Diversifying sport-related concussion measures with baseline balance and ocular-motor scores in professional Zambian football athletes.
Normative values of common sport-related concussion assessment tools may assist clinical diagnosis and management. However, current baseline normative values are not representative of athletic participants across international domains. This study develops healthy baseline norms on the Balance Error Scoring System (BESS), and King-Devick (K-D), providing baseline reference values for professional Zambian football athletes. Of the 125 male participants (aged 24.48 ± 5.41 years) screened for this study, 9 (7.2%) reported a previous history of concussion, 98 (78.4%) completed the Balance Error Scoring System and 88 (70.4%) completed the King-Devick. Descriptive statistics calculated for the BESS and the K-D test included mean, standard deviation, median, interquartile range (IQR), and percentiles ranks. Participants scored a mean ± standard deviation of 10.15 ± 5.6 and a median [IQR] of 9 [6-12.25] errors on the total BESS and completed the K-D test in a mean ± standard deviation 56.85 ± 10.55 seconds and a median [IQR] 55.28 [48.7-64.8] seconds. Cross-cultural awareness and management of sport-related concussion are continuously improving the safety and well-being of athletic participants around the world. The diverse representation in these data may aid in interpretation of post-injury performance during sport-related concussion management in Zambia. This study develops baseline reference values currently lacking within African cultures and demonstrates the feasibility and global clinical utility of two sport-related concussion assessment resources.


Mediators of the Effects of Canagliflozin on Heart Failure in Patients With Type 2 Diabetes.
The purpose of this study was to explore potential mediators of the effects of canagliflozin on heart failure in the CANVAS Program (CANagliflozin cardioVascular Assessment Study; NCT01032629 and CANagliflozin cardioVascular Assessment Study-Renal; NCT01989754). Canagliflozin reduced the risk of heart failure among patients with type 2 diabetes in the CANVAS Program. The mechanism of protection is uncertain. The percentages of mediating effects of 19 biomarkers were determined by comparing the hazard ratios for the effect of randomized treatment from an unadjusted model and from a model adjusting for the biomarker of interest. Multivariable analyses were used to assess the joint effects of biomarkers that mediated most strongly in univariable analyses. Early changes after randomization in levels of 3 biomarkers (urinary albumin:creatinine ratio, serum bicarbonate, and serum urate) were identified as mediating the effect of canagliflozin on heart failure. Average post-randomization levels of 14 biomarkers (systolic blood pressure, low-density lipoprotein and high-density lipoprotein cholesterol, total cholesterol, urinary albumin:creatinine ratio, weight, body mass index, gamma glutamyltransferase, hematocrit, hemoglobin concentration, serum albumin, erythrocyte concentration, serum bicarbonate, and serum urate) were identified as significant mediators. Individually, the 3 biomarkers with the largest mediating effect were erythrocyte concentration (45%), hemoglobin concentration (43%), and serum urate (40%). In a parsimonious multivariable model, erythrocyte concentration, serum urate, and urinary albumin:creatinine ratio were the 3 biomarkers that maximized cumulative mediation (102%). A diverse set of potential mediators of the effect of canagliflozin on heart failure were identified. Some mediating effects were anticipated, whereas others were not. The mediators that were identified support existing and novel hypothesized mechanisms for the prevention of heart failure with sodium glucose cotransporter 2 inhibitors.


Transcriptome analyses of inhibitor-treated schistosome females provide evidence for cooperating Src-kinase and TGFβ receptor pathways controlling mitosis and eggshell formation.
Schistosome parasites cause schistosomiasis, one of the most prevalent parasitemias worldwide affecting humans and animals. Constant pairing of schistosomes is essential for female sexual maturation and egg production, which causes pathogenesis. Female maturation involves signaling pathways controlling mitosis and differentiation within the gonads. In vitro studies had shown before that a Src-specific inhibitor, Herbimycin A (Herb A), and a TGFβ receptor (TβR) inhibitor (TRIKI) have physiological effects such as suppressed mitoses and egg production in paired females. As one Herb A target, the gonad-specifically expressed Src kinase SmTK3 was identified. Here, we comparatively analyzed the transcriptome profiles of Herb A- and TRIKI-treated females identifying transcriptional targets of Src-kinase and TβRI pathways. After demonstrating that TRIKI inhibits the schistosome TGFβreceptor SmTβRI by kinase assays in Xenopus oocytes, couples were treated with Herb A, TRIKI, or both inhibitors simultaneously in vitro. RNA was isolated from females for microarray hybridizations and transcription analyses. The obtained data were evaluated by Gene Ontology (GO) and Ingenuity Pathway Analysis (IPA), but also by manual classification and intersection analyses. Finally, extensive qPCR experiments were done to verify differential transcription of candidate genes under inhibitor influence but also to functionally reinforce specific physiological effects. A number of genes found to be differentially regulated are associated with mitosis and differentiation. Among these were calcium-associated genes and eggshell-forming genes. In situ hybridization confirmed transcription of genes coding for the calcium sensor hippocalcin, the calcium transporter ORAI-1, and the calcium-binding protein calmodulin-4 in the reproductive system pointing to a role of calcium in parasite reproduction. Functional qPCR results confirmed an inhibitor-influenced, varying dependence of the transcriptional activities of Smp14, Smp48, fs800, a predicted eggshell precursor protein and SmTYR1. The results show that eggshell-formation is regulated by at least two pathways cooperatively operating in a balanced manner to control egg production.


A phase 1 and randomized, placebo-controlled phase 2 trial of bevacizumab plus dasatinib in patients with recurrent glioblastoma: Alliance/North Central Cancer Treatment Group N0872.
Src signaling is markedly upregulated in patients with invasive glioblastoma (GBM) after the administration of bevacizumab. The Src family kinase inhibitor dasatinib has been found to effectively block bevacizumab-induced glioma invasion in preclinical models, which led to the hypothesis that combining bevacizumab with dasatinib could increase bevacizumab efficacy in patients with recurrent GBM. After the completion of the phase 1 component, the phase 2 trial (ClinicalTrials.gov identifier NCT00892177) randomized patients with recurrent GBM 2:1 to receive 100 mg of oral dasatinib twice daily (arm A) or placebo (arm B) on days 1 to 14 of each 14-day cycle combined with 10 mg/kg of intravenous bevacizumab on day 1 of each 14-day cycle. The primary endpoint was 6-month progression-free survival (PFS6). In the 121 evaluable patients, the PFS6 rate was numerically, but not statistically, higher in arm A versus arm B (28.9% [95% CI, 19.5%-40.0%] vs 18.4% [95% CI, 7.7%-34.4%]; P = .22). Similarly, there was no significant difference in the median overall survival noted between the treatment arms (7.3 months and 7.7 months, respectively; P = .93). The objective response rate was 15.7% in arm A and 26.3% in arm B (P = .52), but with a significantly longer duration in patients treated on arm A (16.3 months vs 2 months). The incidence of grade ≥3 toxicity was comparable between treatment arms, with hematologic toxicities occurring more frequently in arm A versus arm B (15.7% vs 7.9%) (adverse events were assessed as per the National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.0]). Correlative tissue analysis demonstrated an association between pSRC/LYN signaling in patient tumors and outcome. Despite upregulation of Src signaling in patients with GBM, the combination of bevacizumab with dasatinib did not appear to significantly improve the outcomes of patients with recurrent GBM compared with bevacizumab alone.


