced to support or oppose the use of ART by older women. The arguments presented consider the consequences for the individual, the family and wider society. They cover the potential physical and emotional harm to the older woman, the possible impact on the welfare and wellbeing of the future child, and the impact on the norms, values, customs and traditions of society. After reviewing the evidence, and weighing the opposing arguments, this paper concludes that there is no moral justification for a restriction on the use of ART by postmenopausal women. Allowing access to ART for postmenopausal women is an extension of reproductive autonomy and procreative rights in an age where the promotion of agency, autonomy, individual choice and human rights is paramount.


Diverse Large HIV-1 Non-subtype B Clusters Are Spreading Among Men Who Have Sex With Men in Spain.
In Western Europe, the HIV-1 epidemic among men who have sex with men (MSM) is dominated by subtype B. However, recently, other genetic forms have been reported to circulate in this population, as evidenced by their grouping in clusters predominantly comprising European individuals. Here we describe four large HIV-1 non-subtype B clusters spreading among MSM in Spain. Samples were collected in 9 regions. A pol fragment was amplified from plasma RNA or blood-extracted DNA. Phylogenetic analyses were performed via maximum likelihood, including database sequences of the same genetic forms as the identified clusters. Times and locations of the most recent common ancestors (MRCA) of clusters were estimated with a Bayesian method. Five large non-subtype B clusters associated with MSM were identified. The largest one, of F1 subtype, was reported previously. The other four were of CRF02_AG (CRF02_1; n = 115) and subtypes A1 (A1_1; n = 66), F1 (F1_3; n = 36), and C (C_7; n = 17). Most individuals belonging to them had been diagnosed of HIV-1 infection in the last 10 years. Each cluster comprised viruses from 3 to 8 Spanish regions and also comprised or was related to viruses from other countries: CRF02_1 comprised a Japanese subcluster and viruses from 8 other countries from Western Europe, Asia, and South America; A1_1 comprised viruses from Portugal, United Kingom, and United States, and was related to the A1 strain circulating in Greece, Albania and Cyprus; F1_3 was related to viruses from Romania; and C_7 comprised viruses from Portugal and was related to a virus from Mozambique. A subcluster within CRF02_1 was associated with heterosexual transmission. Near full-length genomes of each cluster were of uniform genetic form. Times of MRCAs of CRF02_1, A1_1, F1_3, and C_7 were estimated around 1986, 1989, 2013, and 1983, respectively. MRCA locations for CRF02_1 and A1_1 were uncertain (however initial expansions in Spain in Madrid and Vigo, respectively, were estimated) and were most probable in Bilbao, Spain, for F1_3 and Portugal for C_7. These results show that the HIV-1 epidemic among MSM in Spain is becoming increasingly diverse through the expansion of diverse non-subtype B clusters, comprising or related to viruses circulating in other countries.


Strong overtones modes in inelastic electron tunneling spectroscopy with cross-conjugated molecules: a prediction from theory.
Cross-conjugated molecules are known to exhibit destructive quantum interference, a property that has recently received considerable attention in single-molecule electronics. Destructive quantum interference can be understood as an antiresonance in the elastic transmission near the Fermi energy and leading to suppressed levels of elastic current. In most theoretical studies, only the elastic contributions to the current are taken into account. In this paper, we study the inelastic contributions to the current in cross-conjugated molecules and find that while the inelastic contribution to the current is larger than for molecules without interference, the overall behavior of the molecule is still dominated by the quantum interference feature. Second, an ongoing challenge for single molecule electronics is understanding and controlling the local geometry at the molecule-surface interface. With this in mind, we investigate a spectroscopic method capable of providing insight into these junctions for cross-conjugated molecules: inelastic electron tunneling spectroscopy (IETS). IETS has the advantage that the molecule interface is probed directly by the tunneling current. Previously, it has been thought that overtones are not observable in IETS. Here, overtones are predicted to be strong and, in some cases, the dominant spectroscopic features. We study the origin of the overtones and find that the interference features in these molecules are the key ingredient. The interference feature is a property of the transmission channels of the π system only, and consequently, in the vicinity of the interference feature, the transmission channels of the σ system and the π system become equally transmissive. This allows for scattering between the different transmission channels, which serves as a pathway to bypass the interference feature. A simple model calculation is able to reproduce the results obtained from atomistic calculations, and we use this to interpret these findings.


Analysis of syntax and word use to predict successful participation in guided self-help for anxiety and depression.
This study investigated whether an analysis of narrative style (word use and cross-clausal syntax) of patients with symptoms of generalised anxiety and depression disorders can help predict the likelihood of successful participation in guided self-help. Texts by 97 people who had made contact with a primary care mental health service were analysed. Outcome measures were completion of the guided self-help programme, and change in symptoms assessed by a standardised scale (CORE-OM). Regression analyses indicated that some aspects of participants' syntax helped to predict completion of the programme, and that aspects of syntax and word use helped to predict improvement of symptoms. Participants using non-finite complement clauses with above-average frequency were four times more likely to complete the programme (95% confidence interval 1.4 to 11.7) than other participants. Among those who completed, the use of causation words and complex syntax (adverbial clauses) predicted improvement, accounting for 50% of the variation in well-being benefit. These results suggest that the analysis of narrative style can provide useful information for assessing the likelihood of success of individuals participating in a mental health guided self-help programme.


Reliable estimation of membrane curvature for cryo-electron tomography.
Curvature is a fundamental morphological descriptor of cellular membranes. Cryo-electron tomography (cryo-ET) is particularly well-suited to visualize and analyze membrane morphology in a close-to-native state and molecular resolution. However, current curvature estimation methods cannot be applied directly to membrane segmentations in cryo-ET, as these methods cannot cope with some of the artifacts introduced during image acquisition and membrane segmentation, such as quantization noise and open borders. Here, we developed and implemented a Python package for membrane curvature estimation from tomogram segmentations, which we named PyCurv. From a membrane segmentation, a signed surface (triangle mesh) is first extracted. The triangle mesh is then represented by a graph, which facilitates finding neighboring triangles and the calculation of geodesic distances necessary for local curvature estimation. PyCurv estimates curvature based on tensor voting. Beside curvatures, this algorithm also provides robust estimations of surface normals and principal directions. We tested PyCurv and three well-established methods on benchmark surfaces and biological data. This revealed the superior performance of PyCurv not only for cryo-ET, but also for data generated by other techniques such as light microscopy and magnetic resonance imaging. Altogether, PyCurv is a versatile open-source software to reliably estimate curvature of membranes and other surfaces in a wide variety of applications.


