Omega-3 fatty acids prevent pressure overload-induced cardiac fibrosis through activation of cyclic GMP/protein kinase G signaling in cardiac fibroblasts.
Omega-3 polyunsaturated fatty acids (eicosapentaenoic acid and docosahexaenoic acid) from fish oil ameliorate cardiovascular diseases. However, little is known about the effects of ω-3 polyunsaturated fatty acids on cardiac fibrosis, a major cause of diastolic dysfunction and heart failure. The present study assessed the effects of ω-3 polyunsaturated fatty acids on cardiac fibrosis. We assessed left ventricular fibrosis and pathology in mice subjected to transverse aortic constriction after the consumption of a fish oil or a control diet. In control mice, 4 weeks of transverse aortic constriction induced significant cardiac dysfunction, cardiac fibrosis, and cardiac fibroblast activation (proliferation and transformation into myofibroblasts). Dietary supplementation with fish oil prevented transverse aortic constriction-induced cardiac dysfunction and cardiac fibrosis and blocked cardiac fibroblast activation. In heart tissue, transverse aortic constriction increased active transforming growth factor-β1 levels and phosphorylation of Smad2. In isolated adult mouse cardiac fibroblasts, transforming growth factor-β1 induced cardiac fibroblast transformation, proliferation, and collagen synthesis. Eicosapentaenoic acid and docosahexaenoic acid increased cyclic GMP levels and blocked cardiac fibroblast transformation, proliferation, and collagen synthesis. Eicosapentaenoic acid and docosahexaenoic acid blocked phospho-Smad2/3 nuclear translocation. DT3, a protein kinase G inhibitor, blocked the antifibrotic effects of eicosapentaenoic acid and docosahexaenoic acid. Eicosapentaenoic acid and docosahexaenoic acid increased phosphorylated endothelial nitric oxide synthase and endothelial nitric oxide synthase protein levels and nitric oxide production. Omega-3 fatty acids prevent cardiac fibrosis and cardiac dysfunction by blocking transforming growth factor-β1-induced phospho-Smad2/3 nuclear translocation through activation of the cyclic GMP/protein kinase G pathway in cardiac fibroblasts.


Outcome after autogenous brachial-basilic upper arm transpositions in the post-National Kidney Foundation Dialysis Outcomes Quality Initiative era.
The Dialysis Outcomes Quality Initiative (DOQI)-inspired push to create autogenous fistulas has led to a resurgence of interest in basilic vein transposition as an autogenous access conduit. We reviewed our experience with autogenous brachial-basilic upper arm transpositions (BTX) to clarify current maturation and patency rates and provide realistic expectations for a tertiary referral vascular practice. We follow an aggressive "all-autogenous" policy with regard to dialysis access and recommend BTX when all cephalic options are exhausted. Prosthetic grafts are not attempted unless all upper extremity veins are unusable. The records of all patients undergoing autogenous basilic and brachial vein upper arm transpositions for hemodialysis access between April 2001 and December 2004 were retrospectively evaluated. Mean follow-up was 10 months (range, 0 to 38 months). Eighty-seven patients underwent 100 basilic and 3 brachial vein transpositions. Most of the patients were already receiving hemodialysis (83%), with a mean of 1.1 (range, 0 to 4) previous access attempts. Perioperative complications included 1 death secondary to a myocardial infarction, 7 hematomas (4 requiring reoperation), and 6 infections (2 requiring reoperation). Steal syndrome developed in five patients. Maturation rate was 79%. Functional primary and secondary patency rates were 23% +/- 5% and 47% +/- 6% at 1 year and 11% +/- 5% and 40% +/- 10% at 2 years, respectively (mean +/- SE). The most common causes of failure for a matured fistula were stenosis within the body of the basilic vein (44%) followed by central venous outflow stenosis (20%). No preoperative variable, including gender, age, diabetes mellitus, presence of ipsilateral hemodialysis catheter, number of previous access attempts, maximal or minimal vein diameter, or obesity, had a significant impact on rate of maturation or long term patency. In our experience, autogenous brachial-basilic upper arm transposition fistulas have initial maturation rates that exceed DOQI guidelines, but disappointing short- to medium-term patency rates. Although these outcomes were obtained within the context of an aggressive all-autogenous policy, the poor durability of these transpositions should prompt further investigation of current access algorithms.


Sailing smoothly across the cultural divide: Constructing effective behavioral science presentations for medical audiences.
Beginning behavioral science faculty, who are critical residency program contributors, face significant immediate challenges that often diminish their effectiveness and increase the time it takes to translate and reformat their expertise into relevant and meaningful educational presentations. Residency program culture and competency-based learning are quite different from the educational objectives and teaching environments found in most behavioral health training programs. The goal of this article is to provide beginning behavior science faculty, who are typically on their own and learning on the job, with a guide to the core educational perspectives and skills required as well as key resources that are available to them. Since a significant portion of behavioral science faculty's teaching time revolves around small and large group presentations, our guide focuses on how to incorporate key strategies and resources into relevant, evidenced-based and, most importantly, effective behavioral health presentations for the program's resident physicians. Specifically, our recommendations include selection of content, methods of content organization, techniques for actively engaging resident physicians in discussing the significance of the topics, and descriptions of numerous Internet resources for the primary mental health topics that concern family medicine trainees. Finally, it is emphasized that the relevant and effective use of these recommendations is dependent upon the behavioral science faculty educator's first understanding and appreciating how physicians' think, speak, and prioritize information while caring for their patients.


Behavior therapy augments response of patients with obsessive-compulsive disorder responding to drug treatment.
In many patients with obsessive-compulsive disorder (OCD), residual symptoms persist despite a clinically meaningful response. The objective of this study was to examine whether addition of behavior therapy would augment treatment outcome in these patients. Ninety-six patients with DSM-IV OCD who had responded to 3 months of drug treatment were randomly assigned to either receive addition of behavior therapy or continue on drug treatment alone for 6 months. Patients who continued on drug treatment alone eventually received addition of behavior therapy for 6 months. Data were gathered from October 1998 to June 2002. OCD patients who received addition of behavior therapy showed a greater improvement in obsessive-compulsive symptoms (Yale-Brown Obsessive Compulsive Scale [Y-BOCS] score change = -3.9 in the completers sample) than those who continued on drug treatment alone (Y-BOCS score change = +3.9 for completers). Significantly more patients who received addition of behavior therapy were in remission compared with those who continued on drug treatment alone (p < .0001 for completers). Patients who received behavior therapy after 6 months of drug treatment alone showed a nonsignificant decline in obsessive-compulsive symptoms (Y-BOCS score change = -2.7 for completers); however, the remission rate found in this group was comparable to the remission rate found in the group of patients receiving addition of behavior therapy directly after responding to drug treatment. The results indicate that addition of behavior therapy is beneficial for patients who have responded to drug treatment. The data also suggest that the effect is greater when behavior therapy is added immediately after attainment of the drug response.


Kinematics and estimated thrust production of swimming harp and ringed seals.
The propulsive motions of swimming harp seals (Phoca groenlandica Erxleben) and ringed seals (Phoca hispida Schreber) were studied by filming individuals in a flume. The seals swam at velocities ranging from 0.6 to 1.42 m s-1. Locomotion was accomplished with alternate lateral sweeps of the hind flippers generated by lateral flexions of the axial body in conjunction with flexion of the flippers. The frequency of the propulsive cycle increased linearly with the swimming velocity, and the maximum angle of attack of the flipper decreased, but the amplitude remained constant. The kinematics and morphology of this hind flipper motion indicated that phocid seals do not swim in the carangiform mode as categorized by Lighthill (1969), but in a distinct mode that mimics swimming by thunniform propulsors. The hind flippers acted as hydrofoils, and the efficiency, thrust power and coefficient of thrust were calculated from unsteady wing theory. The propulsive efficiency was high at approximately 0.85. The thrust power increased curvilinearly with velocity. The drag coefficient ranged from 0.012 to 0.028 and was found to be 2.8-7.0 times higher than the theoretical minimum. The drag coefficient was high compared with that of phocid seals examined during gliding or towing experiments, indicating an increased drag encumbered by actively swimming seals. It was determined that phocid seals are capable of generating sufficient power for swimming with turbulent boundary layer conditions.


Motives for using Facebook, patterns of Facebook activities, and late adolescents' social adjustment to college.
Previous studies have confirmed that Facebook, the leading social networking site among young people, facilitates social connections among college students, but the specific activities and motives that foster social adjustment remain unclear. This study examined associations between patterns of Facebook activity, motives for using Facebook, and late adolescents' social adjustment to the college environment. Anonymous self-report survey data from 193 mostly European American students (M age = 20.32; 54 % female) attending a major Midwestern university indicated that motives and activity patterns were associated directly with social adjustment, but the association between one activity, status updating, and social adjustment also was moderated by the motive of relationship maintenance. Findings provide a more comprehensive portrait of how Facebook use may foster or inhibit social adjustment in college.


MicroRNAs silence gene expression by repressing protein expression and/or by promoting mRNA decay.
microRNAs (miRNAs) represent a novel class of genome-encoded eukaryotic regulatory RNAs that silence gene expression posttranscriptionally. Although the proteins mediating miRNA biogenesis and function have been identified, the precise mechanism by which miRNAs regulate the expression of target mRNAs remains unclear. We summarize recent work from our laboratory demonstrating that miRNAs silence gene expression by at least two independent mechanisms: by repressing translation and/or by promoting mRNA degradation. In Drosophila, both mechanisms require Argonaute 1 (AGO1) and the P-body component GW182. Moreover, mRNA degradation by miRNAs is effected by the enzymes involved in general mRNA decay, including deadenylases and decapping enzymes, which also localize to P bodies. Our findings suggest a model for miRNA function in which AGO1 associates with miRNA targets through miRNA:mRNA base-pairing interactions. GW182 interacts with AGO1 and recruits deadenylases and decapping enzymes, leading to mRNA degradation. However, not all miRNA targets are degraded: Some stay in a translationally silent state, from which they may eventually be released. We propose that the final outcome of miRNA regulation (i.e., degradation vs. translational repression) is influenced by other RNA-binding proteins interacting with the targeted mRNA.