Renal effects evolution in a Chinese population after reduction of cadmium exposure in rice.
Cadmium is a well-known nephrotoxic agent with extremely long biological half-time of 10-30 years in human. To investigate the evolution of cadmium-induced renal effects in the population, a number of 148 residents who lived in cadmium-polluted area were followed-up for 3 years after the reduction of cadmium exposure in rice. Urinary cadmium (UCd), beta(2)-microglobulin (B2M) and albumin (ALB) were analyzed in 1995 and 1998, respectively. The results demonstrated that the changes of renal effects of residents depended on the levels of UCd before inflow of cadmium to human body declined. In cases where UCd were less than 10 microg/g creatinine in 1995, evidence was found indicating significant decreases in proteinuria (i.e., B2M and ALB) 3 years later, whereas, in cases where the excretion of UCd exceeded 10 microg/g creatinine in 1995, progression was observed. The study of dose-response relationships between UCd and B2M or ALB also showed that the cadmium-induced renal dysfunction might be reversible if UCd concentration was low-level before exposure decreasing, otherwise it might be irreversible or aggravated.


The influence of the framework core residues on the biophysical properties of immunoglobulin heavy chain variable domains.
Antibody variable domains differ considerably in stability. Single-chain Fv (scFv) fragments derived from natural repertoires frequently lack the high stability needed for therapeutic application, necessitating reengineering not only to humanize their sequence, but also to improve their biophysical properties. The human V(H)3 domain has been identified as having the best biophysical properties among human subtypes. However, complementarity determining region (CDR) grafts from highly divergent V(H) domains to huV(H)3 frequently fail to reach its superior stability. In previous experiments involving a CDR graft from a murine V(H)9 domain of very poor stability to huV(H)3, a hybrid V(H) framework was obtained which combines the lower core residues of muV(H)9 with the surface residues of huV(H)3. It resulted in a scFv with far better biophysical properties than the corresponding grafts to the consensus huV(H)3 framework. To better understand the origin of the superior properties of the hybrid framework, we constructed further hybrids, but now in the context of the consensus CDR-H1 and -H2 of the original human V(H)3 domain. The new hybrids included elements from either murine V(H)9, human V(H)1 or human V(H)5 domains. From guanidinium chloride-induced equilibrium denaturation measurements, kinetic denaturation experiments, measurements of heat-induced aggregation and comparison of soluble expression yield in Escherichia coli, we conclude that the optimal V(H) framework is CDR-dependent. The present work pinpoints structural features responsible for this dependency and helps to explain why the immune system uses more than one framework with different structural subtypes in framework 1 to optimally support widely different CDRs.


Differential receipt of sentinel lymph node biopsy within practice-based research networks.
Practice-based research networks (PBRNs) are promising for accelerating not only research, but also dissemination of research-based evidence into broader community practice. Sentinel lymph node biopsy (SLNB) is an innovation in breast cancer care associated with equivalent survival and lower morbidity, as compared with standard axillary lymph node dissection. We examined the diffusion of SLNB into practice and whether affiliation with the Community Clinical Oncology Program (CCOP), a cancer-focused PBRN, was associated with more rapid uptake of SLNB. Surveillance Epidemiology and End Results-Medicare data were used to study women diagnosed with stage I or II breast cancer in the years 2000-2005 and undergoing breast-conserving surgery with axillary staging (n=6226). The primary outcome was undergoing SLNB. CCOP affiliation of the surgical physician was ascertained from NCI records. Multivariable generalized linear modeling with generalized estimating equations was used to measure association between CCOP exposure and undergoing SLNB, controlling for potential confounders. Women treated by a CCOP physician had significantly higher odds of receiving SLNB compared with women treated by a non-CCOP physician (OR 2.68; 95% CI, 1.35-5.34). The magnitude of this association was larger than that observed among patients treated by physicians operating in medical school-affiliated hospitals (OR 1.76; 95% CI, 1.30-2.39). Women treated by CCOP-affiliated physicians were more likely to undergo SLNB irrespective of the hospital's medical school affiliation, suggesting that the CCOP PBRN may play a role in the rapid adoption of research-based innovation in community practice.


Rapid Analysis of Diagnostic and Antimicrobial Patterns in R (RadaR): Interactive Open-Source Software App for Infection Management and Antimicrobial Stewardship.
Analyzing process and outcome measures for all patients diagnosed with an infection in a hospital, including those suspected of having an infection, requires not only processing of large datasets but also accounting for numerous patient parameters and guidelines. Substantial technical expertise is required to conduct such rapid, reproducible, and adaptable analyses; however, such analyses can yield valuable insights for infection management and antimicrobial stewardship (AMS) teams. The aim of this study was to present the design, development, and testing of RadaR (Rapid analysis of diagnostic and antimicrobial patterns in R), a software app for infection management, and to ascertain whether RadaR can facilitate user-friendly, intuitive, and interactive analyses of large datasets in the absence of prior in-depth software or programming knowledge. RadaR was built in the open-source programming language R, using Shiny, an additional package to implement Web-app frameworks in R. It was developed in the context of a 1339-bed academic tertiary referral hospital to handle data of more than 180,000 admissions. RadaR enabled visualization of analytical graphs and statistical summaries in a rapid and interactive manner. It allowed users to filter patient groups by 17 different criteria and investigate antimicrobial use, microbiological diagnostic use and results including antimicrobial resistance, and outcome in length of stay. Furthermore, with RadaR, results can be stratified and grouped to compare defined patient groups on the basis of individual patient features. AMS teams can use RadaR to identify areas within their institutions that might benefit from increased support and targeted interventions. It can be used for the assessment of diagnostic and therapeutic procedures and for visualizing and communicating analyses. RadaR demonstrated the feasibility of developing software tools for use in infection management and for AMS teams in an open-source approach, thus making it free to use and adaptable to different settings.


Geography of primary mental health care through the Better Access initiative in South Australia 2006-2010.
To examine how the rates of the use of particular face-to-face primary mental health care services changed in the first 4 years (2006-2010) of the Better Access initiative in both urban and rural regions of South Australia. Time-series analysis of the number of psychology session, psychiatry assessment and general practitioner care plan services recorded in Medicare Australia data. South Australia. Pre-existing data set of South Australian residents who accessed Medicare between 2006 and 2010 MAIN OBJECTIVE MEASURE: Number of services per 100 000 population (service rate). Psychology session service rates increased in all regions, but continued to follow a 'location gradient', being higher in areas closer to Adelaide and lower in areas more distant from Adelaide. Psychiatry assessment service rates increased in Adelaide but did not change in other regions. Rates in remote areas were subject to substantial variation over time. General practitioner care plan service rates increased in Adelaide and in the Riverland, but declined in the Murray Mallee region. Overall, service rates increased in Adelaide and nearby regions, but the results for rural and remote regions were mixed. Possible explanations for the geographical variability include population characteristics (such as socio-economic status), methods of service delivery (visiting practitioners, telepsych), the relative proportion of total health services provided by general practitioners versus other practitioners, or real variations in the need for primary mental health services.