First Report of Turnip ringspot virus in Field Mustard (Brassica chinensis) in Taiwan.
Crucifer crops (Brassica spp.) are important winter vegetables in Taiwan. Five viruses, including Turnip mosaic virus (TuMV), Cucumber mosaic virus (CMV), Radish mosaic virus (RaMV), Beet western yellows virus (BWYV), and Cauliflower mosaic virus (CaMV), have been detected in a range of domestic-grown crucifers during past decades (1). Field mustard plants (Brassica chinensis) showing mosaic in the leaves were collected in the ChiaYi area in December 2007. Spherical virus-like particles, approximately 30 nm in diameter, were readily observed in crude sap of symptomatic plants. Tests by ELISA failed to detect any of the aforementioned viruses. A spherical agent was isolated through mechanical inoculation onto Chenopodium quinoa, and a virus culture was established and inoculated mechanically back to the original host as well as other crucifers. Systemic mosaic appeared on inoculated B. campestris, B. chinensis, and B. juncea, whereas ringspots appeared on inoculated leaves of B. oleracea. Total RNA was extracted from symptomatic leaves and used for reverse transcription (RT)-PCR amplification using degenerate primers for comoviruses (2). Other successive fragments of RNAs 1 and 2 were amplified by specific or degenerate primers designed on the basis of sequences of published Turnip ringspot virus (TuRSV). The RNA 1 (GenBank Accession No. GU968732) and RNA 2 (No. GU968731) of the isolated virus consisted of 6,076 and 3,960 nucleotides, respectively. The number of nucleotides and the arrangement of open reading frames on both RNA 1 and RNA 2 were similar to those of comoviruses. Sequence analysis revealed that the nucleotide sequences of RNA 1 and RNA 2 shared 54.2 to 82.5% and 50.2 to 79.3% similarities, respectively, to those of comoviruses and were most similar to Turnip ringspot virus. The deduced peptides of large and small coat proteins (LCP and SCP) contain 375 amino acids (41.2 kDa) and 251 amino acids (28.5 kDa), respectively. The deduced amino acid sequences of RNA-dependent RNA polymerase (RdRp), LCP, and SCP share 92.0 to 94.5%, 93.1 to 93.3% and 87.3 to 89.6% similarity, respectively, to those of published TuRSV isolates, i.e., -B (GenBank Accession No. GQ222382), -M12 (No. FJ516746), and -Toledo (No. FJ712027) indicating that the newly isolated virus from field mustard in Taiwan is an isolate of TuRSV, hence TuRSV-TW. Comparison of LCP and SCP between current TuRSV-TW and Radish mosaic virus (RaMV; GenBank Accession No. AB295644) showed 74% similarity, which is below the species demarcation level of 75% (3), indicating its discrimination from RaMV. To our knowledge, this is the first report of the occurrence of TuRSV in Taiwan and in the subtropics. References: (1) T. H. Chen et al. Plant Pathol. Bull. 9:39, 2000. (2) V. Maliogka et al. J. Phytopathol. 152:404, 2004. (3) K. Petrzik and I. Koloniuk. Virus Genes 40:290, 2010.


Religious aspects of organ transplantation.
No religion formally forbid donation or receipt of organs or is against transplantation from living or deceased donors. Only some orthodox jews may have religious objections to "opting in." However, transplantation from deceased donors may be discouraged by Native Americans, Roma Gypsies, Confucians, Shintoists, and some Orthodox rabbis. Some South Asia Muslim ulemas (scholars) and muftis (jurists) oppose donation from human living and deceased donors because the human body is an "amanat" (trusteeship) from God and must not be desecrated following death, but they encourage xenotransplantation research. No religion formally obliges one to donate or refuse organs. No religion formally obliges one to consider cadaveric organs "a societal resource" or considers organ donation "a religious duty" (except some rabbis and isolated Muslim and Christian scholars) No religion has a formal position on "bonus points," which is priority on the waiting list. Living organ donation is strongly encouraged only between jesus christians (15 of 28 jesus christians worldwide have donated a kidney). No religion forbid this practice. Directed organ donation to people of the same religion has been proposed only by some Orthodox Jews and some Islamic Ulemas/Muftis. Only some Muslim Ulemas/Muftis and some Asian religions may prefer living donation over cadaveric donation. No religion prefers cadaveric over living donation. No religion formally forbid non-heart-beating donors (nhbd) cadaveric donation or cross-over donation. Due to the sacrad of human life, the Catholic Church is against donation from anencephalic donors or after active euthanasia. No religion formally forbid xenotransplantation. Addressing the participants of the First International Congress of the Society for Organ Sharing in 1991, Pope John Paul II said "There are many questions of an ethical, legal and social nature which need to be more deeply investigated. There are even shameful abuses which call for determined action on the part of medical association and donor societies, and especially of competent legislative bodies" and later on "In effect, the human body is always a personal body, the body of a person. The body cannot be treated as a merely physical or biological entity, nor can its organs and tissues ever be used as item for sale or exchange". Addressing the participants at the XVIII International Congress of the Transplantation Society in 2000, Pope John Paul II said "Accordingly, any procedure which tends to commercialize human organs or to consider them as items of exchange or trade must be considered morally unacceptable, because to use the body as an object is to violate the dignity of the human person" and later on added "The criteria for assigning donated organs should in no way be discriminatory (i.e. based on age, sex, race, religion, social standing, etc.) or utilitarian (i.e. based on work capacity, social usefulness, etc.)." To conclude, according to the Catechism of the Catholic Church Compendium signed by Pope Benedict XVI on june 28, 2005, 476. Are allowed transplantation and organ donation, before and after death? Organ transplantation is morally acceptable with the consent of the donor and without excessive risks for him/her. For the noble act of organ donation after death, the real death of the donor must be fully ascertained.


Clinical Role of Aspirin in Mood Disorders: A Systematic Review.
Worldwide, depression and bipolar disorder affect a large and growing number of people. However, current pharmacotherapy options remain limited. Despite adequate treatment, many patients continue to have subsyndromal symptoms, which predict relapse in bipolar illness and often result in functional impairments. Aspirin, a common nonsteroidal anti-inflammatory drug (NSAID), has purported beneficial effects on mood symptoms, showing protective effects against depression in early cohort studies. This systematic review thus aimed to investigate the role of aspirin in mood disorders. Using the keywords (aspirin or acetylsalicy* or asa) and (mood or depress* or bipolar or mania or suicid*), a comprehensive search of PubMed, EMBASE, Medline, PsycINFO, Clinical Trials Register of the Cochrane Collaboration Depression, Anxiety and Neurosis Group (CCDANTR), Clinicaltrials.gov and Google Scholar databases found 13,952 papers published in English between 1 January 1988 and 1 May 2019. A total of six clinical studies were reviewed. There were two randomized, placebo-controlled, double-blind trials and populations drawn from two main cohort studies (i.e., the Geelong Osteoporosis Study and the Osteoarthritis Initiative study). Using a random-effects model, the pooled hazard ratio of the three cohort studies was 0.624 (95% confidence interval: 0.0503 to 1.198, p = 0.033), supporting a reduced risk of depression with aspirin exposure. Overall, the dropout rates were low, and aspirin appears to be well-tolerated with minimal risk of affective switch. In terms of methodological quality, most studies had a generally low risk of bias. Low-dose aspirin (80 to 100 mg/day) is safe, well-tolerated and potentially efficacious for improving depressive symptoms in both unipolar and bipolar depression. Due to its ability to modulate neuroinflammation and central nervous system processes, aspirin may also have valuable neuroprotective and pro-cognitive effects that deserve further exploration. Further randomized, controlled trials involving the adjunctive use of aspirin should be encouraged to confirm its therapeutic benefits.