Using Anchors to Estimate Clinical State without Labeled Data.
We present a novel framework for learning to estimate and predict clinical state variables without labeled data. The resulting models can used for electronic phenotyping, triggering clinical decision support, and cohort selection. The framework relies on key observations which we characterize and term "anchor variables". By specifying anchor variables, an expert encodes a certain amount of domain knowledge about the problem while the rest of learning proceeds in an unsupervised manner. The ability to build anchors upon standardized ontologies and the framework's ability to learn from unlabeled data promote generalizability across institutions. We additionally develop a user interface to enable experts to choose anchor variables in an informed manner. The framework is applied to electronic medical record-based phenotyping to enable real-time decision support in the emergency department. We validate the learned models using a prospectively gathered set of gold-standard responses from emergency physicians for nine clinically relevant variables.


Barriers to achieving controlled rheumatoid arthritis in the United Arab Emirates: a cross-sectional study.
To better understand the factors that affect low disease activity (DAS28 ≤ 3.2, LDA) in rheumatoid arthritis (RA) and barriers within the UAE, demographic/treatment data and DAS28 scores were collected through chart reviews of 182 consecutive RA patients seen at a private clinic in Dubai over a 2-month period. Patients were separated into a LDA group and a group comprised of moderate (3.2 < DAS28 < 5.1) or high disease activity (DAS28 ≥ 5.1) (MHDA). We then examined variables that may be associated with LDA and re-examined the MHDA group for barriers. While 97 (53 %) of the 182 patients had achieved the treatment target of DAS28 ≤ 3.2, 85 (47 %) had MHDA. A significantly larger portion of LDA patients had been previously treated with sulfasalazine (36 in LDA vs. 14 in MHDA, P = 0.002) or was presently on biological treatments (24 vs. 9, P = 0.013). For the 85 MHDA patients, 40 (22 % of 182) exhibited resistant disease with 25 (13.7 % of 182) failing their current first tier disease-modifying anti-rheumatic drug (DMARD) treatment or combinations and 15 (8.2 % of 182) failing current anti-TNF or biologic treatment. Reasons listed were primarily socioeconomic with 40 % of the resistant disease group unable to afford biologicals and 52 % of the patient-driven preference group discontinuing DMARDs against professional advice. Going forward, emphasis on the agreement between patient and rheumatologist on treatment, specifically regarding how DMARDs help relieve symptoms and their proper use, could help reduce the percentage of MHDA patients in the UAE.


Cervical Cancer Immunotherapy: Facts and Hopes.
It is a sad fact that despite being almost completely preventable through human papillomavirus (HPV) vaccination and screening, cervical cancer remains the fourth most common cancer to affect women worldwide. Persistent high-risk HPV (hrHPV) infection is the primary etiologic factor for cervical cancer. Upward of 70% of cases are driven by HPV types 16 and 18, with a dozen other hrHPVs associated with the remainder of cases. Current standard-of-care treatments include radiotherapy, chemotherapy, and/or surgical resection. However, they have significant side effects and limited efficacy against advanced disease. There are a few treatment options for recurrent or metastatic cases. Immunotherapy offers new hope, as demonstrated by the recent approval of programmed cell death protein 1-blocking antibody for recurrent or metastatic disease. This might be augmented by combination with antigen-specific immunotherapy approaches, such as vaccines or adoptive cell transfer, to enhance the host cellular immune response targeting HPV-positive cancer cells. As cervical cancer progresses, it can foster an immunosuppressive microenvironment and counteract host anticancer immunity. Thus, approaches to reverse suppressive immune environments and bolster effector T-cell functioning are likely to enhance the success of such cervical cancer immunotherapy. The success of nonspecific immunostimulants like imiquimod against genital warts also suggest the possibility of utilizing these immunotherapeutic strategies in cervical cancer prevention to treat precursor lesions (cervical intraepithelial neoplasia) and persistent hrHPV infections against which the licensed prophylactic HPV vaccines have no efficacy. Here, we review the progress and challenges in the development of immunotherapeutic approaches for the prevention and treatment of cervical cancer.


Radiation pneumonitis: a possible lymphocyte-mediated hypersensitivity reaction.
To determine if unilateral thoracic irradiation results in a lymphoid alveolitis in both irradiated and unirradiated lung fields. A prospective, nonrandomized study. Women receiving postoperative radiotherapy for carcinoma of the breast were evaluated both before and 4 to 6 weeks after radiotherapy. Findings after radiotherapy in 15 asymptomatic patients were compared with findings in a group of patients with clinical radiation pneumonitis. History, physical examination, chest radiograph, quantitative gallium lung scanning, respiratory function tests, bronchoalveolar lavage, and lavage lymphocyte subset analysis. After irradiation, lavage lymphocytes increased significantly (34.5% versus 46.8%; P = 0.01) in the 17 patients studied prospectively. There was an associated reduction in vital capacity (102.5% versus 95.5%; P = 0.04). Comparison of results in patients before treatment, after treatment without clinical pneumonitis, and after treatment with clinical pneumonitis showed a dramatic increase in total lymphocytes after irradiation (6.3 versus 9.4 versus 35.2 million, respectively; P = 0.005), particularly in those with clinical pneumonitis. Only in those with clinical pneumonitis was this accompanied by an increase in the gallium index (3.7 versus 3.4 versus 9.0, respectively; P < 0.001). Vital capacity was also progressively reduced (102.5% versus 96.9% versus 76.7%, respectively; P = 0.04), as was diffusing capacity (98.6% versus 91.4% versus 72.6%, respectively; P = 0.003). No statistical differences existed between irradiated and unirradiated sides of the chest in either lavage or gallium lung scan studies. In most patients, a lymphocytic alveolitis develops in both lung fields after strictly unilateral thoracic irradiation; this is more pronounced in patients developing clinical pneumonitis. These findings suggest that radiotherapy may cause a generalized lymphocyte-mediated hypersensitivity reaction.


Systematic Reviews in Craniofacial Trauma-Strengths and Weaknesses.
Despite substantial advances in the management of craniofacial trauma, numerous clinical questions remain. These are increasingly being answered using systematic reviews (SRs). However, caution is warranted as their validity and role in influencing clinical practice has been called into question. A PubMed search was performed in October 2014 to identify SRs published up to and including September 2014 in 35 scientific journals. Two authors independently reviewed the literature and extracted data from included studies. Discrepancies were resolved by consensus. Assessment of multiple systematic reviews (AMSTAR) was used to determine the quality of SRs. The initial search retrieved 3080 articles of which 3051 articles were excluded after screening title and abstract. After full-text review of the remaining 29 articles, 3 additional articles were excluded, thus, leaving 26 SRs for final analysis. Regression analysis demonstrated that the overall number of published SRs increased significantly throughout the period analyzed (P = 0.022). The median AMSTAR score of all SRs was 4.5, consistent with a "poor-to-fair" quality. The interobserver agreement was high, as evidenced by a mean κ of 0.91. Although there appeared to be a trend toward an increase in AMSTAR score by year over the period analyzed, this failed to reach statistical significance in terms of median (P = 0.36) or absolute (P = 0.26) counts. A tremendous opportunity exists for improvements in the quality of SRs focusing on craniofacial trauma. In addition to familiarizing authors with quality criteria for SRs, adoption of strict reporting criteria by scientific journals may result in long-term improvements in the quality of reporting.


Rice Homeodomain Protein WOX11 Recruits a Histone Acetyltransferase Complex to Establish Programs of Cell Proliferation of Crown Root Meristem.
Shoot-borne crown roots are the major root system in cereals. Previous work has shown that the Wuschel-related homeobox gene WOX11 is necessary and sufficient to promote rice (Oryza sativa) crown root emergence and elongation. Here, we show that WOX11 recruits the ADA2-GCN5 histone acetyltransferase module to activate downstream target genes in crown root meristem. Rice ADA2 and GCN5 genes are highly expressed in root meristem and are shown to be essential for cell division and growth. WOX11 and ADA2-GCN5 commonly target and regulate a set of root-specific genes involved in energy metabolism, cell wall biosynthesis, and hormone response, some of which are known to be important for root development. The results indicate that the recruitment of ADA2-GCN5 by WOX11 establishes gene expression programs of crown root meristem cell division and suggest that permissive chromatin modification involving histone acetylation is a strategy for WOX11 to stimulate root meristem development.


Improved survival for individuals with common chronic conditions in the Medicare population.
It is well established that the United States lags behind peer nations in life expectancy, but it is less established that there is heterogeneity in life expectancy trends. We compared mortality trends from 2004 to 2014 for the United States with 17 high-income countries for persons under and over 65. The United States ranked last in survival gains for the young but ranked near the middle for persons over 65, the group with universal access to public insurance. To explore the over-65 mortality trend, we estimated Cox proportional hazards models for individuals soon after entering Medicare. These were estimated separately by race and sex, controlling for 26 chronic conditions and condition-specific time trends. The separate regressions enabled survival comparisons for the 2004 and 2014 cohorts by race and sex, conditional on baseline health. We predicted 5-year survival for all combinations of diabetes, hyperlipidemia, hypertension, and ischemic heart disease (IHD). All 16 combinations of these conditions showed survival gains, with diabetes as a key driver. Notably, survival improved and racial disparities narrowed for individuals with diabetes, hypertension, and IHD. White females, black females, white males, and black males gained 3.61, 3.90, 3.57, and 5.89 percentage points in 5-year survival, respectively.


The haematological features and transfusion management of women who required massive transfusion for major obstetric haemorrhage in the UK: a population based study.
Understanding the coagulopathy of major-obstetric-haemorrhage (MOH) that leads to massive-transfusion (MT) is fundamental to improving outcomes. This study reports on the haematological features and transfusion management of women experiencing MT [defined as transfusion of ≥8 units of red blood cells (RBC) within 24 h of delivery]. One hundred and eighty-one cases [median (interquartile range; IQR) age 33 years (29-36)] were identified from all UK hospitals, using the UK Obstetric Surveillance System between July 2012 and June 2013. The median (IQR) estimated blood loss was 6 l (4·5-8). At presentation, the median platelet count was lowest for placenta accreta, compared with other causes, while the median prothrombin time and fibrinogen were <1·5 × mean normal and <3 g/l, respectively for all aetiologies. Median platelet count and fibrinogen fell to <75 × 10(9) /l and <2 g/l, respectively for all causes during bleeding, except for trauma. The median (IQR) units of RBC, fresh-frozen-plasma (FFP) and cryoprecipitate transfused were 10 (8-14), 6 (4-8) and 2 (2-4), respectively. The median time from the onset of bleeding to delivery of the first RBC unit was significantly shorter for women who delivered via elective caesarean section, compared with others. The coagulopathy of MT during MOH differs significantly depending on its cause, suggesting that more targeted transfusion strategies are required.