Protective effect of curcumin against liver warm ischemia/reperfusion injury in rat model is associated with regulation of heat shock protein and antioxidant enzymes.
To investigate the hypothesis that the protective effects of curcumin in hepatic warm ischemia/reperfusion (I/R) injury are associated with increasing heat shock protein 70 (Hsp70) expression and antioxidant enzyme activity. Sixty Sprague-Dawley male rats were randomly divided into sham, I/R, C + I/R groups. The model of reduced-size liver warm ischemia and reperfusion was used. Curcumin (50 mg/kg) was administered by injection through a branch of superior mesenteric vein at 30 min before ischemia in C + I/R group. Five rats were used to investigate the survival during 1 wk after operation in each group. Blood samples and liver tissues were obtained in the remaining animals after 3, 12, and 24 h of reperfusion to assess serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), liver tissue NO(2)(-) + NO(3)(-), malondialdehyde (MDA) content, superoxide dismutase (SOD), catalase (CAT), nitricoxide synthase (NOS) and myeloperoxidase (MPO) activity, Hsp70 expression and apoptosis ratio. Compared with I/R group, curcumin pretreatment group showed less ischemia/reperfusion-induced injury. CAT and SOD activity and Hsp70 expression increased significantly. A higher rate of apoptosis was observed in I/R group than in C + I/R group, and a significant increase of MDA, NO(2)(-) + NO(3)(-) and MPO level in liver tissues and serum transaminase concentration was also observed in I/R group compared to C + I/R group. Curcumin also decreased the activity of inducible NO synthase (iNOS) in liver after reperfusion, but had no effect on the level of endothelial NO synthase (eNOS) after reperfusion in liver. The 7 d survival rate was significantly higher in C + I/R group than in I/R group. Curcumin has protective effects against hepatic I/R injury. Its mechanism might be related to the overexpression of Hsp70 and antioxidant enzymes.


Enhancing Carrier Mobilities in Organic Thin-Film Transistors Through Morphological Changes at the Semiconductor/Dielectric Interface Using Supercritical Carbon Dioxide Processing.
Charge-carrier mobilities in poly(3-hexylthiophene) (P3HT) organic thin-film transistors (OTFTs) increase 5-fold when OTFTs composed of P3HT films on trichloro (1H, 1H, 2H, 2H-perfluorooctyl) silane (FTS) monolayers supported on SiO2 dielectric substrates (P3HT/FTS/SiO2/Si) are subjected to supercritical carbon dioxide (scCO2) processing. In contrast, carrier mobilities in P3HT/octadecyltrichlorosilane (OTS)/SiO2 OTFTs processed using scCO2 are comparable to mobilities measured in as-cast P3HT/OTS/SiO2/Si devices. Topographical images of the free and buried interfaces of P3HT films reveal that scCO2 selectively alters the P3HT morphology near the buried P3HT/FTS-SiO2 interface; identical processing has negligible effects at the P3HT/OTS-SiO2 interface. A combination of spectroscopic ellipsometry and grazing-incidence X-ray diffraction experiments indicate insignificant change in the orientation distribution of the intermolecular π-π stacking direction of P3HT/FTS with scCO2 processing. The improved mobilities are instead correlated with enhanced in-plane orientation of the conjugated chain backbone of P3HT after scCO2 annealing. These findings suggest a strong dependence of polymer processing on the nature of polymer/substrate interface and the important role of backbone orientation toward dictating charge transport of OTFTs.


Kinetic, stability, and structural changes in high-resolution crystal structures of HIV-1 protease with drug-resistant mutations L24I, I50V, and G73S.
The crystal structures, dimer stabilities, and kinetics have been analyzed for wild-type human immunodeficiency virus type 1 (HIV-1) protease (PR) and resistant mutants PR(L24I), PR(I50V), and PR(G73S) to gain insight into the molecular basis of drug resistance. The mutations lie in different structural regions. Mutation I50V alters a residue in the flexible flap that interacts with the inhibitor, L24I alters a residue adjacent to the catalytic Asp25, and G73S lies at the protein surface far from the inhibitor-binding site. PR(L24I) and PR(I50V), showed a 4% and 18% lower k(cat)/K(m), respectively, relative to PR. The relative k(cat)/K(m) of PR(G73S) varied from 14% to 400% when assayed using different substrates. Inhibition constants (K(i)) of the antiviral drug indinavir for the reaction catalyzed by the mutant enzymes were about threefold and 50-fold higher for PR(L24I) and PR(I50V), respectively, relative to PR and PR(G73S). The dimer dissociation constant (K(d)) was estimated to be approximately 20 nM for both PR(L24I) and PR(I50V), and below 5 nM for PR(G73S) and PR. Crystal structures of the mutants PR(L24I), PR(I50V) and PR(G73S) were determined in complexes with indinavir, or the p2/NC substrate analog at resolutions of 1.10-1.50 Angstrom. Each mutant revealed distinct structural changes relative to PR. The mutated residues in PR(L24I) and PR(I50V) had reduced intersubunit contacts, consistent with the increased K(d) for dimer dissociation. Relative to PR, PR(I50V) had fewer interactions of Val50 with inhibitors, in agreement with the dramatically increased K(i). The distal mutation G73S introduced new hydrogen bond interactions that can transmit changes to the substrate-binding site and alter catalytic activity. Therefore, the structural alterations observed for drug-resistant mutations were in agreement with kinetic and stability changes.


Experimental parameterisation of principal physics in buoyancy variations of marine teleost eggs.
It is generally accepted that the high buoyancy of pelagic marine eggs is due to substantial influx of water across the cell membrane just before ovulation. Here we further develop the theoretical basis by applying laboratory observations of the various components of the fertilized egg in first-principle equations for egg specific gravity (ρ(egg)) followed by statistical validation. We selected Atlantic cod as a model animal due to the affluent amount of literature on this species, but also undertook additional dedicated experimental works. We found that specific gravity of yolk plus embryo is central in influencing ρ(egg) and thereby the buoyancy. However, our established framework documents the effect on ρ(egg) of the initial deposition of the heavy chorion material in the gonad prior to spawning. Thereafter, we describe the temporal changes in ρ(egg) during incubation: Generally, the eggs showed a slight rise in ρ(egg) from fertilization to mid-gastrulation followed by a gradual decrease until full development of main embryonic organs just before hatching. Ontogenetic changes in ρ(egg) were significantly associated with volume and mass changes of yolk plus embryo. The initial ρ(egg) at fertilization appeared significantly influenced by the chorion volume fraction which is determined by the combination of the final chorion volume of the oocyte and of the degree of swelling (hydrolyzation) prior to spawning. The outlined principles and algorithms are universal in nature and should therefore be applicable to fish eggs in general.


Relationship of body mass index with periodontal health status of green marble mine laborers in Kesariyaji, India.
It is evident from literature that an increased body mass index (BMI) may be a potential risk factor for periodontitis. Association between BMI and periodontitis has been ascribed to unhealthy dietary patterns with insufficient micronutrients and excess sugar and fat content. The present study population has been plagued by unhealthy nutritional practices, hence the present study intended to assess the relation between BMI and periodontal status among green marble mine laborers of Kesariyaji, in the Udaipur district of Rajasthan, India. The study sample comprised of 513 subjects aged 18-54 years, drawn using the stratified cluster sampling procedure. BMI was calculated as the ratio of the subject's body weight (in kg) to the square of their height (in meters). Periodontal status was recorded using the Community Periodontal Index (CPI). Binary multiple logistic regression analysis was executed to assess the relation between body mass index and periodontitis. The dependent variable for logistic regression analysis was categorized into control group (scores 0 - 2 of the CPI) and periodontitis group (scores 3 and 4 of the CPI). The overall prevalence of periodontal disease was 98.2%. Caries status and mean number of teeth present deteriorated with the poor periodontal status. Subjects had an increased risk of periodontitis by 57% for each 1kg/m(2) increase in the body mass index, which means that a higher body mass index could be a potential risk factor for periodontitis among the adults aged 18 to 54 years. In conclusion, evaluation of the body mass index could be used in periodontal risk assessment.