Tissue Crowding Induces Caspase-Dependent Competition for Space.
Regulation of tissue size requires fine tuning at the single-cell level of proliferation rate, cell volume, and cell death. Whereas the adjustment of proliferation and growth has been widely studied [1-5], the contribution of cell death and its adjustment to tissue-scale parameters have been so far much less explored. Recently, it was shown that epithelial cells could be eliminated by live-cell delamination in response to an increase of cell density [6]. Cell delamination was supposed to occur independently of caspase activation and was suggested to be based on a gradual and spontaneous disappearance of junctions in the delaminating cells [6]. Studying the elimination of cells in the midline region of the Drosophila pupal notum, we found that, contrary to what was suggested before, Caspase 3 activation precedes and is required for cell delamination. Yet, using particle image velocimetry, genetics, and laser-induced perturbations, we confirmed [6] that local tissue crowding is necessary and sufficient to drive cell elimination and that cell elimination is independent of known fitness-dependent competition pathways [7-9]. Accordingly, activation of the oncogene Ras in clones was sufficient to compress the neighboring tissue and eliminate cells up to several cell diameters away from the clones. Mechanical stress has been previously proposed to contribute to cell competition [10, 11]. These results provide the first experimental evidences that crowding-induced death could be an alternative mode of super-competition, namely mechanical super-competition, independent of known fitness markers [7-9], that could promote tumor growth.


Molecular clock mirages.
The hypothesis of the molecular clock proposes that molecular evolution occurs at rates that persist through time and across lineages, for a given gene. The neutral theory of molecular evolution predicts that the clock will be a Poisson process, with equal mean and variance. Experimental data have shown that the variance is typically larger than the mean. Hypotheses have been advanced to account for the hypervariance of molecular evolution. Four recent papers show that none of the predictive hypotheses that have been proposed can be generally maintained. The conclusion is that molecular evolution is dependent on the fickle process of natural selection. But it is a time-dependent process, so that accumulation of empirical data often yields an approximate clock, as a consequence of the expected convergence of large numbers.


Effects of neuroendocrine changes on results of ambulatory blood pressure monitoring (ABPM) in adolescent girls with anorexia nervosa.
Anorexia nervosa (AN) is characterized by marked neuroendocrine and autonomic dysfunctions. In the recent studies using automatic blood pressure monitoring (ABPM), lower BP values and lack of circardian variation of BP in anorectic patients were demonstrated. Unfortunately effects of hormonal changes, that may explain BP abnormalities were not analysed together. The aim of our study was the assessment of ABPM and hormonal status in anorectic girls. The study was performed on hospitalized 25 female anorectic adolescents aged 12-18 years. Control group was 17 age and height matched girls with normal weight and negative history for hypertension. ABPM was performed between 5 and 7 day of hospitalization, every 30 minutes during active period and every 60 minutes during sleep. Hormones (FSH, LH, estradiol, cortisol and fT4) serum concentrations were also evaluated. Mean systolic BP values were significantly lower in patients with AN in comparison to controls. Maximal diastolic and mean arterial pressure values for the whole day and active period but not for sleep were lower in AN than in controls. Anorectic girls showed tendency to night-time bradycardia. Moreover, there were no physiological circadian variations of BP in AN. We conclude that hormonal regulation of blood pressure and heart rate in anorectic patients is at least partially preserved. Lower blood pressure values, bradycardia and lack of physiological night fall of BP in anorectic patients may result from altered autonomic system function resulting from hormonal disturbances and other centrally mediated mechanisms.


Changes in Sleep Architecture under Sustained Pain in Adult Male Rats Subjected to Neonatal Short-Lasting Local Inflammatory Insult.
Neonatal, short-lasting, local, nociceptive insult by carrageenan can cause long-term alterations in somatosensory and neurohumoral systems. We previously revealed hyporesponsiveness of the autonomic nervous system (ANS) after painful stimulation of adult rats in a neonatal carrageenan-induced pain model. Sleep disturbance has been highly correlated with pain and ANS activity. In the present study, adult rats that had received an intraplantar injection of carrageenan on postnatal day 1 were investigated to determine if there were alterations in their sleep architecture upon the stimulation of pain. Polysomnographic and heart rate variability recordings were carried out, with a wireless transmission of data, for 24 h under baseline conditions and after an intraplantar injection of complete Freund's adjuvant to induce sustained nociception. Increased active awake (AW) and decreased quiet sleep (QS) and paradoxical sleep (PS) times were noted in the control animals. In the carrageenan-treated rats, the AW time increased but with decreased alertness, as revealed by decreases in beta and increases in theta power. The QS time did not decrease. The PS time decreased during the first 12 h, then increased during the following 12 h, suggesting an early rebound of formerly deprived PS time. Sympathetic activation under sustained pain was not apparent in any stage of sleep in carrageenan-treated rats and was even suppressed in AW time. An impaired sympathetic reaction to pain may have contributed to the atypical changes in sleep architecture in these rats. In conclusion, pain in early life has a long-term effect on the cardiovascular-autonomic-electroencephalographic responses to pain later in life. The physiological relevance of these results remains undetermined.


Concomitant socioeconomic, behavioral, and biological factors associated with the disproportionate HIV infection burden among Black men who have sex with men in 6 U.S. cities.
American Black men who have sex with men (MSM) are disproportionately affected by HIV, but the factors associated with this concentrated epidemic are not fully understood. Black MSM were enrolled in 6 US cities to evaluate a multi-component prevention intervention, with the current analysis focusing on the correlates of being newly diagnosed with HIV compared to being HIV-uninfected or previously diagnosed with HIV. HPTN 061 enrolled 1553 Black MSM whose median age was 40; 30% self-identified exclusively as gay or homosexual, 29% exclusively as bisexual, and 3% as transgender. About 1/6(th) (16.2%) were previously diagnosed with HIV (PD); of 1263 participants without a prior HIV diagnosis 7.6% were newly diagnosed (ND). Compared to PD, ND Black MSM were younger (p<0.001); less likely to be living with a primary partner (p<0.001); more likely to be diagnosed with syphilis (p<0.001), rectal gonorrhea (p = 0.011) or chlamydia (p = 0.020). Compared to HIV-uninfected Black MSM, ND were more likely to report unprotected receptive anal intercourse (URAI) with a male partner in the last 6 months (p<0.001); and to be diagnosed with syphilis (p<0.001), rectal gonorrhea (p = 0.004), and urethral (p = 0.025) or rectal chlamydia (p<0.001). They were less likely to report female (p = 0.002) or transgender partners (p = 0.018). Multivariate logistic regression analyses found that ND Black MSM were significantly more likely than HIV-uninfected peers to be unemployed; have STIs, and engage in URAI. Almost half the men in each group were poor, had depressive symptoms, and expressed internalized homophobia. ND HIV-infected Black MSM were more likely to be unemployed, have bacterial STIs and engage in URAI than other Black MSM. Culturally-tailored programs that address economic disenfranchisement, increase engagement in care, screen for STIs, in conjunction with safer sex prevention interventions, may help to decrease further transmission in this heavily affected community.