Intravenous fluids for abdominal aortic surgery.
Surgery on the abdominal aorta to treat aneurysms or occlusive disease is a major undertaking which requires intensive physiological support and fluid management. Blood products are often used but the main fluid replacement is with crystalloids or colloids. For years there has been controversy over which fluid is optimal and a number of studies have examined the subject. This is an update of a Cochrane review first published in 2000 and previously updated in 2002. To determine the effectiveness of different non-blood replacement fluids used in abdominal aorta procedures with a view to identifying the optimal fluid for use. The Cochrane Peripheral Vascular Diseases Group searched their Specialised Register (August 2009) and the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2009, Issue 3) for publications describing randomised controlled trials of non-blood replacement fluids in abdominal aortic surgery. In addition, the reference lists from retrieved trials were screened for further information about trials. Randomised controlled trials assessing the effects of at least one specific non-blood fluid used for replacement therapy in operations on, and confined to, the abdominal aorta. Data were extracted and then entered into the Review Manager software where statistical analyses were performed. Thirty-eight trials involving 1589 patients were included. Patients undergoing aortic surgery had various physiological parameters measured before and after their operation (these were cardiac, respiratory, haematological, and biochemical). Patients were randomised to a fluid type. This review demonstrated that no single fluid affects any outcome measure significantly more than another fluid across a range of outcomes. The death rate in these studies was 2.45% (39 patients). Despite the confirmed beneficial effects of colloids in this review, further studies are still required. There are no studies examining the effects of combination fluid therapy. The primary research outcome was death, for which results were limited; therefore, future studies should pay more attention to short-term outcomes such as minimising the need for allogenic blood transfusion, complications (organ failure), and length of stay in both the intensive care unit and hospital.


Fibrin gels engineered with pro-angiogenic growth factors promote engraftment of pancreatic islets in extrahepatic sites in mice.
With a view toward reduction of graft loss, we explored pancreatic islet transplantation within fibrin matrices rendered pro-angiogenic by incorporation of minimal doses of vascular endothelial growth factor-A165 and platelet-derived growth factor-BB presented complexed to a fibrin-bound integrin-binding fibronectin domain. Engineered matrices allowed for extended release of pro-angiogenic factors and for their synergistic signaling with extracellular matrix-binding domains in the post-transplant period. Aprotinin addition delayed matrix degradation and prolonged pro-angiogenic factor availability within the graft. Both subcutaneous (SC) and epididymal fat pad (EFP) sites were evaluated. We show that in the SC site, diabetes reversal in mice transplanted with 1,000 IEQ of syngeneic islets was not observed for islets transplanted alone, while engineered matrices resulted in a diabetes median reversal time (MDRT) of 38 days. In the EFP site, the MDRT with 250 IEQ of syngeneic islets within the engineered matrices was 24 days versus 86 days for islets transplanted alone. Improved function of engineered grafts was associated with enhanced and earlier (by day 7) angiogenesis. Our findings show that by engineering the transplant site to promote prompt re-vascularization, engraftment and long-term function of islet grafts can be improved in relevant extrahepatic sites.


Raloxifene, a selective estrogen receptor modulator, is renoprotective: a post-hoc analysis.
Estrogens have a protective effect on kidney fibrosis in several animal models. Here, we tested the effect of raloxifene, an estrogen receptor modulator, on the change in serum creatinine or estimated glomerular filtration rate (eGFR) and incident kidney-related adverse events. We performed a post-hoc analysis of the multiple outcomes of raloxifene evaluation trial, a double-masked, placebo-controlled randomized clinical trial encompassing 7705 post-menopausal women (aged 31-80 years) with osteoporosis. Participants were randomized to either of two doses of raloxifene, 60 or 120 mg/day, or placebo. Serum creatinine was measured at a central laboratory at baseline and annually. Adverse events were assessed every 6 months and uniformly categorized. Compared with those in the placebo group, participants on raloxifene had a slower yearly rate of increase in creatinine (significant at the low dose) and a significantly slower yearly rate of decrease in eGFR for both doses over 3 years of follow-up. Raloxifene was associated with significantly fewer kidney-related adverse events compared with placebo. Thus, treatment with raloxifene was safe and renoprotective. Clinical trials of raloxifene in post-menopausal women with kidney disease designed to look at kidney outcomes are needed to confirm these findings.


Management of malignant pleural mesothelioma: a French multicenter retrospective study (GFPC 0802 study).
Malignant pleural mesothelioma (MPM) is a rare disease with poor prognosis in spite of significant improvement in survival, due to new chemotherapy regimens. We describe here patients' profiles and management in daily practice in France. Observational retrospective study. Data were collected from medical files. All patients with histologically proven MPM diagnosed from January 2005 to December 2008 were included in the participating sites. Four hundred and six patients were included in 37 sites: mean age 68.9 ± 9.8 years, male predominance (sex ratio 3.27), latency of the disease 45.7 years, epithelioïd type 83 %. Diagnosis was made using thoracoscopy in 80.8 % of patients. Radical surgery was performed in 6.2 % of cases. Chemotherapy was administered to 74.6 % of patients. First line regimens consisted mainly of platinum + pemetrexed (91 %) or pemetrexed alone (7 %). Objective response rate was 17.2 % and another 41.6 % of patients experienced disease stabilization. Half of these patients underwent second line chemotherapy (platinium + pemetrexed 31.6 %, pemetrexed alone 24.6 %), resulting in a 6 % response rate. Third-line chemotherapy (56 patients) yielded disease control in 5.4 % of cases. The management of MPM in France is usually in accordance with guidelines. Response rates are somewhat lower than those described in clinical trials.


Genetics and immunity of Anopheles response to the entomopathogenic fungus Metarhizium anisopliae overlap with immunity to Plasmodium.
Entomopathogenic fungi have been explored as a potential biopesticide to counteract the insecticide resistance issue in mosquitoes. However, little is known about the possibility that genetic resistance to fungal biopesticides could evolve in mosquito populations. Here, we detected an important genetic component underlying Anopheles coluzzii survival after exposure to the entomopathogenic fungus Metarhizium anisopliae. A familiality study detected variation for survival among wild mosquito isofemale pedigrees, and genetic mapping identified two loci that significantly influence mosquito survival after fungus exposure. One locus overlaps with a previously reported locus for Anopheles susceptibility to the human malaria parasite Plasmodium falciparum. Candidate gene studies revealed that two LRR proteins encoded by APL1C and LRIM1 genes in this newly mapped locus are required for protection of female A. coluzzii from M. anisopliae, as is the complement-like factor Tep1. These results indicate that natural Anopheles populations already segregate frequent genetic variation for differential mosquito survival after fungal challenge and suggest a similarity in Anopheles protective responses against fungus and Plasmodium. However, this immune similarity raises the possibility that fungus-resistant mosquitoes could also display enhanced resistance to Plasmodium, suggesting an advantage of selecting for fungus resistance in vector populations to promote naturally diminished malaria vector competence.


Do childhood growth indicators in developing countries cluster? Implications for intervention strategies.
The effectiveness of geographic targeting in nutrition programmes depends largely on the degree to which malnutrition clusters within particular areas. This study investigates the extent to which the childhood nutrition indicators, stunting (height-for-age Z-score <-2) and wasting (weight-for-height Z-score <-2), are spatially clustered; this information is used to determine the implications of spatial clustering for the effectiveness of geographic targeting. Analysis of data from Demographic and Health Survey (DHS) results. Clustering is assessed by calculating intra-cluster correlation coefficients (ICCs). Estimating the proportion of malnourished children covered by a programme successfully targeting 10% of clusters with the highest malnutrition prevalences allows an assessment of the effectiveness of geographic targeting. Fifty-eight DHS III (1992-1997) and DHS IV (1998-2001) reports from 46 developing countries. Pre-school children of mothers interviewed by DHS. The extent of clustering of nutritional status was surprisingly low (median ICC for national samples: stunting=0.054, wasting=0.032) and most countries were characterised by having an ICC <0.1--i.e. low clustering--for childhood undernutrition (91% of countries for wasting and 78% for stunting). Our assessment of the effectiveness of geographic targeting showed that coverage was better for wasting than for stunting; for wasting, 23% of countries would achieve less than 20% coverage, compared with 76% of countries achieving less than 20% coverage for stunting. Coverage is dependent on the overall prevalence of malnutrition and the ICC. Childhood nutritional status is determined at the household, or even individual, level; nutrition programmes that are geographically targeted may result in high levels of under-coverage and leakage, thereby compromising their cost-effectiveness; the lack of clustering questions the appropriateness of current nutrition interventions.


Influence of patient literacy on the effectiveness of a primary care-based diabetes disease management program.
Low literacy is an important barrier for patients with diabetes, but interventions to address low literacy have not been well examined. To examine the role of literacy on the effectiveness of a comprehensive disease management program for patients with diabetes. Analysis of the influence of literacy on glycemic control and systolic blood pressure using data from a randomized controlled trial (conducted from February 2001 through April 2003) of a comprehensive diabetes management program. Participants were 217 patients aged 18 years or older with type 2 diabetes and poor glycemic control (glycosylated hemoglobin [HbA1c] levels > or =8.0%) and presenting to a US academic general internal medicine practice. All communication to patients was individualized and delivered to enhance comprehension among patients with low literacy. Intervention patients received intensive disease management from a multidisciplinary team. Control patients received an initial management session and continued with usual care. Achievement of goal HbA1c levels and systolic blood pressure at 12-month follow-up for control and intervention patients stratified by literacy status. Complete 12-month data were available for 193 patients (89%). Among patients with low literacy, intervention patients were more likely than control patients to achieve goal HbA1c levels (< or =7.0%) (42% vs 15%, respectively; adjusted odds ratio [OR], 4.6; 95% confidence interval [CI], 1.3 to 17.2; P = .02). Patients with higher literacy had similar odds of achieving goal HbA1c levels regardless of intervention status (24% vs 23%; adjusted OR, 1.0; 95% CI, 0.4 to 2.5; P = .98). Improvements in systolic blood pressure were similar by literacy status. Literacy may be an important factor for predicting who will benefit from an intervention for diabetes management. A diabetes disease management program that addresses literacy may be particularly beneficial for patients with low literacy, and increasing access to such a program could help reduce health disparities.