The Long-Term Impact of Renin-Angiotensin System (RAS) Inhibition on Cardiorenal Outcomes (LIRICO): A Randomized, Controlled Trial.
The comparative effectiveness of treatment with angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or their combination in people with albuminuria and cardiovascular risk factors is unclear. In a multicenter, randomized, open label, blinded end point trial, we evaluated the effectiveness on cardiovascular events of ACE or ARB monotherapy or combination therapy, targeting BP<130/80 in patients with moderate or severe albuminuria and diabetes or other cardiovascular risk factors. End points included a primary composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, and hospitalization for cardiovascular causes and a revised end point of all-cause mortality. Additional end points included ESRD, doubling of serum creatinine, albuminuria, eGFR, BP, and adverse events. Because of slow enrollment, the trial was modified and stopped 41% short of targeted enrollment of 2100 participants, corresponding to 35% power to detect a 25% reduced risk in the primary outcome. Our analysis included 1243 adults, with median follow-up of 2.7 years. Efficacy outcomes were similar between groups (ACE inhibitor versus ARB, ACE inhibitor versus combination, ARB versus combination) as were rates of serious adverse events. The rate of permanent discontinuation for ARB monotherapy (6.3%) was significantly lower than for ACE inhibitor monotherapy (15.7%) or combined therapy (18.3%). Patients may tolerate ARB monotherapy better than ACE inhibitor monotherapy. However, data from this trial and similar trials, although as yet inconclusive, show no trend suggesting differences in mortality and renal outcomes with ACE inhibitors or ARBs as dual or monotherapy in patients with albuminuria and diabetes or other cardiovascular risk factors.


WNT signaling inducing activity in ascites predicts poor outcome in ovarian cancer.
High grade serous carcinoma of the ovary, fallopian tube, and peritoneum (HGSC) is the deadliest gynecological disease which results in a five-year survival rate of 30% or less. HGSC is characterized by the early and rapid development of metastases accompanied by a high frequency of ascites i.e. the pathological accumulation of fluid in peritoneum. Ascites constitute a complex tumor microenvironment and contribute to disease progression by largely unknown mechanisms. Methods: Malignant ascites obtained from HGSC patients who had undergone cytoreductive surgery were tested for their ability to induce WNT signaling in the Kuramochi cell line, a novel and clinically relevant in vitro model of HGSC. Next, cancer spheroids (the main form of metastatic cancer cells in ascites) were evaluated with respect to WNT signaling. Kuramochi cells were used to determine the role of individual WNT signaling branches in the adoption of metastatic stem cell-like behavior by HGSC cells. Furthermore, we analyzed genomic and transcriptomic data on WNT/Planar Cell Polarity (PCP) components retrieved from public cancer databases and corroborated with primary patient samples and validated antibodies on the protein level. Results: We have shown that ascites are capable of inducing WNT signaling in primary HGSC cells and HGSC cell line, Kuramochi. Importantly, patients whose ascites cannot activate WNT pathway present with less aggressive disease and a considerably better outcome including overall survival (OS). Functionally, the activation of non-canonical WNT/PCP signaling by WNT5A (and not canonical WNT/β-catenin signaling by WNT3A) promoted the metastatic stem-cell (metSC) like behavior (i.e. self-renewal, migration, and invasion) of HGSC cells. The pharmacological inhibition of casein kinase 1 (CK1) as well as genetic ablation (dishevelled 3 knock out) of the pathway blocked the WNT5A-induced effect. Additionally, WNT/PCP pathway components were differentially expressed between healthy and tumor tissue as well as between the primary tumor and metastases. Additionally, ascites which activated WNT/PCP signaling contained the typical WNT/PCP ligand WNT5A and interestingly, patients with high levels of WNT5A protein in their ascites exhibited poor progression-free survival (PFS) and OS in comparison to patients with low or undetectable ascitic WNT5A. Together, our results suggest the existence of a positive feedback loop between tumor cells producing WNT ligands and ascites that distribute WNT activity to cancer cells in the peritoneum, in order to promote their pro-metastatic features and drive HGSC progression. Conclusions: Our results highlight the role of WNT/PCP signaling in ovarian cancerogenesis, indicate a possible therapeutic potential of CK1 inhibitors for HGSC, and strongly suggest that the detection of WNT pathway inducing activity ascites (or WNT5A levels in ascites as a surrogate marker) could be a novel prognostic tool for HGSC patients.


[The treatment of Parkinson's disease].
Parkinson's disease belongs to the most prevalent neurodegenerative disorders and manifests both with motor and non-motor symptoms. Symptomatic treatment of this disorder became more multifaceted over the past years: besides classical dopaminergic drugs and physiotherapy, novel invasive escalation treatment strategies became gold standard in many countries. On the other hand, non-motor symptoms significantly impacts quality of life in many patients which necessitates initiation of adequate therapy.


Sperm characteristics in a sample of healthy adolescents in São Paulo, Brazil.
The article presents preliminary data from a prospective investigation in a sample of healthy 14-17-year-old students from a technical school in Sao Paulo, Brazil. Ninety-six Tanner stage 5 and thirty-one Tanner stage 4 adolescents were evaluated: testicular volume was measured using a Prader orchidometer, and semen analysis was performed according to standard procedures. Median testicular volume was 20.0 ml among Tanner 5 students and 15.0 ml in Tanner 4 students in both the right and left testes. No significant differences were found in sperm volume or motility. Median concentration was 66.0 million/ml for Tanner 5 and 47.0 million/ml for Tanner 4 subjects. Morphological patterns showed abnormal forms in 81.9% of Tanner 5 and 93.6% of Tanner 4 adolescents. Oligospermia (sperm concentration < 5 million/ml) was observed in 7.3% of Tanner stage 5 and 12.9% of Tanner stage 4 individuals. Azoospermia was observed in 3 students (1.8%), with counts less than 1.0 in 8 students (4.8%). The authors discuss the observed results, analyzing the potential implications arising from biological development and potential environmental exposures.


Achieving efficient photodynamic therapy under both normoxia and hypoxia using cyclometalated Ru(ii) photosensitizer through type I photochemical process.
Photodynamic therapy (PDT) through the generation of singlet oxygen utilizing photosensitizers (PSs) is significantly limited under hypoxic conditions in solid tumors. So it is meaningful to develop effective PSs which can maintain excellent therapeutic effects under hypoxia. Here we reported a coumarin-modified cyclometalated Ru(ii) photosensitizer (Ru2), which exhibits lower oxidation potential and stronger absorption in the visible region than the coumarin-free counterpart. The evaluation of the PDT effect was performed under both normoxia and hypoxia. The results showed that Ru2 has a better therapeutic effect than the coumarin-free counterpart in in vitro experiments. Especially under hypoxia, Ru2 still retained an excellent PDT effect, which can be attributed to the direct charge transfer between the excited PS and an adjacent substrate through a type I photochemical process, forming highly-oxidative hydroxyl radicals to damage tumor cells. The anti-tumor activity of Ru2 was further proven to be effective in tumor-bearing mice, and tumor growth was inhibited remarkably under PDT treatment.


Creativity: an organizational schema.
To describe an organizational schema of human creativity. Previous research has concluded that creativity involves something novel and useful, but whether creativity is common or rare, domain-specific or domain-general, quantitative or qualitative, or personal or social remains unresolved. Extant research from neurobiology, psychology, cognitive science, and neuroeconomics was used to generate a novel synthesis that explains human creative behavior. Creativity is the attempt to bridge the gap between what is and what should be. It emerges from the interplay of 5 commonly shared factors: motivation, perception, action, temperament, and social interaction. The reward value of what exists compared with an imagined possibility generates the motivational voltage that drives the creative effort. Action to attain the goal requires a dexterously executed plan, and dexterity levels are influenced by both practice effects and biologic biases. Temperament sustains the creative effort during periods of nonreward in anticipation of goal completion. Societal esthetics measure the success of creative efforts. Personal skill sets derived from nature and nurture vary between individuals and determine one's own creative phenotype. Despite great qualitative and quantitative differences between individuals, the neurobiologic principles of creative behavior are the same from the least to the most creative among us.