Tropomyosin - master regulator of actin filament function in the cytoskeleton.
Tropomyosin (Tpm) isoforms are the master regulators of the functions of individual actin filaments in fungi and metazoans. Tpms are coiled-coil parallel dimers that form a head-to-tail polymer along the length of actin filaments. Yeast only has two Tpm isoforms, whereas mammals have over 40. Each cytoskeletal actin filament contains a homopolymer of Tpm homodimers, resulting in a filament of uniform Tpm composition along its length. Evidence for this 'master regulator' role is based on four core sets of observation. First, spatially and functionally distinct actin filaments contain different Tpm isoforms, and recent data suggest that members of the formin family of actin filament nucleators can specify which Tpm isoform is added to the growing actin filament. Second, Tpms regulate whole-organism physiology in terms of morphogenesis, cell proliferation, vesicle trafficking, biomechanics, glucose metabolism and organ size in an isoform-specific manner. Third, Tpms achieve these functional outputs by regulating the interaction of actin filaments with myosin motors and actin-binding proteins in an isoform-specific manner. Last, the assembly of complex structures, such as stress fibers and podosomes involves the collaboration of multiple types of actin filament specified by their Tpm composition. This allows the cell to specify actin filament function in time and space by simply specifying their Tpm isoform composition.


Gene expression of transforming growth factor beta-1 in rabbit zone II flexor tendon wound healing: evidence for dual mechanisms of repair.
The postoperative outcome of hand flexor tendon repair can be complicated by adhesions between the repair site and surrounding tissue. To date, the biology of hand flexor tendon wound healing remains controversial--both intrinsic (resident tenocyte) and extrinsic (tendon sheath fibroblast and inflammatory cell) processes may contribute to repair. Transforming growth factor beta-1 is a cytokine that plays multiple roles in wound healing but is also implicated in the pathogenesis of excessive scar formation. This study examines the activation of transforming growth factor beta-1 mRNA in a rabbit zone II flexor tendon wound-healing model. Forty New Zealand White rabbit forepaws underwent complete transection and repair of the middle digit flexor digitorum profundus tendon in zone II. Tendons were harvested at increasing time intervals (1, 3, 7, 14, 28, and 56 days) and analyzed by in situ hybridization and immunohistochemistry to determine the expression patterns of transforming growth factor beta-1. A small number of tenocytes exhibited expression of transforming growth factor beta-1 mRNA at baseline in nonwounded control tendon specimens. The surrounding tendon sheath in these control specimens also revealed low numbers of fibroblasts and inflammatory cells expressing transforming growth factor beta-1 mRNA. In contrast, flexor tendons subjected to transection and repair exhibited increased signal for transforming growth factor beta-1 mRNA in both resident tenocytes and infiltrating fibroblasts and inflammatory cells from the tendon sheath. These data demonstrate that (1) normal unwounded tenocytes and tendon sheath cells are capable of transforming growth factor beta-1 production, (2) this cytokine is activated in the tendon wound environment, as evidenced by mRNA upregulation, and (3) the upregulation of this cytokine in both "intrinsic" tenocytes and "extrinsic" tendon sheath fibroblasts and inflammatory cells supports dual mechanisms for tendon repair. Because transforming growth factor beta-1 is thought to contribute to the pathogenesis of excessive scar formation, the findings presented here suggest that perioperative biochemical modulation of transforming growth factor beta-1 levels may help limit flexor tendon adhesion formation.


HDAC7 inhibits osteoclastogenesis by reversing RANKL-triggered β-catenin switch.
The bone-resorbing osteoclast is essential for skeletal remodeling, yet its deregulation contributes to diseases such as osteoporosis and cancer bone metastasis. Here we identify histone deacetylase 7 (HDAC7) as a key negative regulator of osteoclastogenesis and bone resorption using both in vitro cellular and molecular analyses and in vivo characterization of conditional HDAC7-knockout mice. Bone marrow osteoclast differentiation assays reveal that HDAC7 overexpression suppresses, whereas HDAC7 deletion enhances, osteoclastogenesis. Mechanistically, in the absence of receptor activator of nuclear factor κ-B ligand (RANKL), HDAC7 attenuates β-catenin function and cyclin D1 expression, thereby reducing precursor proliferation; upon RANKL activation, HDAC7 suppresses NFATc1 and prevents β-catenin down-regulation, thereby blocking osteoclast differentiation. Consequently, HDAC7 deletion in the osteoclast lineage results in a 26% reduction in bone mass (P = 0.003) owing to 102% elevated bone resorption (P = 0.01). These findings are clinically significant in light of the remarkable therapeutic potentials of HDAC inhibitors for several diseases such as cancer, diabetes, and neurodegeneration.


Spinal facilitation of descending motor input.
Highly varying patterns of electrostimulation (Dynamic Stimulation, DS) delivered to the dorsal cord through an epidural array with 18 independent electrodes transiently facilitate corticospinal motor responses, even after spinal injury. To partly unravel how corticospinal input are affected by DS, we introduced a corticospinal platform that allows selective cortical stimulation during the multisite acquisition of cord dorsum potentials (CDPs) and the simultaneous supply of DS. Firstly, the epidural interface was validated by the acquisition of the classical multisite distribution of CDPs on the dorsal cord and their input-output profile elicited by pulses delivered to peripheral nerves. Apart from increased EMGs, DS selectively increased excitability of the spinal interneurons that first process corticospinal input, without changing the magnitude of commands descending from the motor cortex, suggesting a novel correlation between muscle recruitment and components of cortically-evoked CDPs. Finally, DS increases excitability of post-synaptic spinal interneurons at the stimulation site and their responsiveness to any residual supraspinal control, thus supporting the use of electrical neuromodulation whenever the motor output is jeopardized by a weak volitional input, due to a partial disconnection from supraspinal structures and/or neuronal brain dysfunctions.


Evaluation of the methodological quality of systematic reviews of health status measurement instruments.
A systematic review of measurement properties of health-status instruments is a tool for evaluating the quality of instruments. Our aim was to appraise the quality of the review process, to describe how authors assess the methodological quality of primary studies of measurement properties, and to describe how authors evaluate results of the studies. Literature searches were performed in three databases. One hundred and forty-eight reviews were included. The purpose of included reviews was to identify health status instruments used in an evaluative application and to report on the measurement properties of these instruments. Two independent reviewers selected the articles and extracted the data. Reviews were often of low quality: 22% of the reviews used one database, the search strategy was often poorly described, and in many cases it was not reported whether article selection (75%) and data extraction (71%) was done by two independent reviewers. In 11 reviews the methodological quality of the primary studies was evaluated for all measurement properties, and of these 11 reviews only 7 evaluated the results. Methods to evaluate the quality of the primary studies and the results differed widely. The poor quality of reviews hampers evidence-based selection of instruments. Guidelines for conducting and reporting systematic reviews of measurement properties should be developed.