A Novel Prokaryote-Type ECF/ABC Transporter Module in Chloroplast Metal Homeostasis.
During evolution, chloroplasts, which originated by endosymbiosis of a prokaryotic ancestor of today's cyanobacteria with a eukaryotic host cell, were established as the site for photosynthesis. Therefore, chloroplast organelles are loaded with transition metals including iron, copper, and manganese, which are essential for photosynthetic electron transport due to their redox capacity. Although transport, storage, and cofactor-assembly of metal ions in chloroplasts are tightly controlled and crucial throughout plant growth and development, knowledge on the molecular nature of chloroplast metal-transport proteins is still fragmentary. Here, we characterized the soluble, ATP-binding ABC-transporter subunits ABCI10 and ABCI11 in Arabidopsis thaliana, which show similarities to components of prokaryotic, multisubunit ABC transporters. Both ABCI10 and ABCI11 proteins appear to be strongly attached to chloroplast-intrinsic membranes, most likely inner envelopes for ABCI10 and possibly plastoglobuli for ABCI11. Loss of ABCI10 and ABCI11 gene products in Arabidopsis leads to extremely dwarfed, albino plants showing impaired chloroplast biogenesis and deregulated metal homeostasis. Further, we identified the membrane-intrinsic protein ABCI12 as potential interaction partner for ABCI10 in the inner envelope. Our results suggest that ABCI12 inserts into the chloroplast inner envelope membrane most likely with five predicted α-helical transmembrane domains and represents the membrane-intrinsic subunit of a prokaryotic-type, energy-coupling factor (ECF) ABC-transporter complex. In bacteria, these multisubunit ECF importers are widely distributed for the uptake of nickel and cobalt metal ions as well as for import of vitamins and several other metabolites. Therefore, we propose that ABCI10 (as the ATPase A-subunit) and ABCI12 (as the membrane-intrinsic, energy-coupling T-subunit) are part of a novel, chloroplast envelope-localized, AAT energy-coupling module of a prokaryotic-type ECF transporter, most likely involved in metal ion uptake.


Local variation in diet composition of the Japanese serow during winter.
We investigated local geographical variation in the plant composition and quality (crude protein) of the diet of the Japanese serow (Capricornis crispus) by analyzing rumen contents. We collected the rumen contents from 111 Japanese serows culled for pest control between January and March 1997 in Shizuoka Prefecture, central Japan. The composition of the diet, characterized by a high proportion of browse (65.2%), including green plant leaves (55.3%), confirmed that the Japanese serow is a typical browser, at least in winter. Although the composition of the diet varied geographically even within Shizuoka Prefecture (i.e. the northern populations included less green broad leaves, and more grasses and Sasa spp.), altitude did not affect the composition. Latitudinal variation in plant composition of the diet was explained by a shift in plant availability within vegetation zones from evergreen broad-leaf to deciduous broad-leaf forests. Lack of variation in the diet plant composition with changes in altitude may be explained by probably greater altitudinal than latitudinal variation in the territories of the Japanese serow, and by greater individual variation in food habits. Diet quality remained at a constant high level regardless of altitudinal and latitudinal variation in diet plant composition. This suggests that the Japanese serow maintains a high-quality diet by selective feeding, which is possible only when the serow is at low population density and in possession of a territory.


Physical Activity and Prostate Cancer: An Updated Review.
Prostate cancer affects a major proportion of older men, and effective preventive measures are few. Earlier suggestions of 10-30% risk reduction from vigorous physical activity thus merit further analysis. This narrative review updates information on associations between physical activity and prostate cancer, seeking activity patterns associated with maximal risk reduction. Systematic searches of Ovid/MEDLINE and PubMed databases from 1996 to June 2016 have linked the terms prostate neoplasms/prostate cancer with occupation, occupational title, sedentary job or heavy work, exercise, physical activity, sports, athletes, physical education/training or aerobic fitness. Combining these searches with findings from earlier reviews, 85 analyses were captured, although three were repeat analyses of the same data set. Seven analyses reported increased risk, and a further 31 showed no clear relationship. However, 24 analyses found a trend to diminished risk, and 21 a significant decrease (10-30% or more) in at least some subject subsets. Benefit was seen more consistently in occupational than in leisure studies, usually with adolescence or the early 20 s as the optimal age for preventive activity. In general, benefit showed a dose-response relationship, with vigorous activity required for maximal effect. Furthermore, several recent observational studies have indicated that physical activity is beneficial in preventing disease recurrence and improving survival following the diagnosis and treatment of prostate cancer. Despite continued research, conclusive proof of an association between regular physical activity and a low risk of prostate cancer remains elusive. However, reports that exercise exacerbates risk are few, and despite issues around controls, covariates, and co-morbidities, an impressive number of studies have now found significant benefit, suggesting that regular physical activity is important in terms of disease development, progression, and therapy. Given also the many other health benefits of an active lifestyle, it can be recommended as a potentially useful measure in the prevention of prostate cancer.


Morphology and ultrastructure of medial rectus subgroup motoneurons in the macaque monkey.
There are two muscle fiber types in extraocular muscles: those receiving a single motor endplate, termed singly innervated fibers (SIFs), and those receiving multiple small terminals along their length, termed multiply innervated fibers (MIFs). In monkeys, these two fiber types receive input from different motoneuron pools: SIF motoneurons found within the extraocular motor nuclei, and MIF motoneurons found along their periphery. For the monkey medial rectus muscle, MIF motoneurons are found in the C-group, while SIF motoneurons lie in the A- and B-groups. We analyzed the somatodendritic morphology and ultrastructure of these three subgroups of macaque medial rectus motoneurons to better understand the structural determinants controlling the two muscle fiber types. The dendrites of A- and B-group motoneurons lay within the oculomotor nucleus, but those of the C-group motoneurons were located outside the nucleus, and extended into the preganglionic Edinger-Westphal nucleus. A- and B-group motoneurons were very similar ultrastructurally. In contrast, C-group motoneurons displayed significantly fewer synaptic contacts on their somata and proximal dendrites, and those contacts were smaller in size and lacked dense-cored vesicles. However, the synaptic structure of C-group distal dendrites was quite similar to that observed for A- and B-group motoneurons. Our anatomical findings suggest that C-group MIF motoneurons have different physiological properties than A- and B-group SIF motoneurons, paralleling their different muscle fiber targets. Moreover, primate C-group motoneurons have evolved a special relationship with the preganglionic Edinger-Westphal nucleus, suggesting these motoneurons play an important role in near triad convergence to support increased near work requirements.


Small-volume rapid-mix device for subsecond kinetic analysis in flow cytometry.
Rapid-mix flow cytometry has emerged as a powerful tool for mechanistic analysis of ligand binding, cell response, and molecular assembly. Although progress has come from improving sample delivery capabilities, little attention has been paid to the volumetric requirements associated with precious biological reagents. By using programmable syringes, valves, and other fluidic components, we created a modular, precisely regulated rapid-mix device for the delivery of small-volume samples to the flow cytometer. The device was tested using a bead-based assay in which the binding kinetics between native biotin and fluorescein biotin-bearing beads were characterized. Bead suspensions and reagents paired in 35- to 45-microl aliquots were efficiently mixed by the device and delivered to the flow cytometer. Kinetic data associated with the fluorescein biotin beads were analyzed and used to calibrate the performance characteristics of the device in terms of sample delivery and mixing efficiency. The rapid-mix device is capable of detecting subsecond kinetics of biological reactions using microliter volume of samples. Dimensions of the device have been minimized, and the quantitative aspects of sample delivery and analysis have been optimized. Further, the modular design has been optimized for adaptation to a variety of experimental protocols.


Youth-to-Senior Transition in Elite European Club Soccer.
The priority for soccer academies is to develop youth players that graduate and transfer directly to their senior squads. The aim of this study was to assess the effectiveness of this direct youth-to-senior pathway by examining the extent to which club-trained players (CTPs) are currently involved in elite male European soccer. Relevant demographic longitudinal studies between 2009 and 2020 conducted by the International Centre for Sports Studies Football Observatory were analysed. The main findings were that the proportion of CTPs in senior squads has decreased from 23% to 17% over this time period, while the proportion of expatriates (EXPs) has increased from 35% to 42%. Moreover, clubs resorted more frequently to making new signings (NS, i.e. association-trained players (ATPs) and/or EXPs), with squad proportion increasing from 37% to 44%, while only launching one debutant (DBT, i.e. CTP with no previous senior experience) on average per season. Similar trends are observed in the evolution of playing time: while the fielding of CTPs remained constant (15%), EXPs and NS are fielded increasingly more (49% and 36%, respectively), despite a positive relationship between CTP match fielding and league ranking, with a Spearman Rank correlation r = 0.712 (95% confidence interval [0.381-0.881]), p < 0.01. In conclusion, young talents are still provided opportunities; however, these are limited and increasingly less frequent at their parent clubs. This potentially suggests a dysfunctional direct youth-to-senior development pathway.


[History of the scientific work of Eduardo Cruz-Coke Lassabe].
Eduardo Cruz Coke M.D., (1899-1974) was one of the precursors and pioneers of biomedical research in Chile, as professor of Physiological and Pathological Chemistry at the University of Chile, from 1925 to 1962. He was a disciple of Dr. Juan Noe and studied in Europe with the Nobel Prize winners Otto Warburg, Jean Perrin, Louis de Broglie and Frederic G. Hopkins. In Chile, he founded a scientific academy with disciples that later obtained the National Sciences Award, such as Hector Croxatto, Jorge Mardones, Hermann Niemeyer, Luis Vargas and Jorge Allende. He carried out pioneering research in metabolism, nutrition, endocrinology, oncology and nephrogenic hypertension. He published more than 50 scientific papers in French, English and Spanish. He founded scientific societies, edited journals and created the National Commission of Nuclear Energy. His books were "The ionic acidity in the clinic", "Preventive and directed medicine", "The adrenal cortex". He was Ministry of Health between 1937 and 1938 and passed important socio-medical bills. He obtained the distinguished international awards in Europe, the U.S.A. and Latin America. The Biomedical Sciences Institute of the University of Chile carries his name.