Bridging the digital divide by increasing computer and cancer literacy: community technology centers for head-start parents and families.
This article describes the establishment of two community technology centers affiliated with Head Start early childhood education programs focused especially on Latino and African American parents of children enrolled in Head Start. A 6-hour course concerned with computer and cancer literacy was presented to 120 parents and other community residents who earned a free, refurbished, Internet-ready computer after completing the program. Focus groups provided the basis for designing the structure and content of the course and modifying it during the project period. An outcomes-based assessment comparing program participants with 70 nonparticipants at baseline, immediately after the course ended, and 3 months later suggested that the program increased knowledge about computers and their use, knowledge about cancer and its prevention, and computer use including health information-seeking via the Internet. The creation of community computer technology centers requires the availability of secure space, capacity of a community partner to oversee project implementation, and resources of this partner to ensure sustainability beyond core funding.


In Vivo Three-dimensional Brain Imaging with Chemiluminescence Probes in Alzheimer's Disease Models.
Optical three-dimensional (3D) molecular imaging is highly desirable for providing precise distribution of the target-of-interest in disease models. However, such 3D imaging is still far from wide applications in biomedical research; 3D brain optical molecular imaging, in particular, has rarely been reported. In this report, we designed chemiluminescence probes with high quantum yields (QY), relatively long emission wavelengths, and high signal-to-noise ratios (SNRs) to fulfill the requirements for 3D brain imaging in vivo. With assistance from density-function theory (DFT) computation, we designed ADLumin-Xs by locking up the rotation of the double-bond via fusing the furan ring to the phenyl ring. Our results showed that ADLumin-5 had a high quantum yield of chemiluminescence and could bind to amyloid beta (Aβ). Remarkably, ADLumin-5's radiance intensity in brain areas could reach 4×107 photon/s/cm2/sr, which is probably 100-fold higher than most chemiluminescence probes for in vivo imaging. Because of its strong emission, we demonstrated that ADLumin-5 could be used for in vivo 3D brain imaging in transgenic mouse models of Alzheimer's disease (AD).


Major Histocompatibility Complex Genes Map to Two Chromosomes in an Evolutionarily Ancient Reptile, the Tuatara Sphenodon punctatus.
Major histocompatibility complex (MHC) genes are a central component of the vertebrate immune system and usually exist in a single genomic region. However, considerable differences in MHC organization and size exist between different vertebrate lineages. Reptiles occupy a key evolutionary position for understanding how variation in MHC structure evolved in vertebrates, but information on the structure of the MHC region in reptiles is limited. In this study, we investigate the organization and cytogenetic location of MHC genes in the tuatara (Sphenodon punctatus), the sole extant representative of the early-diverging reptilian order Rhynchocephalia. Sequencing and mapping of 12 clones containing class I and II MHC genes from a bacterial artificial chromosome library indicated that the core MHC region is located on chromosome 13q. However, duplication and translocation of MHC genes outside of the core region was evident, because additional class I MHC genes were located on chromosome 4p. We found a total of seven class I sequences and 11 class II β sequences, with evidence for duplication and pseudogenization of genes within the tuatara lineage. The tuatara MHC is characterized by high repeat content and low gene density compared with other species and we found no antigen processing or MHC framework genes on the MHC gene-containing clones. Our findings indicate substantial differences in MHC organization in tuatara compared with mammalian and avian MHCs and highlight the dynamic nature of the MHC. Further sequencing and annotation of tuatara and other reptile MHCs will determine if the tuatara MHC is representative of nonavian reptiles in general.


Impact of 25(OH)D3 on spontaneous reperfusion and SYNTAX score in patients with ST-elevation myocardial infarction.
The aim of this study was to evaluate the potential relationship between 25-hydroxyvitamin D3 (25[OH]D3), the Synergy between PCI with Taxus and Cardiac Surgery (SYNTAX) score, and spontaneous reperfusion (SR) in patients with ST-elevation myocardial infarction (STEMI). A total of 148 consecutive patients with acute STEMI who underwent primary percutaneous coronary intervention were retrospectively enrolled in the study. In all, 36 patients with a TIMI 3 flow score (spontaneous reperfusion [SR]) before coronary intervention constituted Group 1, and 112 patients with a TIMI flow score of 0-2 served as Group 2. The SYNTAX score and the in-hospital major adverse cardiovascular event (MACE) rate were significantly higher in Group 2 (p<0.001, p=0.012, respectively). The mean 25(OH)D3 level was significantly higher in Group 1 (p=0.003). Age, Killip class, left ventricular ejection fraction, and N-terminal pro-B-type natriuretic peptide were correlated with the SYNTAX score, and 25(OH)D3, troponin-I, C-reactive protein, and creatinine were weakly correlated with the SYNTAX score. Multilogistic regression analysis indicated that the SYNTAX score (p<0.001), Rentrop collateral (p=0.049), and troponin-I (p=0.004) were significantly effective at predicting SR, and 25(OH)D3 (p=0.079) and high-density lipoprotein (p=0.055) were borderline effective. A lower level of 25(OH)D3 may be associated with the absence of SR, increased disease severity, and inhospital MACE rates in patients with STEMI.


Ipsilateral femoral shaft and neck fractures: are cephalomedullary nails appropriate?
A retrospective review was conducted to examine rates of malreduction and nonunion in ipsilateral femoral neck and shaft fractures using different fixation strategies. Twenty-two consecutive patients with 23 fractures were identified. Participants were treated with various fixation strategies for ipsilateral femoral neck and shaft fractures. Cephalomedullary devices were used in 13 cases, while cannulated screws and a retrograde femoral nail were used in nine cases. One patient was treated with cannulated screws and external fixation of the femoral shaft. Radiographic assessment of the quality of reduction and union of both fractures was evaluated. Clinical and radiographic follow-up was available in 20 fractures (87%) with a mean of 12 months (range 3-50). Two femoral neck nonunions occurred; both had fair reductions of the fractures obtained by closed maneuvers, and two-device fixation was used in each. One femoral shaft nonunion occurred in a fracture treated with a cephalomedullary nail. All three united after revision surgery. No cases of osteonecrosis or conversion to hip arthroplasty were noted. A combination of retrograde femoral nailing and screw fixation of the femoral neck or placement of a cephalomedullary nail can provide excellent reduction and rate of union in the treatment of this injury pattern. Excellent reduction of the femoral neck fracture is key to preventing femoral neck nonunion.