Large-scale metal nanoelectrode arrays based on printed nanowire lithography for nanowire complementary inverters.
Nanowire (NW) complementary inverters based on NW channels and NW electrodes are a promising core logic unit of future subminiature, high density and textile-type configured electronic circuits. However, existing approaches based on short NWs (<150 μm) or non-woven nanofibers cannot provide precisely-coordinated NW inverters due to the difficulty in the position and alignment control of each NW. In particular, the large-scale fabrication of highly-aligned metal nanoelectrode (NE) arrays with low resistivity is a challenging issue. Here, we developed large-scale-aligned AgNE arrays with very low resistivity by using printed NW lithography, and then demonstrated NW complementary inverters by combining with direct-printed organic semiconducting NWs. The width of the AgNEs was controlled from 250 to 1000 nm; their resistivity was 2.6 μΩ cm which is quite comparable with that of Ag films (1.6 μΩ cm). We expect that this approach will facilitate advances in the large-scale fabrication of nanoelectronics which will be compatible with printed electronics.


Disaster nursing: a retrospective review.
A plethora of information exists in the literature regarding emergencies and disasters. Nevertheless, significant gaps in the science related to nurses working during disasters are revealed. Few studies have addressed the perspective of nurses and their intent to respond to future disasters. Because nurses are invaluable to disaster response efforts, more research is essential to validate current findings and elucidate the needs of nurses who respond to disasters and other health emergencies. There is a paucity of research in the literature describing nurses' lived experiences of working during hurricanes. Natural disasters inevitably inflict human suffering, and nurses are expected to respond and provide services during these catastrophic times. Lost within this expectation are the experiences and concerns of the nurses who are called upon and intend to respond to the disaster, and yet are themselves affected by the disaster. Understanding the experiences and needs of nurses who decide to respond to the call of duty and work during disasters remains unclear in the literature. Research in the area of disaster response intentions by nurses becomes the initial step in understanding the phenomenon of working during a disaster and creating innovative approaches that address working during disasters. Disaster policies have been developed and implemented at the international, national, state, local, and hospital level. Nevertheless, disasters continue to adversely impact communities and hospitals at all levels causing injuries, death, and destruction of infrastructure. To reduce the impact of disasters, continued research is needed to inform and strengthen future disaster policies. Knowledge gained from future research has great potential to inform nursing education, research, and practice, as well as health policy related to the care of individuals and responders before, during, and after disasters.


CandidaDB: a multi-genome database for Candida species and related Saccharomycotina.
CandidaDB (http://genodb.pasteur.fr/CandidaDB) was established in 2002 to provide the first genomic database for the human fungal pathogen Candida albicans. The availability of an increasing number of fully or partially completed genome sequences of related fungal species has opened the path for comparative genomics and prompted us to migrate CandidaDB into a multi-genome database. The new version of CandidaDB houses the latest versions of the genomes of C. albicans strains SC5314 and WO-1 along with six genome sequences from species closely related to C. albicans that all belong to the CTG clade of Saccharomycotina-Candida tropicalis, Candida (Clavispora) lusitaniae, Candida (Pichia) guillermondii, Lodderomyces elongisporus, Debaryomyces hansenii, Pichia stipitis-and the reference Saccharomyces cerevisiae genome. CandidaDB includes sequences coding for 54 170 proteins with annotations collected from other databases, enriched with illustrations of structural features and functional domains and data of comparative analyses. In order to take advantage of the integration of multiple genomes in a unique database, new tools using pre-calculated or user-defined comparisons have been implemented that allow rapid access to comparative analysis at the genomic scale.


GIPC gene family (Review).
GIPC1/GIPC/RGS19IP1, GIPC2, and GIPC3 genes constitute the human GIPC gene family. GIPC1 and GIPC2 show 62.0% total-amino-acid identity. GIPC1 and GIPC3 show 59.9% total-amino-acid identity. GIPC2 and GIPC3 show 55.3% total-amino-acid identity. GIPCs are proteins with central PDZ domain and GIPC homology (GH1 and GH2) domains. PDZ, GH1, and GH2 domains are conserved among human GIPCs, Xenopus GIPC/Kermit, and Drosophila GIPC/ LP09416. Bioinformatics revealed that GIPC genes are linked to prostanoid receptor genes and DNAJB genes in the human genome as follows: GIPC1 gene is linked to prostaglandin E receptor 1 (PTGER1) gene and DNAJB1 gene in human chromosome 19p13.2-p13.1 region; GIPC2 gene to prostaglandin F receptor (PTGFR) gene and DNAJB4 gene in human chromosome 1p31.1-p22.3 region; GIPC3 gene to thromboxane A2 receptor (TBXA2R) gene in human chromosome 19p13.3 region. GIPC1 and GIPC2 mRNAs are expressed together in OKAJIMA, TMK1, MKN45 and KATO-III cells derived from diffuse-type of gastric cancer, and are up-regulated in several cases of primary gastric cancer. PDZ domain of GIPC family proteins interact with Frizzled-3 (FZD3) class of WNT receptor, insulin-like growth factor-I (IGF1) receptor, receptor tyrosine kinase TrkA, TGF-beta type III receptor (TGF-beta RIII), integrin alpha6A subunit, transmembrane glycoprotein 5T4, and RGS19/RGS-GAIP. Because RGS19 is a member of the RGS family that regulate heterotrimeric G-protein signaling, GIPCs might be scaffold proteins linking heterotrimeric G-proteins to seven-transmembrane-type WNT receptor or to receptor tyrosine kinases. Therefore, GIPC1, GIPC2 and GIPC3 might play key roles in carcinogenesis and embryogenesis through modulation of growth factor signaling and cell adhesion.


Results and Outcomes After Midshaft Clavicle Fracture: Matched Pair Analysis of Operative Versus Nonoperative Management.
This study evaluated patients with displaced clavicle fractures treated surgically vs nonoperatively. The authors hypothesized that functional outcomes would be no different. A retrospective comparative study was performed of 138 patients with closed midshaft clavicle fractures. Sixty-nine patients were treated operatively and matched for sex, age, and fracture pattern to 69 patients treated nonoperatively. Charts and radiographs were reviewed, and the American Shoulder and Elbow Surgeons survey was administered. A poor outcome was defined as a treatment complication or an American Shoulder and Elbow Surgeons score less than 60. There were 116 men and 22 women with a mean age of 37.7 years and fracture patterns of 15B-1 (n=78), 15B-2 (n=48), and 15B-3 (n=12). Thirty-seven percent were tobacco smokers, with 23 treated operatively and 28 nonoperatively. Ten (14.5%) initially nonoperative patients underwent plate fixation at a mean of 25.9 weeks (range, 7-48 weeks) because of persistent pain and motion at the fracture site. Fifteen (21.7%) of the 69 patients treated acutely with surgery had 16 complications, which resulted in secondary procedures in 11 patients (15.9%). Overall, poor outcomes occurred in 21 (30.4%) of 69 after fixation and in 19 (27.5%) of 69 in the nonoperative group. Unemployment (P=.05) and tobacco use (P=.03) were associated with poor outcome, irrespective of type of treatment. Initial nonoperative treatment presents a reasonable option for many patients. No differences in complications or poor outcomes were noted for surgical vs nonoperative treatment. Social factors proved to be greater predictors of outcome than other patient or injury features. Management of clavicle fractures should be individualized with assessment of patient expectations and activity level. Social factors should also be considered. [Orthopedics. 2018; 41(5):e689-e694.].