An exploration of the complex biogeographical history of the Neotropical banner-wing damselflies (Odonata: Polythoridae).
The New World Tropics has experienced a dynamic landscape across evolutionary history and harbors a high diversity of flora and fauna. While there are some studies addressing diversification in Neotropical vertebrates and plants, there is still a lack of knowledge in arthropods. Here we examine temporal and spatial diversification patterns in the damselfly family Polythoridae, which comprises seven genera with a total of 58 species distributed across much of Central and South America. Our time-calibrated phylogeny for 48 species suggests that this family radiated during the late Eocene (~ 33 Ma), diversifying during the Miocene. As with other neotropical groups, the Most Recent Common Ancestor (MRCA) of most of the Polythoridae genera has a primary origin in the Northern Andes though the MRCA of at least one genus may have appeared in the Amazon Basin. Our molecular clock suggests correlations with some major geographical events, and our biogeographical modeling (with BioGeoBEARS and RASP) found a significant influence of the formation of the Pebas and Acre systems on the early diversification of these damselflies, though evidence for the influence of the rise of the different Andean ranges was mixed. Diversification rates have been uniform in all genera except one-Polythore-where a significant increase in the late Pliocene (~ 3 mya) may have been influenced by recent Andean uplift. The biogeographical models implemented here suggest that the Pebas and Acre Systems were significant geological events associated with the diversification of this damselfly family; while diversification in the tree shows some correlation with mountain building events, it is possible that other abiotic and biotic changes during our study period have influenced diversification as well. The high diversification rate observed in Polythore could be explained by the late uplift of the Northern Andes. However, it is possible that other intrinsic factors like sexual and natural selection acting on color patterns could be involved in the diversification of this genus.


Unique lipids of primate spermatozoa: desmosterol and docosahexaenoic acid.
Spermatozoa represent a tissue readily accessible for study after various exogenous perturbations. To characterize the lipid composition of monkey sperm and to establish a baseline from which dietary or pharmaceutical influences may then be evaluated, we collected semen samples from five rhesus monkeys by electroejaculation and analyzed the sperm for sterols, fatty acid composition, and the molecular species of the ethanolamine glycerophospholipids. Two sterols were identified: cholesterol, 41%, and desmosterol, 59% of total sterols. Desmosterol was found only in the free form. Cholesterol existed in three different forms: free, 60%; esterified, 20%; and sulfated, 20%. Docosahexaenoic acid (22:6, DHA) was almost the only n-3 fatty acid in sperm phospholipids, 24% of the total fatty acids. DHA was present mainly in phosphatidylcholine and phosphatidylethanolamine. Oleic and palmitic acids were the predominant monounsaturated and saturated fatty acids. The ethanolamine glycerophospholipids were separated into three subclasses: diacyl 49%, alkenylacyl 43%, and alkylacyl 8%. Thirteen molecular species were identified and quantified. The sn-1 position of these molecular species contained exclusively 16:0, 18:0, or 18:1. The sn-2 position contained n-3, n-6, and n-9, as well as saturated fatty acids. The molecular species having n-3 fatty acids in the sn-2 position contributed 43, 73, and 100% of the total in the diacyl, alkenylacyl, and alkylacyl subclasses, respectively. The presence of the unusual sterol, desmosterol, a cholesterol precursor not found in measurable quantities in any other tissue suggests an important functional and structural role for desmosterol in spermatozoa. The other unique lipids, cholesterol sulfate and the n-3 docosahexaenoic acid, may also have a significant role in the function of spermatozoa.


Proton-transfer-induced 3D/2D hybrid perovskites suppress ion migration and reduce luminance overshoot.
Perovskite light-emitting diodes (PeLEDs) based on three-dimensional (3D) polycrystalline perovskites suffer from ion migration, which causes overshoot of luminance over time during operation and reduces its operational lifetime. Here, we demonstrate 3D/2D hybrid PeLEDs with extremely reduced luminance overshoot and 21 times longer operational lifetime than 3D PeLEDs. The luminance overshoot ratio of 3D/2D hybrid PeLED is only 7.4% which is greatly lower than that of 3D PeLED (150.4%). The 3D/2D hybrid perovskite is obtained by adding a small amount of neutral benzylamine to methylammonium lead bromide, which induces a proton transfer from methylammonium to benzylamine and enables crystallization of 2D perovskite without destroying the 3D phase. Benzylammonium in the perovskite lattice suppresses formation of deep-trap states and ion migration, thereby enhances both operating stability and luminous efficiency based on its retardation effect in reorientation.


Updating the Mediterranean Diet Pyramid towards Sustainability: Focus on Environmental Concerns.
Nowadays the food production, supply and consumption chain represent a major cause of ecological pressure on the natural environment, and diet links worldwide human health with environmental sustainability. Food policy, dietary guidelines and food security strategies need to evolve from the limited historical approach, mainly focused on nutrients and health, to a new one considering the environmental, socio-economic and cultural impact-and thus the sustainability-of diets. To present an updated version of the Mediterranean Diet Pyramid (MDP) to reflect multiple environmental concerns. We performed a revision and restructuring of the MDP to incorporate more recent findings on the sustainability and environmental impact of the Mediterranean Diet pattern, as well as its associations with nutrition and health. For each level of the MDP we provided a third dimension featuring the corresponding environmental aspects related to it. The new environmental dimension of the MDP enhances food intake recommendations addressing both health and environmental issues. Compared to the previous 2011 version, it emphasizes more strongly a lower consumption of red meat and bovine dairy products, and a higher consumption of legumes and locally grown eco-friendly plant foods as much as possible.


Registered nurses' use of computerised decision support in medication reviews.
Purpose The purpose of this paper is to explore the implications of registered nurses' (RNs) use of a computerized decision support system (CDSS) in medication reviews. Design/methodology/approach The paper employs a quasi-experimental, one-group pre-test/post-test design with three- and six-month follow-ups subsequent to the introduction of a CDSS. In total, 11 RNs initiated and prepared a total of 54 medication reviews. The outcome measures were the number of drug-related problems (DRPs) as reported by the CDSS and the RNs, respectively, the RNs' views on the CDSS, and changes in the quality of drug treatment. Findings The CDSS significantly indicated more DRPs than the RNs did, such as potential adverse drug reactions (ADRs). The RNs detected additional problems, outside the scope of the CDSS, such as lack of adherence. They considered the CDSS beneficial and wanted to continue using it. Only minor changes were found in the quality of drug treatments, with no significant changes in the drug-specific quality indicators (e.g. inappropriate drugs). However, the use of renally excreted drugs in reduced renal function decreased. Practical implications The RNs' use of a CDSS in medication reviews is of value in detecting potential ADRs and interactions. Yet, in order to have an impact on outcomes in the quality of drug treatment, further measures are needed. These may involve development of inter-professional collaboration, such as established procedures for the implementation of medication reviews, including the use of CDSS. Originality/value This is, to the best of the authors' knowledge, the first study to explore the implications of medication reviews, initiated and prepared by RNs who use a CDSS. The paper adds further insight into the RNs' role in relation to quality of drug treatments.


Clearance of Escherichia coli O157:H7 infection in calves by rectal administration of bovine lactoferrin.
Enterohemorrhagic Escherichia coli (EHEC) strains, of which E. coli O157:H7 is the best-studied serotype, are an important group of foodborne pathogens causing severe illness in humans worldwide. The main reservoirs for EHEC are ruminants, mostly cattle, which harbor the bacteria in their intestinal tracts without showing clinical symptoms. In this study, we used bovine lactoferrin, a natural occurring bactericidal and immunomodulating protein, as an antibacterial agent against EHEC infection in cattle. Nine 3-month-old Holstein-Friesian calves were experimentally infected with EHEC (strain NCTC12900). Three animals received a daily rectal spray treatment with bovine lactoferrin, three animals received an oral treatment, and three animals served as a control group. Blood samples were collected weekly and fecal samples twice weekly to monitor antibody responses and fecal excretion, respectively. Animals in the rectal group ceased shedding within 26 days of the experimental treatment and remained negative. This beneficial effect of bovine lactoferrin was not observed in the oral group, where animals were still shedding at the time of euthanasia (day 61). All groups developed serum responses, but no clear differences could be observed between the groups. However, the results indicate that the use of bovine lactoferrin as a rectal treatment can be a useful strategy to preclude further transmission of EHEC infections from cattle to humans.


Evidence for a selective effect of ethanol on N-methyl-d-aspartate responses: ethanol affects a subtype of the ifenprodil-sensitive N-methyl-d-aspartate receptors.
An extracellular electrophysiological approach was used to determine the effect of ethanol on responses to N-methyl-D-aspartate (NMDA) across several brain regions in urethane-anesthetized rats. The results indicated that, in most brain regions, ethanol inhibited the NMDA-induced increases in firing rate for some, but not all, spontaneously active neurons. Ethanol functioned as an NMDA antagonist for some neurons in the medial septum, red nucleus, deep mesencephalic nucleus, substantia nigra reticulata, ventral tegmental area and cerebellum. In the hippocampus, ethanol inhibited NMDA responses from all neurons. However, ethanol was not found to be active against NMDA responses in the lateral septum, suggesting that there is a degree of regional specificity for ethanol inhibition of NMDA responses. It was then established in unanesthetized rats that ethanol also antagonized responses to NMDA in some, but not all, neurons in the medial septum and cortex, indicating that the differential action of ethanol on NMDA responses obtained in the urethane-anesthetized rats was not due to the anesthetic. Based on an earlier study showing that the effects of ifenprodil and ethanol on NMDA responses were correlated, the ability of ethanol to inhibit NMDA responses was compared with changes produced by ifenprodil on the same neurons, where ethanol did or did not affect NMDA responses. In the several brain regions investigated, ethanol inhibited NMDA responses in a subgroup of neurons in which ifenprodil inhibited NMDA-induced increases in firing. For all neurons investigated, if a cell was insensitive to ifenprodil antagonism of NMDA responses then ethanol also was ineffective against the response to NMDA. These results suggest that ethanol acts on an ifenprodil-sensitive NMDA receptor subtype. Given that previous investigations have suggested that the NMDA receptor type 2B subunit is essential for the action of ifenprodil, the positive relationship between the actions of ifenprodil and ethanol on responses to NMDA is consistent with the hypothesis that the combination of specific receptor subunits forming an NMDA receptor on a neuron determines the ability of ethanol to antagonize an NMDA response.