The Biological Assessment and Rehabilitation of the World's Rivers: An Overview.
The biological assessment of rivers i.e., their assessment through use of aquatic assemblages, integrates the effects of multiple-stressors on these systems over time and is essential to evaluate ecosystem condition and establish recovery measures. It has been undertaken in many countries since the 1990s, but not globally. And where national or multi-national monitoring networks have gathered large amounts of data, the poor water body classifications have not necessarily resulted in the rehabilitation of rivers. Thus, here we aimed to identify major gaps in the biological assessment and rehabilitation of rivers worldwide by focusing on the best examples in Asia, Europe, Oceania, and North, Central, and South America. Our study showed that it is not possible so far to draw a world map of the ecological quality of rivers. Biological assessment of rivers and streams is only implemented officially nation-wide and regularly in the European Union, Japan, Republic of Korea, South Africa, and the USA. In Australia, Canada, China, New Zealand, and Singapore it has been implemented officially at the state/province level (in some cases using common protocols) or in major catchments or even only once at the national level to define reference conditions (Australia). In other cases, biological monitoring is driven by a specific problem, impact assessments, water licenses, or the need to rehabilitate a river or a river section (as in Brazil, South Korea, China, Canada, Japan, Australia). In some countries monitoring programs have only been explored by research teams mostly at the catchment or local level (e.g., Brazil, Mexico, Chile, China, India, Malaysia, Thailand, Vietnam) or implemented by citizen science groups (e.g., Southern Africa, Gambia, East Africa, Australia, Brazil, Canada). The existing large-extent assessments show a striking loss of biodiversity in the last 2-3 decades in Japanese and New Zealand rivers (e.g., 42% and 70% of fish species threatened or endangered, respectively). A poor condition (below Good condition) exists in 25% of South Korean rivers, half of the European water bodies, and 44% of USA rivers, while in Australia 30% of the reaches sampled were significantly impaired in 2006. Regarding river rehabilitation, the greatest implementation has occurred in North America, Australia, Northern Europe, Japan, Singapore, and the Republic of Korea. Most rehabilitation measures have been related to improving water quality and river connectivity for fish or the improvement of riparian vegetation. The limited extent of most rehabilitation measures (i.e., not considering the entire catchment) often constrains the improvement of biological condition. Yet, many rehabilitation projects also lack pre-and/or post-monitoring of ecological condition, which prevents assessing the success and shortcomings of the recovery measures. Economic constraints are the most cited limitation for implementing monitoring programs and rehabilitation actions, followed by technical limitations, limited knowledge of the fauna and flora and their life-history traits (especially in Africa, South America and Mexico), and poor awareness by decision-makers. On the other hand, citizen involvement is recognized as key to the success and sustainability of rehabilitation projects. Thus, establishing rehabilitation needs, defining clear goals, tracking progress towards achieving them, and involving local populations and stakeholders are key recommendations for rehabilitation projects (Table 1). Large-extent and long-term monitoring programs are also essential to provide a realistic overview of the condition of rivers worldwide. Soon, the use of DNA biological samples and eDNA to investigate aquatic diversity could contribute to reducing costs and thus increase monitoring efforts and a more complete assessment of biodiversity. Finally, we propose developing transcontinental teams to elaborate and improve technical guidelines for implementing biological monitoring programs and river rehabilitation and establishing common financial and technical frameworks for managing international catchments. We also recommend providing such expert teams through the United Nations Environment Program to aid the extension of biomonitoring, bioassessment, and river rehabilitation knowledge globally.


Anatomical distribution of the chemorepellent semaphorin III/collapsin-1 in the adult rat and human brain: predominant expression in structures of the olfactory-hippocampal pathway and the motor system.
Alterations in neuronal connectivity of the mature central nervous system (CNS) appear to depend on a delicate balance between growth-promoting and growth-inhibiting molecules. To begin to address a potential role of the secreted chemorepulsive protein semaphorin(D)III/collapsin-1 (semaIII/coll-1) in structural plasticity during adulthood, we used high-resolution nonradioactive in situ hybridization to identify neural structures that express semaIII/coll-1 mRNA in the mature rat and human brain. SemaIII/coll-1 was expressed in distinct but anatomically and functionally linked structures of the adult nervous system. The olfactory-hippocampal pathway displayed semaIII/coll-1 expression in a continuum of neuronal structures, including mitral and tufted cells of the olfactory bulb, olfactory tubercle, and piriform cortex; and distinct nuclei of the amygdaloid complex, the superficial layers of the entorhinal cortex, and the subiculum of the hippocampal formation. In addition, prominent labeling was found in neuronal components of the motor system, particularly in cerebellar Purkinje cells and in subpopulations of cranial and spinal motoneurons. Retrograde tracing combined with in situ hybridization also revealed that the staining of semaIII/coll-1 within the entorhinal cortex was present in the stellate neurons that project via the perforant path to the molecular layer of the dentate gyrus. Like in the rat, the human brain displayed discrete expression of semaIII/coll-1. Among the structures examined, the most prominent staining was observed in the cellular islands of the superficial layers of the human entorhinal cortex. The constitutive expression of the chemorepellent semaIII/coll-1 in discrete populations of neurons in the mature rat and human CNS raises the possibility that, in addition to its function as repulsive axon guidance cue during development, semaIII/coll-1 might be involved in restricting structural changes that occur in the wiring of the intact CNS.


Taxonomic re-evaluation of whorl-forming Streptomyces (formerly Streptoverticillium) species by using phenotypes, DNA-DNA hybridization and sequences of gyrB, and proposal of Streptomyces luteireticuli (ex Katoh and Arai 1957) corrig., sp. nov., nom. rev.
The taxonomic status of 64 strains of whorl-forming Streptomyces (formerly Streptoverticillium) species was re-evaluated and strains were reclassified on the basis of their phenotypes, DNA-DNA hybridization data and partial sequences of gyrB, the structural gene of the B subunit of DNA gyrase. These strains, which consisted of 46 species and eight subspecies with validly published names and 13 species whose names have not been validly published [including 10 strains examined by the International Streptomyces Project (ISP)], were divided into two groups, namely typical and atypical whorl-forming Streptomyces species, based on their phenotypes and gyrB gene sequences. The typical whorl-forming species (59 strains) were divided into six major clusters of three or more species, seven minor clusters of two species and five single-member clusters, based on the threshold value of 97 % gyrB sequence similarity. Major clusters were typified by Streptomyces abikoensis, Streptomyces cinnamoneus, Streptomyces distallicus, Streptomyces griseocarneus, Streptomyces hiroshimensis and Streptomyces netropsis. Phenotypically, members of each cluster resembled each other closely except for the S. distallicus cluster, which was divided phenotypically into the S. distallicus and Streptomyces stramineus subclusters, and the S. netropsis cluster, which was divided into the S. netropsis and Streptomyces eurocidicus subclusters. Strains in each minor cluster closely resembled each other phenotypically. DNA-DNA relatedness between the representative species and others in each major cluster and/or subcluster, and between strains in the minor clusters, was >70 %, indicating that the major clusters and/or subclusters and the minor clusters each comprise a single species. It was concluded that 59 strains of typical whorl-forming Streptomyces species consisted of the following 18 species, including subjective synonym(s): S. abikoensis, Streptomyces ardus, Streptomyces blastmyceticus, S. cinnamoneus, S. eurocidicus, S. griseocarneus, S. hiroshimensis, Streptomyces lilacinus, 'Streptomyces luteoreticuli', Streptomyces luteosporeus, Streptomyces mashuensis, Streptomyces mobaraensis, Streptomyces morookaense, S. netropsis, Streptomyces orinoci, S. stramineus, Streptomyces thioluteus and Streptomyces viridiflavus.


Priming is swell, but it's far from simple.
Clearly, structural priming is a valuable tool for probing linguistic representation. But we don't think that the existing results provide strong support for Branigan & Pickering's (B&P's) model, largely because the priming effects are more confusing and diverse than their theory would suggest. Fortunately, there are a number of other experimental tools available, and linguists are increasingly making use of them.