Increased CD4+ T cell levels during IL-7 administration of antiretroviral therapy-treated simian immunodeficiency virus-positive macaques are not dependent on strong proliferative responses.
CD4(+) T cell depletion is a fundamental component of HIV infection and AIDS pathogenesis and is not always reversed following antiretroviral therapy (ART). In this study, the SIV-infected rhesus macaque model was used to assess recombinant simian IL-7 in its glycosylated form (rsIL-7gly) to enhance regeneration of CD4(+) T cells, particularly the crucial central memory compartment, after ART. We assessed the impact of rsIL-7gly administration as single injections and as a cluster of three doses. Irrespective of the dosing strategy used, the rsIL-7gly administration transiently increased proliferation of both central memory and naive cells, in both CD4(+) and CD8(+) subsets, without increasing SIV levels in the blood. Administration of rsIL-7gly at intervals of 4-6 wk maximized the proliferative response to therapy but resulted in only transient increases in peripheral blood T cell counts. Although more frequent rsIL-7gly "clustered" dosing (three times weekly with 2 wk of rest and then repeat) induced only an initial proliferative burst by CD4(+) T cells, this dosing strategy resulted in sustained increases in peripheral blood CD4(+) T cell counts. The clustered rsIL-7gly treatment regimen was shown to increase the half-life of a BrdU label among memory T cells in the blood when compared with that of macaques treated with ART alone, which is consistent with enhanced cell survival. These results indicate that dosing intervals have a major impact on the response to rsIL-7gly in SIV-positive ART-treated rhesus macaques and that optimum dosing strategies may be ones that induce CD4(+) T cell proliferation initially and provide increased CD4(+) T cell survival.


The M2-muscarinic receptor inhibits the development of streptozotocin-induced neuropathy in mouse urinary bladder.
We investigate the role of M(2)-muscarinic receptors in maintaining neurogenic bladder contraction during hyperglycemia. Mice were injected with a single dose of streptozotocin (125 mg/kg), and neurogenic contraction of urinary bladder from wild type and M(2)-muscarinic receptor knockout (M(2) KO) mice was measured at 8 to 24 weeks after treatment. In wild-type bladder lacking urothelium, the summation of the cholinergic (64%) and purinergic (56%) components of the electrical-field-stimulated response exceeded 100%, indicating a reserve capacity. Although the cholinergic component was slightly less in the M(2) KO mouse, the total electrical-field-stimulated contraction was the same as wild type. The cholinergic and purinergic components of contraction in wild-type bladder were minimally affected by streptozotocin treatment. In M(2) KO bladder, streptozotocin treatment reduced both the cholinergic (after 8-9 and 20-24 weeks) and purinergic (after 20-24 weeks only) components. The loss of function was approximately 50 to 70%. Similar results were observed in bladder with intact urothelium. M(2) KO bladder was more sensitive to the relaxant effect of isoproterenol compared with wild type, and this difference significantly increased at the early and late time points after streptozotocin treatment. In the presence of urothelium, however, this difference in isoproterenol sensitivity was smaller with streptozotocin treatment, but this trend reversed over time. Our results show that M(2) receptors oppose urinary bladder distension in wild-type bladder and inhibit streptozotocin-induced neuropathy.


Caffeine Consumption During Pregnancy Accelerates the Development of Cognitive Deficits in Offspring in a Model of Tauopathy.
Psychoactive drugs used during pregnancy can affect the development of the brain of offspring, directly triggering neurological disorders or increasing the risk for their occurrence. Caffeine is the most widely consumed psychoactive drug, including during pregnancy. In Wild type mice, early life exposure to caffeine renders offspring more susceptible to seizures. Here, we tested the long-term consequences of early life exposure to caffeine in THY-Tau22 transgenic mice, a model of Alzheimer's disease-like Tau pathology. Caffeine exposed mutant offspring developed cognitive earlier than water treated mutants. Electrophysiological recordings of hippocampal CA1 pyramidal cells in vitro revealed that early life exposure to caffeine changed the way the glutamatergic and GABAergic drives were modified by the Tau pathology. We conclude that early-life exposure to caffeine affects the Tau phenotype and we suggest that caffeine exposure during pregnancy may constitute a risk-factor for early onset of Alzheimer's disease-like pathology.


Mechanisms for interferon-α-induced depression and neural stem cell dysfunction.
New neurons generated by the neural stem cells (NSCs) in the adult hippocampus play an important role in emotional regulation and respond to the action of antidepressants. Depression is a common and serious side effect of interferon-α (IFN-α), which limits its use as an antiviral and antitumor drug. However, the mechanism(s) underlying IFN-induced depression are largely unknown. Using a comprehensive battery of behavioral tests, we found that mice subjected to IFN-α treatment exhibited a depression-like phenotype. IFN-α directly suppressed NSC proliferation, resulting in the reduced generation of new neurons. Brain-specific mouse knockout of the IFN-α receptor prevented IFN-α-induced depressive behavioral phenotypes and the inhibition of neurogenesis, suggesting that IFN-α suppresses hippocampal neurogenesis and induces depression via its receptor in the brain. These findings provide insight for understanding the neuropathology underlying IFN-α-induced depression and for developing new strategies for the prevention and treatment of IFN-α-induced depressive effects.


Chfr and RNF8 synergistically regulate ATM activation.
Protein ubiquitination is a crucial component of the DNA damage response. To study the mechanism of the DNA damage-induced ubiquitination pathway, we analyzed the impact of the loss of two E3 ubiquitin ligases, RNF8 and Chfr. Notably, DNA damage-induced activation of ATM kinase is suppressed in cells deficient in both RNF8 and Chfr (double-knockout, or DKO), and DKO mice develop thymic lymphomas that are nearly diploid but harbor clonal chromosome translocations. Moreover, DKO mice and cells are hypersensitive to ionizing radiation. We present evidence that RNF8 and Chfr synergistically regulate histone ubiquitination to control histone H4 Lys16 acetylation through MRG15-dependent acetyltransferase complexes. Through these complexes, RNF8 and Chfr affect chromatin relaxation and modulate ATM activation and DNA damage response pathways. Collectively, our findings demonstrate that two chromatin-remodeling factors, RNF8 and Chfr, function together to activate ATM and maintain genomic stability in vivo.