Reporting of the estimated glomerular filtration rate was associated with increased use of angiotensin-converting enzyme inhibitors and angiotensin-II receptor blockers in CKD.
Many guidelines suggest that angiotensin-converting enzyme inhibitors and angiotensin-II receptor antagonists (collectively referred to as renin, angiotensin, aldosterone system blockers (RAAS blockers)) are the preferred treatment for hypertension in most patients with chronic kidney disease (CKD). Improving the recognition of CKD with the introduction of eGFR reporting was intended to have more patients recognized with and treated for this disease. To quantify this, we examined trends in RAAS-blocker use over an 88-month period before and after routine eGFR reporting in southwestern Ontario, Canada. An intervention analysis with seasonal time-series modeling on linked health administrative data for 45,361 ambulatory residents with CKD (eGFR stages 3-5) older than 65 years was performed with a primary outcome of RAAS-blocker usage. The reporting of eGFR was associated with a significant increase in the use of RAAS blockers, as the prescription rate was 571 per 1000 patients with CKD prior to reporting but improved to 607 per 1000 after reporting. There was a significant increase in RAAS-blocker use attributable to eGFR reporting of 19 per 1000 CKD patients. Since about 8% of the adult population has CKD, this equates to about 15,200 new patients receiving RAAS-blocker treatment by 1 year after the introduction of eGFR reporting in community laboratories. Thus, eGFR reporting contributes to improved, guideline-appropriate care of older patients with CKD.


A typology of bullying behaviours: the experiences of Australian nurses.
This study sought to explore the nature of bullying in the Australian nursing workplace. While there is widespread concern about the extent and consequences of bullying among nurses, to date, there have been no published reports cataloguing the types of behaviours that constitute bullying. Reported here are findings from the first stage of a three-stage sequential mixed methods study. The first, qualitative stage of this study employed in-depth, semi structured interviews with 26 nurses who had experienced bullying from two Australian area health services. Content analysis of the verbatim interview transcripts was performed using the nvivo 7 software program. The analysis identified six major categories and constituent sub-categories. The typology of bullying behaviours reported here is one of these major categories. The typology of behaviours developed from the study provides detailed insights into the complexity of bullying experienced by nurses. The behaviours were labelled: personal attack, erosion of professional competence and reputation, and attack through work roles and tasks. These themes provide insight into the construct of bullying by providing a detailed catalogue of bullying behaviours that show that bullying is frequently masked in work tasks or work processes and focused on damaging the reputation and status of targets. The detailed catalogue of bullying behaviours draws attention to the breadth of the bullying experience. It is anticipated the typology will be of use to nurses, managers and other professionals who are interested in responding to the problem of bullying in nursing.


Laryngoscopic, acoustic, perceptual, and functional assessment of voice in rock singers.
The present study aimed to vocally assess a group of rock singers who use growl voice and reinforced falsetto. A group of 21 rock singers and a control group of 18 pop singers were included. Singing and speaking voice was assessed through acoustic, perceptual, functional and laryngoscopic analysis. No significant differences were observed between groups in most of the analyses. Acoustic and perceptual analysis of the experimental group demonstrated normality of speaking voice. Endoscopic evaluation showed that most rock singers presented during singing voice a high vertical laryngeal position, pharyngeal compression and laryngeal supraglottic compression. Supraglottic activity during speaking voice tasks was also observed. However, overall vocal fold integrity was demonstrated in most of the participants. Slightly abnormal observations were demonstrated in few of them. Singing voice handicap index revealed that the most affected variable was the physical sphere, followed by the social and emotional spheres. Although growl voice and reinforced falsetto represent laryngeal and pharyngeal hyperfunctional activity, they did not seem to contribute to the presence of any major vocal fold disorder in our subjects. Nevertheless, we cannot rule out the possibility that more evident vocal fold disorders could be found in singers who use these techniques more often and during a longer period of time.


Allosteric activation transitions in enzymes and biomolecular motors: insights from atomistic and coarse-grained simulations.
The chemical step in enzymes is usually preceded by a kinetically distinct activation step that involves large-scale conformational transitions. In "simple" enzymes this step corresponds to the closure of the active site; in more complex enzymes, such as biomolecular motors, the activation step is more complex and may involve interactions with other biomolecules. These activation transitions are essential to the function of enzymes and perturbations in the scale and/or rate of these transitions are implicated in various serious human diseases; incorporating key flexibilities into engineered enzymes is also considered a major remaining challenge in rational enzyme design. Therefore it is important to understand the underlying mechanism of these transitions. This is a significant challenge to both experimental and computational studies because of the allosteric and multi-scale nature of such transitions. Using our recent studies of two enzyme systems, myosin and adenylate kinase (AK), we discuss how atomistic and coarse-grained simulations can be used to provide insights into the mechanism of activation transitions in realistic systems. Collectively, the results suggest that although many allosteric transitions can be viewed as domain displacements mediated by flexible hinges, there are additional complexities and various deviations. For example, although our studies do not find any evidence for "cracking" in AK, our results do underline the contribution of intra-domain properties (e.g., dihedral flexibility) to the rate of the transition. The study of mechanochemical coupling in myosin highlights that local changes important to chemistry require stabilization from more extensive structural changes; in this sense, more global structural transitions are needed to activate the chemistry in the active site. These discussions further emphasize the importance of better understanding factors that control the degree of co-operativity for allosteric transitions, again hinting at the intimate connection between protein stability and functional flexibility. Finally, a number of topics of considerable future interest are briefly discussed.


Highly comparative time-series analysis: the empirical structure of time series and their methods.
The process of collecting and organizing sets of observations represents a common theme throughout the history of science. However, despite the ubiquity of scientists measuring, recording and analysing the dynamics of different processes, an extensive organization of scientific time-series data and analysis methods has never been performed. Addressing this, annotated collections of over 35 000 real-world and model-generated time series, and over 9000 time-series analysis algorithms are analysed in this work. We introduce reduced representations of both time series, in terms of their properties measured by diverse scientific methods, and of time-series analysis methods, in terms of their behaviour on empirical time series, and use them to organize these interdisciplinary resources. This new approach to comparing across diverse scientific data and methods allows us to organize time-series datasets automatically according to their properties, retrieve alternatives to particular analysis methods developed in other scientific disciplines and automate the selection of useful methods for time-series classification and regression tasks. The broad scientific utility of these tools is demonstrated on datasets of electroencephalograms, self-affine time series, heartbeat intervals, speech signals and others, in each case contributing novel analysis techniques to the existing literature. Highly comparative techniques that compare across an interdisciplinary literature can thus be used to guide more focused research in time-series analysis for applications across the scientific disciplines.


Long-term effects of early adolescent methamphetamine exposure on depression-like behavior and the hypothalamic vasopressin system in mice.
Methamphetamine (MA) has neurotoxic effects on the adult human brain that can lead to deficits in behavior and cognition. However, relatively little research has examined the behavioral or neurotoxic effects of MA in adolescents. The rising rates of adolescent MA use make it imperative that we understand the long-term effects of MA exposure on the adolescent brain and how these effects may differ from those seen in adults. In this study, the long-term effects of MA exposure during early adolescence on behavior and the vasopressin system in the paraventricular nucleus of the hypothalamus in late adolescent and adult male and female C57BL/6J mice were examined. MA exposure increased depression-like behavior in the Porsolt forced swim test in both late adolescent and adult male and female mice. Late adolescent male mice exposed to MA also showed a decrease in the number of vasopressin-immunoreactive neurons in the paraventricular nucleus compared to sex-matched saline-treated controls. Thus, similar to humans exposed to MA during adolescence, mice exposed to MA during adolescence show increased depression-like behavior later in life. These changes in behavior may be related to MA-induced alterations in vasopressin and the hypothalamic-pituitary-adrenal axis, especially in males.


Cost effectiveness of Iran national plasma contract fractionation program.
Plasma derived medicines (PDM) including immunoglobulins, clotting factors and albumin are life saving medicines which due to their high costs are inaccessible for many patients living in developing countries. By contrary substantial volume of plasma as raw materials for production of these medicines are discarded worldwide. Good quality recovered plasma, as a result of separation of donated blood into its components, could be used for production of PDM. In 2011 Iranian donors donated about 2 million units of blood. A shift from administration of whole blood to components therapy has resulted in the generation of over 250,000 liters of surplus of recovered plasma. This created a good opportunity for Iran's health care system to use this plasma for production of PDM. Therefore Iran national transfusion service has started a contract fractionation program for converting recovered plasma into PDM. This program not only provided essential PDM for Iran pharmaceutical market but also has created a direct saving of about 8.5 million Euros in 2011 for national health sector. In addition this program has drastically contributed to improvement of overall quality of working procedures and services provided by Iran national blood transfusion organization.