A minimum dataset for a Level 1 echocardiogram: a guideline protocol from the British Society of Echocardiography.
The British Society of Echocardiography has previously outlined a minimum dataset for a standard transthoracic echocardiogram, and this remains the basis on which an echocardiographic study should be performed. The importance of ultrasound in excluding critical conditions that may require urgent treatment is well known. Several point-of-care echo protocols have been developed for use by non-echocardiography specialists. However, these protocols are often only used in specific circumstances and are usually limited to 2D echocardiography. Furthermore, although the uptake in training for these protocols has been reasonable, there is little in the way of structured support available from accredited sonographers in the ongoing training and re-accreditation of those undertaking these point-of-care scans. In addition, it is well recognised that the provision of echocardiography on a 24/7 basis is extremely challenging, particularly outside of tertiary cardiac centres. Consequently, following discussions with NHS England, the British Society of Echocardiography has developed the Level 1 echocardiogram in order to support the rapid identification of critical cardiac pathology that may require emergency treatment. It is intended that these scans will be performed by non-specialists in echocardiography and crucially are not designed to replace a full standard transthoracic echocardiogram. Indeed, it is expected that a significant number of patients, in whom a Level 1 echocardiogram is required, will need to have a full echocardiogram performed as soon as is practically possible. This document outlines the minimum dataset for a Level 1 echocardiogram. The accreditation process for Level 1 echo is described separately.


Thioredoxin-like2/2-Cys peroxiredoxin redox cascade acts as oxidative activator of glucose-6-phosphate dehydrogenase in chloroplasts.
Thiol-based redox regulation is crucial for adjusting chloroplast functions under fluctuating light environments. We recently discovered that the thioredoxin-like2 (TrxL2)/2-Cys peroxiredoxin (2CP) redox cascade supports oxidative thiol modulation by using hydrogen peroxide (H2O2) as an oxidizing force. This system plays a key role in switching chloroplast metabolism (e.g. Calvin-Benson cycle) during light to dark transitions; however, information on its function is still limited. In this study, we report a novel protein-activation mechanism based on the TrxL2/2CP redox cascade. Glucose-6-phosphate dehydrogenase (G6PDH) catalyzes the first step of the oxidative pentose phosphate pathway (OPPP). Biochemical studies, including redox state determination and measurement of enzyme activity, suggested that the TrxL2/2CP pathway is involved in the oxidative activation of G6PDH. It is thus likely that the TrxL2/2CP redox cascade shifts chloroplast metabolism to night mode by playing a dual role, namely, down-regulation of the Calvin-Benson cycle and up-regulation of OPPP. G6PDH was also directly oxidized and activated by H2O2, particularly when H2O2 concentration was elevated. Therefore, G6PDH is thought to be finely tuned by H2O2 levels in both direct and indirect manners.


SH3BP4 Regulates Intestinal Stem Cells and Tumorigenesis by Modulating β-Catenin Nuclear Localization.
Wnt signals at the base of mammalian crypts play a pivotal role in intestinal stem cell (ISC) homeostasis, whereas aberrant Wnt activation causes colon cancer. Precise control of Wnt signal strength is governed by a number of negative inhibitory mechanisms acting at distinct levels of the cascade. Here, we identify the Wnt negative regulatory role of Sh3bp4 in the intestinal crypt. We show that the loss of Sh3bp4 increases ISC and Paneth cell numbers in murine intestine and accelerates adenoma development in Apcmin mice. Mechanistically, human SH3BP4 inhibits Wnt signaling downstream of β-catenin phosphorylation and ubiquitination. This Wnt inhibitory role is dependent on the ZU5 domain of SH3BP4. We further demonstrate that SH3BP4 is expressed at the perinuclear region to restrict nuclear localization of β-catenin. Our data uncover the tumor-suppressive role of SH3BP4 that functions as a negative feedback regulator of Wnt signaling through modulating β-catenin's subcellular localization.


Age-related EBV-associated B-cell lymphoproliferative disorders constitute a distinct clinicopathologic group: a study of 96 patients.
We have recently reported EBV+ B-cell lymphoproliferative disorders (LPD) occurring predominantly in elderly patients, which shared features of EBV+ B-cell neoplasms arising in the immunologically deteriorated patients despite no predisposing immunodeficiency and were named as senile or age-related EBV+ B-cell LPDs. To further characterize this disease, age-related EBV+ B-cell LPDs were compared with EBV-negative diffuse large B-cell lymphomas (DLBCL). Among 1,792 large B-cell LPD cases, 96 EBV+ cases with available clinical data set were enrolled for the present study. For the control group, 107 patients aged over 40 years with EBV-negative DLBCL were selected. We compared clinicopathologic data between two groups and determined prognostic factors by univariate and multivariate analysis. Patients with age-related EBV+ B-cell LPDs showed a higher age distribution and aggressive clinical features or parameters than EBV-negative DLBCLs: 44% with performance status >1, 58% with serum lactate dehydrogenase level higher than normal, 49% with B symptoms, and higher involvement of skin and lung. Overall survival was thus significantly inferior in age-related EBV+ group than in DLBCLs. Univariate and multivariate analyses further identified two factors, B symptoms and age older than 70 years, independently predictive for survival. A prognostic model using these two variables well defined three risk groups: low risk (no adverse factors), intermediate risk (one factor), and high risk (two factors). These findings suggest that age-related EBV+ B-cell LPDs constitute a distinct group, and innovative therapeutic strategies such as EBV-targeted T-cell therapy should be developed for this uncommon disease.


Reaching the unreached through trained and skilled birth attendants in Ethiopia: a cluster randomized controlled trial study protocol.
Despite improvements since 1990 to 2014, maternal mortality ratio (MMR) remains high in Ethiopia. One of the key drivers of maternal mortality in Ethiopia is the very low coverage of Skilled Birth attendance (SBA) in rural Ethiopia. This cluster randomized trial piloted an innovative approach of deploying trained community reproductive nurses (CORN) to hard to reach/unreachable rural Ethiopia to improve the coverage of SBA. We used a three-arm cluster randomized trial to test the effect of deploying CORN in rural communities in South Ethiopia to improve SBA and other maternal health indicators. A total of 282 villages/clusters (94 from each arm) were randomly selected in the three districts of the zone for the study. The intervention was implemented in four consecutive phases that aimed at of provision of essential maternal, neonatal and child health (MNCH) services mainly focusing on SBA. The CORN were trained and deployed in health centres (arm 1) and in the community/health posts (arm2). A third arm (arm 3) consisting control villages without the intervention. A baseline and end line assessment was conducted to compare the difference in the proportion of SBA and other MNCH service uptake across the three arms Data was entered into computer, edited, cleaned, and analyzed using Epi-data statistical software. The presentation followed the Consolidated Standards of Reporting Trials (CONSORT) statement guidelines for cluster-randomized trials. This trial is designed to test the impact of an innovative and newly designed means of distribution for the national health extension program strategy with additional service package with no change to the target population. The focus is on effect of CORN in revitalizing the Health Extension Program (HEP) through improving SBA service uptake and other maternal health service uptake indicators. The study findings may guide national policy to strengthen and shape the already existing HEP that has certain limitations to improve maternal health indicators. The competency based training methodology could provide feedback for health science colleges to improve the national nursing or midwifery training curriculum. clinicaltrails.gov NCT02501252 dated on July 14, 2015.