The musician effect: does it persist under degraded pitch conditions of cochlear implant simulations?
Cochlear implants (CIs) are auditory prostheses that restore hearing via electrical stimulation of the auditory nerve. Compared to normal acoustic hearing, sounds transmitted through the CI are spectro-temporally degraded, causing difficulties in challenging listening tasks such as speech intelligibility in noise and perception of music. In normal hearing (NH), musicians have been shown to better perform than non-musicians in auditory processing and perception, especially for challenging listening tasks. This "musician effect" was attributed to better processing of pitch cues, as well as better overall auditory cognitive functioning in musicians. Does the musician effect persist when pitch cues are degraded, as it would be in signals transmitted through a CI? To answer this question, NH musicians and non-musicians were tested while listening to unprocessed signals or to signals processed by an acoustic CI simulation. The task increasingly depended on pitch perception: (1) speech intelligibility (words and sentences) in quiet or in noise, (2) vocal emotion identification, and (3) melodic contour identification (MCI). For speech perception, there was no musician effect with the unprocessed stimuli, and a small musician effect only for word identification in one noise condition, in the CI simulation. For emotion identification, there was a small musician effect for both. For MCI, there was a large musician effect for both. Overall, the effect was stronger as the importance of pitch in the listening task increased. This suggests that the musician effect may be more rooted in pitch perception, rather than in a global advantage in cognitive processing (in which musicians would have performed better in all tasks). The results further suggest that musical training before (and possibly after) implantation might offer some advantage in pitch processing that could partially benefit speech perception, and more strongly emotion and music perception.


Structure and function of primitive immunoglobulin superfamily neural cell adhesion molecules: a lesson from studies on planarian.
Precise wiring and proper remodeling of the neural network are essential for its normal function. The freshwater planarian is an attractive animal in which to study the formation and maintenance of the neural network due to its high regenerative capability and developmental plasticity. Although a recent study revealed that homologs of netrin and its receptors are required for regeneration and maintenance of the planarian central nervous system (CNS), the roles of cell adhesion in the formation and maintenance of the planarian neural network remain poorly understood. In the present study, we found primitive immunoglobulin superfamily cell adhesion molecules (IgCAMs) in a planarian that are homologous to vertebrate neural IgCAMs. We identified planarian orthologs of NCAM, L1CAM, contactin and DSCAM, and designated them DjCAM, DjLCAM, DjCTCAM and DjDSCAM, respectively. We further confirmed that they function as cell adhesion molecules using cell aggregation assays. DjCAM and DjDSCAM were found to be differentially expressed in the CNS. Functional analyses using RNA interference revealed that DjCAM is partly involved in axon formation, and that DjDSCAM plays crucial roles in neuronal cell migration, axon outgrowth, fasciculation and projection.


AtDUR3 encodes a new type of high-affinity urea/H+ symporter in Arabidopsis.
Urea is the major nitrogen form supplied as fertilizer in agricultural plant production but also an important nitrogen metabolite in plants. We report the cloning and functional characterization of AtDUR3, a high-affinity urea transporter in plants. AtDUR3 contains 14 putative transmembrane-spanning domains and represents an individual member in Arabidopsis that belongs to a superfamily of sodium-solute symporters. Heterologous expression in urea uptake-defective yeast as well as two-electrode voltage clamp and uptake studies using (14)C-labeled urea in AtDUR3-expressing oocytes demonstrated that AtDUR3 mediates urea transport. In both heterologous systems, urea transport was stimulated at low pH. In oocytes, inward currents indicated that urea is cotransported with protons. By contrast, a supply of Na(+) ions could not stimulate urea transport. Transport of (14)C-labeled urea by AtDUR3 in oocytes exhibited saturation kinetics with a K(m) of approximately 3 micro M. AtDUR3 was expressed in shoots and roots and upregulated during early germination and under nitrogen deficiency in roots. We propose a role of AtDUR3 in urea uptake by plant cells at low external urea concentrations.


Listener-based analysis of surface importance for acoustic metrics.
Acoustic quality in room acoustics is measured by well defined quantities, like definition, which can be derived from simulated impulse response filters or measured values. These take into account the intensity and phase shift of multiple reflections due to a wave front emanating from a sound source. Definition (D50) and clarity (C50) for example correspond to the fraction of the energy received in total to the energy received in the first 50 ms at a certain listener position. Unfortunately, the impulse response measured at a single point does not provide any information about the direction of reflections, and about the reflection surfaces which contribute to this measure. For the visualization of room acoustics, however, this information is very useful since it allows to discover regions with high contribution and provides insight into the influence of all reflecting surfaces to the quality measure. We use the phonon tracing method to calculate the contribution of the reflection surfaces to the impulse response for different listener positions. This data is used to compute importance values for the geometry taking a certain acoustic metric into account. To get a visual insight into the directional aspect, we map the importance to the reflecting surfaces of the geometry. This visualization indicates which parts of the surfaces need to be changed to enhance the chosen acoustic quality measure. We apply our method to the acoustic improvement of a lecture hall by means of enhancing the overall speech comprehensibility (clarity) and evaluate the results using glyphs to visualize the clarity (C50) values at listener positions throughout the room.


Advanced age promotes colonic dysfunction and gut-derived lung infection after stroke.
Bacterial infection a leading cause of death among patients with stroke, with elderly patients often presenting with more debilitating outcomes. The findings from our retrospective study, supported by previous clinical reports, showed that increasing age is an early predictor for developing fatal infectious complications after stroke. However, exactly how and why older individuals are more susceptible to infection after stroke remains unclear. Using a mouse model of transient ischaemic stroke, we demonstrate that older mice (>12 months) present with greater spontaneous bacterial lung infections compared to their younger counterparts (7-10 weeks) after stroke. Importantly, we provide evidence that older poststroke mice exhibited elevated intestinal inflammation and disruption in gut barriers critical in maintaining colonic integrity following stroke, including reduced expression of mucin and tight junction proteins. In addition, our data support the notion that the localized pro-inflammatory microenvironment driven by increased tumour necrosis factor-α production in the colon of older mice facilitates the translocation and dissemination of orally inoculated bacteria to the lung following stroke onset. Therefore, findings of this study demonstrate that exacerbated dysfunction of the intestinal barrier in advanced age promotes translocation of gut-derived bacteria and contributes to the increased risk to poststroke bacterial infection.