Epidermal growth factor receptor cooperates with signal transducer and activator of transcription 3 to induce epithelial-mesenchymal transition in cancer cells via up-regulation of TWIST gene expression.
Aberrant epidermal growth factor receptor (EGFR) signaling is a major cause of tumor progression and metastasis; the underlying mechanisms, however, are not well understood. In particular, it remains elusive whether deregulated EGFR pathway is involved in epithelial-mesenchymal transition (EMT), an early event that occurs during metastasis of cancers of an epithelial origin. Here, we show that EGF induces EGFR-expressing cancer cells to undergo a transition from the epithelial to the spindle-like mesenchymal morphology. EGF reduced E-cadherin expression and increased that of mesenchymal proteins. In search of a downstream mediator that may account for EGF-induced EMT, we focused on transcription repressors of E-cadherin, TWIST, SLUG, and Snail and found that cancer cells express high levels of TWIST and that EGF enhances its expression. EGF significantly increases TWIST transcripts and protein in EGFR-expressing lines. Forced expression of EGFR reactivates TWIST expression in EGFR-null cells. TWIST expression is suppressed by EGFR and Janus-activated kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) inhibitors, but not significantly by those targeting phosphoinositide-3 kinase and MEK/ERK. Furthermore, constitutively active STAT3 significantly activates the TWIST promoter, whereas the JAK/STAT3 inhibitor and dominant-negative STAT3 suppressed TWIST promoter. Deletion/mutation studies further show that a 26-bp promoter region contains putative STAT3 elements required for the EGF-responsiveness of the TWIST promoter. Chromatin immunoprecipitation assays further show that EGF induces binding of nuclear STAT3 to the TWIST promoter. Immunohistochemical analysis of 130 primary breast carcinomas indicates positive correlations between non-nuclear EGFR and TWIST and between phosphorylated STAT3 and TWIST. Together, we report here that EGF/EGFR signaling pathways induce cancer cell EMT via STAT3-mediated TWIST gene expression.


Dietary recommendations for children and adolescents: a guide for practitioners: consensus statement from the American Heart Association.
Since the American Heart Association last presented nutrition guidelines for children, significant changes have occurred in the prevalence of cardiovascular risk factors and nutrition behaviors in children. Overweight has increased, whereas saturated fat and cholesterol intake have decreased, at least as percentage of total caloric intake. Better understanding of children's cardiovascular risk status and current diet is available from national survey data. New research on the efficacy of diet intervention in children has been published. Also, increasing attention has been paid to the importance of nutrition early in life, including the fetal milieu. This scientific statement summarizes current available information on cardiovascular nutrition in children and makes recommendations for both primordial and primary prevention of cardiovascular disease beginning at a young age.


International students' experience of a western medical school: a mixed methods study exploring the early years in the context of cultural and social adjustment compared to students from the host country.
Few studies have addressed the challenges associated with international students as they adapt to studying medicine in a new host country. Higher level institutions have increasing numbers of international students commencing programmes. This paper explores the experiences of a cohort of students in the early years of medical school in Ireland, where a considerable cohort are from an international background. A mixed exploratory sequential study design was carried out with medical students in the preclinical component of a five year undergraduate programme. Data for the qualitative phase was collected through 29 semi-structured interviews using the peer interview method. Thematic analysis from this phase was incorporated to develop an online questionnaire combined with components of the Student Adaptation to College Questionnaire and Student Integration Questionnaire. First year students were anonymously surveyed online. The Mokken Scaling procedure was used to investigate the students' experiences, both positive and negative. Three main themes are identified; social adjustment, social alienation and cultural alienation. The response rate for the survey was 49% (467 Respondents). The Mokken Scaling method identified the following scales (i) Positive experience of student life; (ii) Social alienation, which comprised of negative items about feeling lonely, not fitting in, being homesick and (iii) Cultural alienation, which included the items of being uncomfortable around cultural norms of dress and contact between the sexes. With the threshold set to H = 0.4. Subscales of the positive experiences of student life scale are explored further. Overall student adjustment to a western third level college was good. Students from regions where cultural distance is greatest reported more difficulties in adjusting. Students from these regions also demonstrate very good adaptation. Some students from the host country and more similar cultural backgrounds were also struggling. Acculturation is more complex than being associated with cultural distance and worthy of further exploration.


Experiences with and attitudes towards geriatric screening among older emergency department patients: a qualitative study.
The patient perspective on the use of screening for high risks of adverse health outcomes in Emergency Department (ED) care is underexposed, although it is an important perspective influencing implementation in routine care. This study explores the experiences with, and attitudes towards geriatric screening in routine ED care among older people who visited the ED. This was a qualitative study using individual face-to-face semi-structured interviews. Interviews were conducted in older patients (≥70 years) who completed the 'Acutely Presenting Older Patient' screener while visiting the ED of a Dutch academic hospital. Purposive convenience sampling was used to select a heterogeneous sample of participants regarding age, disease severity and the result from screening. Transcripts were analyzed inductively using thematic analysis. After 13 interviews (7 women, median age 82 years), data saturation was reached. The participants had noticed little of the screening administration during triage and screening was considered as a normal part of ED care. Most participants believed that geriatric screening contributes to assessing older patients holistically, recognizing geriatric problems early and comforting patients with communication and attention. None of the participants had a negative attitude towards screening or thought that screening is discrimination on age. Care providers should communicate respectfully with frail older patients and involve them in decision-making. Older patients experienced geriatric screening as a normal part of ED care and had predominantly positive attitudes towards its use in the ED. This qualitative study advocates for continuing the implementation of geriatric screening in routine ED practice.


An oncogenic KRAS transcription program activates the RHOGEF ARHGEF2 to mediate transformed phenotypes in pancreatic cancer.
Activating mutations of KRAS are nearly ubiquitous in pancreatic adenocarcinomas occurring in greater than 90% of cases. Cellular transformation by oncogenic RAS requires the RHO guanine exchange factor ARHGEF2 (also known as GEF-H1) for tumor growth and survival. Here, we find oncogenic KRAS activates ARHGEF2 through a minimal RAS responsive promoter. We have determined the endogenous ARHGEF2 promoter is positively regulated by the transcription factors ELK1, ETS1, SP1 and SP3 and negatively regulated by the RAS responsive element binding protein (RREB1). We find that the panel of ARHGEF2-regulating transcription factors modulates RAS transformed phenotypes including cellular viability, anchorage-independent growth and invasion-migration of pancreatic cancer cells. RREB1 knockdown activates the amplitude and duration of RHOA via increased ARHGEF2 expression. By relieving the negative regulation of RREB1 on the ARHGEF2 promoter, we determined that ETS1 and SP3 are essential for the normal expression of ARHGEF2 and contribute to the migratory behavior of pancreatic cancer cells. Furthermore, enforced expression of ARHGEF2 rescues loss of SP3 driven invasion-migration and anchorage-independent growth defective phenotypes through restored activation of RHOA. Collectively, our results identify a transcription factor program required for RAS transformation and provide mechanistic insight into the highly metastatic behavior of pancreatic cancer.


Connectome spectral analysis to track EEG task dynamics on a subsecond scale.
We present an approach for tracking fast spatiotemporal cortical dynamics in which we combine white matter connectivity data with source-projected electroencephalographic (EEG) data. We employ the mathematical framework of graph signal processing in order to derive the Fourier modes of the brain structural connectivity graph, or "network harmonics". These network harmonics are naturally ordered by smoothness. Smoothness in this context can be understood as the amount of variation along the cortex, leading to a multi-scale representation of brain connectivity. We demonstrate that network harmonics provide a sparse representation of the EEG signal, where, at certain times, the smoothest 15 network harmonics capture 90% of the signal power. This suggests that network harmonics are functionally meaningful, which we demonstrate by using them as a basis for the functional EEG data recorded from a face detection task. There, only 13 network harmonics are sufficient to track the large-scale cortical activity during the processing of the stimuli with a 50 ms resolution, reproducing well-known activity in the fusiform face area as well as revealing co-activation patterns in somatosensory/motor and frontal cortices that an unconstrained ROI-by-ROI analysis fails to capture. The proposed approach is simple and fast, provides a means of integration of multimodal datasets, and is tied to a theoretical framework in mathematics and physics. Thus, network harmonics point towards promising research directions both theoretically - for example in exploring the relationship between structure and function in the brain - and practically - for example for network tracking in different tasks and groups of individuals, such as patients.


Comparative biology of aging.
Virtually, all research on basic mechanisms of aging has used species that are short lived and thus demonstrably unsuccessful at combating basic aging processes. A novel comparative approach would use a diversity of populations and species, focusing on those with particularly long, healthy lives, seeking the causative mechanisms that distinguish them from shorter lived relatives. Species of interest from this perspective include the naked mole rat, a mouse-size rodent that lives up to 30 years in the laboratory, and the little brown bat, which lives up to 34 years in the wild. Comparisons among dogs of different sizes, which differ by more than 50% in health span might also prove rewarding, as might novel species chosen because of their similarity to humans in certain key traits. Primates, because of their sophisticated cognitive ability, are a group of special value, and small, short-lived primates like the common marmoset might prove especially beneficial. Cell repositories and tissue banks from key species, as well as genomic and analytic tools optimized for comparative studies, would make valuable contributions to a new comparative approach to basic aging research.


Current issues and problems in welding science.
Losses of life and property due to catastrophic failure of structures are often traced to defective welds. However, major advances have taken place in welding science and technology in the last few decades. With the development of new methodologies at the crossroad of basic and applied sciences, the promise of science-based tailoring of composition, structure, and properties of the weldments may be fulfilled. This will require resolution of several contemporary issues and problems concerning the structure and properties of the weldments as well as intelligent control and automation of the welding processes.


The cooperation of FGF receptor and Klotho is involved in excretory canal development and regulation of metabolic homeostasis in Caenorhabditis elegans.
FGFs have traditionally been associated with cell proliferation, morphogenesis, and development; yet, a subfamily of FGFs (FGF19, -21, and -23) functions as hormones to regulate glucose, lipid, phosphate, and vitamin D metabolism with impact on energy balance and aging. In mammals, Klotho and beta-Klotho are type 1 transmembrane proteins that function as obligatory co-factors for endocrine FGFs to bind to their cognate FGF receptors (FGFRs). Mutations in Klotho/beta-Klotho or fgf19, -21, or -23 are associated with a number of human diseases, including autosomal dominant hypophosphatemic rickets, premature aging disorders, and diabetes. The Caenorhabditis elegans genome contains two paralogues of Klotho/beta-Klotho, klo-1, and klo-2. klo-1 is expressed in the C. elegans excretory canal, which is structurally and functionally paralogous to the vertebrate kidney. KLO-1 associates with EGL-15/FGFR, suggesting a role for KLO-1 in the fluid homeostasis phenotype described previously for egl-15/fgfr mutants. Altered levels of EGL-15/FGFR signaling lead to defects in excretory canal development and function in C. elegans. These results suggest an evolutionarily conserved function for the FGFR-Klotho complex in the development of excretory organs such as the mammalian kidney and the worm excretory canal. These results also suggest an evolutionarily conserved function for the FGFR-Klotho axis in metabolic regulation.