Combined use of direct analysis in real-time/Orbitrap mass spectrometry and micro-Raman spectroscopy for the comprehensive characterization of real explosive samples.
Direct Analysis in Real Time (DART™) high-resolution Orbitrap™ mass spectrometry (HRMS) in combination with Raman microscopy was used for the detailed molecular level characterization of explosives including not only the charge but also the complex matrix of binders, plasticizers, polymers, and other possible organic additives. A total of 15 defused military weapons including grenades, mines, rockets, submunitions, and mortars were examined. Swabs and wipes were used to collect trace (residual) amounts of explosives and their organic constituents from the defused military weapons and micrometer-size explosive particles were transferred using a vacuum suction-impact collection device (vacuum impactor) from wipe and swap samples to an impaction plate made of carbon. The particles deposited on the carbon plate were then characterized using micro-Raman spectroscopy followed by DART-HRMS providing fingerprint signatures of orthogonal nature. The optical microscope of the micro-Raman spectrometer was first used to localize and characterize the explosive charge on the impaction plate which was then targeted for identification by DART-HRMS analysis in both the negative and positive modes. Raman spectra of the explosives TNT, RDX and PETN were acquired from micrometer size particles and characterized by the presence of their characteristic Raman bands obtained directly at the surface of the impaction plate nondestructively without further sample preparation. Negative mode DART-HRMS confirmed the types of charges contained in the weapons (mainly TNT, RDX, HMX, and PETN; either as individual components or as mixtures). These energetic compounds were mainly detected as deprotonated species [M-H](-), or as adduct [M + (35)Cl](-), [M + (37)Cl](-), or [M + NO3](-) anions. Chloride adducts were promoted in the heated DART reagent gas by adding chloroform vapors to the helium stream using an "in-house" delivery method. When the polarity was switched to positive mode, DART-HRMS revealed a very complex distribution of polymeric binders (mainly polyethylene glycols and polypropylene glycols), plasticizers (e.g., dioctyl sebacate, tributyl phosphate), as well as wax-like compounds whose structural features could not be precisely assigned. In positive mode, compounds were identified either as protonated molecules or ammonium adduct species. These results clearly demonstrate the complementarity of micro-Raman microscopy combined with DART-MS. The former technique provides structural information on the type of explosives present at the surface of the sample, whereas the latter provides not only a confirmation of the nature of the explosive charge but also useful additional information regarding the nature of the complex organic matrix of binders, plasticizers, polymers, oils, and potentially other organic additives and contaminants present in the sample. Combining these two techniques provides a powerful tool for the screening, comprehensive characterization, and differentiation of particulate explosive samples for forensic sciences and homeland security applications. Graphical Abstract Comprehensive characterization of explosive particles collected from swipe samples by micro-Raman and DART™-HRMS.


Monitoring of Hepatitis B Virus (HBV) DNA and Risk of HBV Reactivation in B-Cell Lymphoma: A Prospective Observational Study.
There is no standard management of reactivation of hepatitis B virus (HBV) infection in HBV-resolved patients without hepatitis B surface antigen (HBsAg), but with antibodies against hepatitis B core antigen and/or antibodies against HBsAg (anti-HBs). We conducted a prospective observational study to evaluate the occurrence of HBV reactivation by serial monthly monitoring of HBV DNA and to establish preemptive therapy guided by this monitoring in B-cell non-Hodgkin lymphoma (B-NHL) treated with rituximab plus corticosteroid-containing chemotherapy (R-steroid-chemo). The primary endpoint was the incidence of HBV reactivation defined as quantifiable HBV DNA levels of ≥ 11 IU/mL. With a median HBV DNA follow-up of 562 days, HBV reactivation was observed in 21 of the 269 analyzed patients. The incidence of HBV reactivation at 1.5 years was 8.3% (95% confidence interval, 5.5-12.4). No hepatitis due to HBV reactivation was observed in patients who received antiviral treatment when HBV DNA levels were between 11 and 432 IU/mL. An anti-HBs titer of <10 mIU/mL and detectable HBV DNA remaining below the level of quantification at baseline were independent risk factors for HBV reactivation (hazard ratio, 20.6 and 56.2, respectively; P < .001). Even in 6 patients with a rapid increase of HBV due to mutations, the monthly HBV DNA monitoring was effective at preventing HBV-related hepatitis. Monthly monitoring of HBV DNA is useful for preventing HBV reactivation-related hepatitis among B-NHL patients with resolved HBV infection following R-steroid-chemo (UMIN000001299).


The insulin resistance syndrome in native Hawaiians. Native Hawaiian Health Research (NHHR) Project.
To investigate whether fasting hyperinsulinemia is associated with a clustering of cardiovascular disease (CVD) risk factors, manifesting as the insulin resistance syndrome (IRS), in a population of native Hawaiians. A total of 574 native Hawaiians > or = 30 years of age were examined for blood pressure, waist-to-hip ratio (WHR), BMI, oral glucose tolerance, and fasting lipid, insulin, and C-peptide concentrations. All statistical analyses (n = 384) excluded 190 individuals who had NIDDM or who were taking hypertension medication. Using logistic regression analysis, fasting insulin and C-peptide levels were compared with CVD risk factors (glucose intolerance, hypertension, central adiposity, elevated triglyceride levels, and low HDL cholesterol levels) after adjusting for age and obesity. Sixty-six percent of native Hawaiians were overweight or obese, and 70% were found to have central adiposity. Fasting insulin concentrations were correlated with BMI, WHR, blood pressure, and triglyceride, HDL cholesterol, and glucose concentrations. Fasting insulin was also significantly associated with an increasing number of CVD risk factors in each participant (P < 0.001). Fasting insulin and C-peptide concentrations were independently associated with glucose intolerance, high triglyceride levels, and low HDL cholesterol levels. However, only fasting C-peptide concentrations were independently associated with hypertension and central adiposity. Apparent differences in the correlates of fasting insulin and C-peptide may be related to multiple factors and warrant further evaluation. This study provides cross-sectional data confirming the existence of the IRS in native Hawaiians. However, further longitudinal studies are needed to examine the relationship of insulin resistance and/or surrogate markers to increased rates of NIDDM and CVD mortality in native Hawaiians.


Evaluation of retinal nerve fiber layer thickness and axonal transport 1 and 2 weeks after 8 hours of acute intraocular pressure elevation in rats.
To compare in vivo retinal nerve fiber layer thickness (RNFLT) and axonal transport at 1 and 2 weeks after an 8-hour acute IOP elevation in rats. Forty-seven adult male Brown Norway rats were used. Procedures were performed under anesthesia. The IOP was manometrically elevated to 50 mm Hg or held at 15 mm Hg (sham) for 8 hours unilaterally. The RNFLT was measured by spectral-domain optical coherence tomography. Anterograde and retrograde axonal transport was assessed from confocal scanning laser ophthalmoscopy imaging 24 hours after bilateral injections of 2 μL 1% cholera toxin B-subunit conjugated to AlexaFluor 488 into the vitreous or superior colliculi, respectively. Retinal ganglion cell (RGC) and microglial densities were determined using antibodies against Brn3a and Iba-1. The RNFLT in experimental eyes increased from baseline by 11% at 1 day (P < 0.001), peaked at 19% at 1 week (P < 0.0001), remained 11% thicker at 2 weeks (P < 0.001), recovered at 3 weeks (P > 0.05), and showed no sign of thinning at 6 weeks (P > 0.05). There was no disruption of anterograde transport at 1 week (superior colliculi fluorescence intensity, 75.3 ± 7.9 arbitrary units [AU] for the experimental eyes and 77.1 ± 6.7 AU for the control eyes) (P = 0.438) or 2 weeks (P = 0.188). There was no obstruction of retrograde transport at 1 week (RCG density, 1651 ± 153 per mm(2) for the experimental eyes and 1615 ± 135 per mm(2) for the control eyes) (P = 0.63) or 2 weeks (P = 0.25). There was no loss of Brn3a-positive RGC density at 6 weeks (P = 0.74) and no increase in microglial density (P = 0.92). Acute IOP elevation to 50 mm Hg for 8 hours does not cause a persisting axonal transport deficit at 1 or 2 weeks or a detectable RNFLT or RGC loss by 6 weeks but does lead to transient RNFL thickening that resolves by 3 weeks.