Therapeutic Effect of Supercritical CO2 Extracts of Curcuma Species with Cancer Drugs in Rhabdomyosarcoma Cell Lines.
Synergistic effect of supercritical CO2 extracts of Curcuma species with conventional chemotherapeutic drugs was investigated in human alveolar (SJRH30) and embryonal (RD) rhabdomyosarcoma cell lines. The Curcuma amada (mango ginger) (CA) extract showed the highest levels of cytotoxicity with inhibitory concentration IC50 values of 7.133 µg/ml and 7.501 µg/ml for SJRH30 and RD cell lines, respectively, as compared with Curcuma longa (turmeric) and Curcuma xanthorrhiza (Javanese turmeric) extracts. CA showed synergistic cytotoxic effects with vinblastine (VBL) and cyclophosphamide (CP) as indicated by the combination index values of <1 for VBL + CA, CP + CA, and VBL + CP + CA combinations in both embryonal and alveolar rhabdomyosarcomas. When lower doses of CA (0.1-0.2 µg/ml) were combined with cancer drugs like CP and VBL, caspase-3 activity increased significantly compared with individual agents and correlated with the percentage of apoptotic cells. CA in combination with VBL and CP induced a higher percentage of apoptosis than single agents in both cell lines. CA also modulated the expression of genes associated with intrinsic pathway of apoptosis (Bcl-2, Bax, Bak, and p53) and also inhibited the expression of genes associated with inflammation such as COX-2 and NF-κB. Xenograft studies with SJRH30 tumors in nude mice showed that CA treatment inhibited tumor growth rate with and without VBL and increased the survival rate significantly. These results suggest that CA can be evaluated further as an adjuvant with cancer drugs for the treatment of rhabdomyosarcoma patients. Copyright © 2015 John Wiley & Sons, Ltd.


Elevated Th1- or Th0-like cytokine mRNA in peripheral circulation of patients with rheumatoid arthritis. Modulation by treatment with anti-ICAM-1 correlates with clinical benefit.
The current studies examined whether cytokine patterns indicative of an imbalance in Th1 and Th2 cells could be identified in PBMC of patients with active rheumatoid arthritis (RA). To investigate this possibility, a reproducible PCR technique to assess cytokine mRNA levels in PBMC was employed that minimized in vitro manipulation of the cells. Seven of 14 RA patients had increased mRNA levels for IL-2, 5/14 for IFN-gamma, 3/14 for IL-4, and 4/14 for the IL-2R alpha-chain, compared with normal donors. Whereas 4 patients had elevated mRNA for IL-2 and IFN-gamma, indicative of an increase in activated Th1 or Th0 cells, 1 of 14 patients expressed low levels of IL-2 and IFN-gamma and high levels of IL-4 mRNA. Seven RA patients were treated with a mAb to ICAM-1 (CD54). To determine whether changes in cytokine mRNA levels might be associated with and/or account for the anti-inflammatory effect of anti-ICAM-1 mAb therapy, changes in cytokine mRNA levels were assessed and correlated with clinical improvement. Anti-ICAM-1 mAb administration was followed by a prompt and transient increase of IFN-gamma mRNA. Elevation of IFN-gamma mRNA expression throughout the treatment period reflected a temporary increase in the number of circulating CD3+CD4+ T cells, suggestive of altered circulatory patterns of activated Th1-like cells and was related to clinical efficacy. The results indicate that elevated cytokine mRNA levels characteristic for Th1 cells can be detected in the PBMC in active RA and, furthermore, that anti-ICAM-1 mAb may be beneficial in RA by altering the recruitment of activated Th1-like cells into the synovium. This assumption further strengthens the hypothesis of a significant contribution of Th1-like cells to the pathogenesis of RA.


Effects of water quality, sanitation, handwashing, and nutritional interventions on child development in rural Kenya (WASH Benefits Kenya): a cluster-randomised controlled trial.
Poor nutrition and infectious diseases can prevent children from reaching their developmental potential. We aimed to assess the effects of improvements in water, sanitation, handwashing, and nutrition on early child development in rural Kenya. In this cluster-randomised controlled trial, we enrolled pregnant women in their second or third trimester from three counties (Kakamega, Bungoma, and Vihiga) in Kenya's western region, with an average of 12 households per cluster. Groups of nine geographically adjacent clusters were block-randomised, using a random number generator, into the six intervention groups (including monthly visits to promote target behaviours), a passive control group (no visits), or a double-sized active control group (monthly household visits to measure child mid-upper arm circumference). The six intervention groups were: chlorinated drinking water; improved sanitation; handwashing with soap; combined water, sanitation, and handwashing; improved nutrition through counselling and provision of lipid-based nutrient supplements; and combined water, sanitation, handwashing, and nutrition. Here we report on the prespecified secondary child development outcomes: gross motor milestone achievement assessed with the WHO module at year 1, and communication, gross motor, personal social, and combined scores measured by the Extended Ages and Stages Questionnaire (EASQ) at year 2. Masking of participants was not possible, but data assessors were masked. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01704105. Between Nov 27, 2012, and May 21, 2014, 8246 women residing in 702 clusters were enrolled. No clusters were lost to follow-up, but 2212 households with 2279 children were lost to follow-up by year 2. 5791 (69%) children were measured at year 1 and 6107 (73%) at year 2. At year 1, compared with the active control group, the combined water, sanitation, handwashing, and nutrition group had greater rates of attaining the standing with assistance milestone (hazard ratio 1·23, 95% CI 1·09-1·40) and the walking with assistance milestone (1·32, 1·17-1·50), and the handwashing group had a greater rate of attaining the standing alone milestone (1·15, 1·01-1·31). There were no differences when comparing the other intervention groups with the active control group on any of the motor milestone measures at year 1. At year 2, there were no differences among groups for the communication, gross motor, personal social, or combined EASQ scores. The handwashing and combined water, sanitation, handwashing, and nutrition interventions might have improved child motor development after 1 year, although after 2 years there were no other differences between groups. Future research should examine ways to make community health and nutrition programmes more effective at supporting child development. Bill & Melinda Gates Foundation.


Essential role of ER-alpha-dependent NO production in resveratrol-mediated inhibition of restenosis.
Resveratrol (Resv), a red wine polyphenol, is known to exhibit vascular protective effects and reduce vascular smooth muscle cell mitogenesis. Vascular smooth muscle cell proliferation is a critical factor in the pathogenesis of restenosis, the renarrowing of vessels that often occurs after angioplasty and/or stent implantation. Although Resv has been shown to be an estrogen receptor (ER) modulator, the role of the ER in Resv-mediated protection against restenosis has not yet been elucidated in vivo. Therefore, with the use of a mouse carotid artery injury model, our objective was to determine the role of ER in modulating Resv-mediated effects on neointimal hyperplasia. Female wild-type and ER-α(-/-) mice were administered a high-fat diet ± Resv for 2 wk. A carotid artery endothelial denudation procedure was conducted, and the mice were administered a high-fat diet ± Resv for an additional 2 wk. Resv-treated wild-type mice exhibited a dramatic decrease in restenosis, with an increased arterial nitric oxide (NO) synthase (NOS) activity and NO production. However, in the ER-α(-/-) mice, Resv failed to afford protection and failed to increase NO production, apparently because of a decreased availability of the NOS cofactor tetrahydrobiopterin. To verify the role of NO in Resv-mediated effects, mice were coadministered Resv plus a nonselective NOS inhibitor, N(G)-nitro-l-arginine methyl ester (l-NAME). Cotreatment with l-NAME significantly attenuated the antirestenotic properties of Resv. These data thus suggest that Resv inhibits vascular proliferative responses after injury, predominately through an ER-α-dependent increase in NO production.


Differences in Antibiotic Resistance of MRSA Infections in Patients with Various Types of Otitis Media.
We investigated the epidemiological and antibiotic resistance differences in methicillin-resistant Staphylococcus aureus (MRSA) infections in patients with otitis media with effusion (OME), acute otitis media (AOM), chronic suppurative otitis media (CSOM), and chronic cholesteatomatous otitis media (CCOM). We conducted a retrospective study of patients with newly identified MRSA infections from January 2009 through January 2017. Overall, 3,522 patients from 10 tertiary referral hospitals were included in the study. An antibiotic sensitivity test was performed for each isolate. MRSA infections in patients with CSOM and CCOM were more resistant to ciprofloxacin, clindamycin, erythromycin, gentamicin, levofloxacin, and tetracycline. Patients showed good susceptibility to rifampicin, trimethoprim/sulfamethoxazole (TMP/SMX), and vancomycin. MRSA infections in various otitis media cases showed different resistance patterns. MRSA infections in patients with COM and CCOM were more resistant to antibiotics than those in patients with OME and AOM.


Prospective analysis of long-term psychosocial outcomes in breast reconstruction: two-year postoperative results from the Michigan Breast Reconstruction Outcomes Study.
To prospectively evaluate the psychosocial outcomes and body image of patients 2 years postmastectomy reconstruction using a multicenter, multisurgeon approach. Although breast reconstruction has been shown to confer significant psychosocial benefits in breast cancer patients at year 1 postreconstruction, we considered the possibility that psychosocial outcomes may remain in a state of flux for years after surgery. Patients were recruited as part of the Michigan Breast Reconstruction Outcome Study, a 12 center, 23 surgeon prospective cohort study of mastectomy reconstruction patients. Two-sided paired sample t tests were used to compare change scores for the various psychosocial subscales. Multiple regression analysis was used to determine whether the magnitude of the change score varied by procedure type. Preoperative and postoperative year 2 surveys were received from 173 patients; 116 with immediate and 57 with delayed reconstruction. For the immediate reconstruction cohort, significant improvements were observed in all psychosocial subscales except for body image. This occurred essentially independent of procedure type. In the cohort with delayed reconstruction, significant change scores were observed only in body image. Women with transverse rectus abdominis musculocutaneous flaps had significantly greater gains in body image scores (P = 0.003 and P = 0.034, respectively) when compared with expander/implants. General psychosocial benefits and body image gains continued to manifest at 2 years postmastectomy reconstruction. In addition, procedure type had a surprisingly limited effect on psychosocial well being. With outcomes evolving beyond year 1, these data support the need for additional longitudinal breast reconstruction outcome studies.