A Review of a Steady State Coherent Bio-modulator for Tinnitus Relief and Summary of Efficiency and Safety Data from the Clinical Study Program and Post Market Clinical Follow-up.
To evaluate a non-energy consuming light bio-modulator patch creating coherency for tinnitus relief. Three independent clinical studies and continuous post market clinical follow up have been performed during the year 2012 to 2018. The first study was a limited interventional investigation with 10 patients, the second was a larger interventional study with finally 48 patients further investigated, and the third a randomized, placebo-controlled, double-blind study with 82 patients. In the clinical studies patch performance evaluated with questionnaires related to tinnitus, quality-of-life, and safety were assessed prior, during and after the end of treatment. In all studies the treatment time was 3 weeks and the patches were placed behind one year. The first study indicated a relief with half of the patients at the end of the treatment. Still two years after the study one third reported tinnitus relief. However, the numbers of patients were low. The second study showed a responder relief in 58% directly after end of treatment and 60% one month after. The third study showed that the biomodulator patch had statistical significant three times more responders than placebo one month after end of treatment, measured as a decrease from baseline in at least 2 points in tinnitus annoyance visual analogue scale as a minimal clinical significant difference. Tinnitus handicap inventory was improved by mean-16 points significantly for the active responder group, but with no statistically significant changes for the placebo group or between the groups. The biomodulator patch was safe and well-tolerated in all three studies. The post market clinical follow up has shown a 30% reported relief and with no new risks or unexpected issues affecting the effectiveness or safety. Taken under consideration the lack of easy-to-use alternative and the low risk profile, this patch device could highly be recommended to try for tinnitus relief as a conclusion based on the clinical studies and post market surveys. Further studies of how this bio-modulator more specific act on the auditory system, how long this may sustain and if there can be subgroups of patients or variations in the treatment time, delayed onset, number of patches, and frequency for more efficiency needs to be considered.


Transduction of glycan-lectin binding using near-infrared fluorescent single-walled carbon nanotubes for glycan profiling.
There is significant interest in developing new detection platforms for characterizing glycosylated proteins, despite the lack of easily synthesized model glycans or high affinity receptors for this analytical problem. In this work, we demonstrate a sensor array employing recombinant lectins as glycan recognition sites tethered via Histidine tags to Ni(2+) complexes that act as fluorescent quenchers for semiconducting single-walled carbon nanotubes (SWNTs) embedded in a chitosan hydrogel spot to measure binding kinetics of model glycans. We examine, as model glycans, both free and streptavidin-tethered biotinylated monosaccharides. Two higher-affined glycan-lectin pairs are explored: fucose (Fuc) to PA-IIL and N-acetylglucosamine (GlcNAc) to GafD. The dissociation constants (K(D)) for these pairs as free glycans (106 and 19 μM, respectively) and streptavidin-tethered (142 and 50 μM respectively) were found. The absolute detection limit for the current platform was found to be 2 μg of glycosylated protein or 100 ng of free glycan to 20 μg of lectin. Glycan detection (GlcNAc-streptavidin at 10 μM) is demonstrated at the single nanotube level as well by monitoring the fluorescence from individual SWNT sensors tethered to GafD lectin. Over a population of 1000 nanotubes, 289 of the SWNT sensors had signals strong enough to yield kinetic information (K(D) of 250 ± 10 μM). We are also able to identify the locations of "strong transducers" on the basis of dissociation constant (four sensors with K(D) < 10 μM) or overall signal modulation (eight sensors with >5% quench response). We report the key finding that the brightest SWNTs are not the best transducers of glycan binding. SWNTs ranging in intensity between 50 and 75% of the maximum show the greatest response. The ability to pinpoint strong-binding, single sensors is promising to build a nanoarray of glycan-lectin transducers as a high throughput method to profile glycans without protein labeling or glycan liberation pretreatment steps.


Body size and adiposity indicators and their relationship with blood pressure levels in Ibos of Nigeria.
Racial Predisposition to Hypertension, obesity and other cardiovascular diseases (CVD) have been the subject of some recent researches. The various anthropometric and obesity indicators and their relationship with blood pressure parameters in the Ibos of Nigeria were studied. Using the simple random design, 569 males and females Nigerians of Ibo ethnicity, ages 20 to 80 years were enrolled for this study. Systolic and diastolic blood pressure (SBP & DBP), body mass index (BMI), waist hip ratio (WHR), waist height ratio (WHTR), waist circumference (We), triceps, subscapular, calf and sum of three skin fold thicknesses (TSF, SSF, eSF,& STS respectively) and other anthropometric parameters were measured. The mean SBP for the study was 119.6 +/- 23 mmHg and DBP 79.8 +/- 13mmhg. Males showed higher mean values of 5mmHg in SBP and 3mmHg in DBP than the females. we was 3cm larger in the females than the males. BMI, WHTR, and STS were all larger in the females than in the males. The highest level of association noted in the study was between we and WHTR (r = 0.926, P < 0.01). The levels of correlations of the blood pressure parameters with the obesity indices were higher with DBP than SBP. For both sexes; we was the highest predictor of DBP, followed by WHTR. Age gave the highest prediction of SBP. This work notes WHTR as the best predictor of central obesity and also a better index for screening CVD risk factors in the Ibos.


Imaging features of neonatal systemic juvenile xanthogranuloma: a case report and review of the literature.
Juvenile xanthogranuloma (JXG) is the most common non-Langerhans cell histiocytic disorder in children. This report describes the case of a 28-day-old boy that presented with multiple subcutaneous nodular lesions on the trunk and extremities, and multiple red nodular lesions on the scrotum. Magnetic resonance imaging (MRI) of the brain showed a well-demarcated extra-axial dura-based mass that appeared isointense or slightly hyperintense on T1-weighted images, hypointense on T2-weighted images and had intense enhancement on gadolinium-enhanced T1-weighted images. Computed tomography (CT) or MRI scans of the chest and abdomen revealed multiple scattered nodular or patchy lesions of varying sizes in the lungs, liver and left kidney. Histological analysis of a subcutaneous mass suggested JXG. The patient was diagnosed with neonatal systemic JXG with involvement of the central nervous system, lungs, liver, kidneys, subcutaneous soft tissue and skin. CT and MRI after 3 months of treatment with methylprednisolone sodium succinate demonstrated that the lesions were obviously diminished. This report discusses the imaging findings in this current case of multi-organ JXG and reviews the imaging literature on this condition to improve awareness of the lesions in order to help radiologists establish an accurate differential diagnosis when confronted with similar cases.


How Can the Health System Retain Women in HIV Treatment for a Lifetime? A Discrete Choice Experiment in Ethiopia and Mozambique.
Option B+, an approach that involves provision of antiretroviral therapy (ART) to all HIV-infected pregnant women for life, is the preferred strategy for prevention of mother to child transmission of HIV. Lifelong retention in care is essential to its success. We conducted a discrete choice experiment in Ethiopia and Mozambique to identify health system characteristics preferred by HIV-infected women to promote continuity of care. Women living with HIV and receiving care at hospitals in Oromia Region, Ethiopia and Zambézia Province, Mozambique were shown nine choice cards and asked to select one of two hypothetical health facilities, each with six varying characteristics related to the delivery of HIV services for long term treatment. Mixed logit models were used to estimate the influence of six health service attributes on choice of clinics. 2,033 women participated in the study (response rate 97.8% in Ethiopia and 94.7% in Mozambique). Among the various attributes of structure and content of lifelong ART services, the most important attributes identified in both countries were respectful provider attitude and ability to obtain non-HIV health services during HIV-related visits. Availability of counseling support services was also a driver of choice. Facility type, i.e., hospital versus health center, was substantially less important. Efforts to enhance retention in HIV care and treatment for pregnant women should focus on promoting respectful care by providers and integrating access to non-HIV health services in the same visit, as well as continuing to strengthen counseling.


Methane storms on Saturn's moon Titan.
The presence of dry fluvial river channels and the intense cloud activity in the south pole of Titan over the past few years suggest the presence of methane rain. The nitrogen atmosphere of Titan therefore appears to support a methane meteorological cycle that sculptures the surface and controls its properties. Titan and Earth are the only worlds in the Solar System where rain reaches the surface, although the atmospheric cycles of water and methane are expected to be very different. Here we report three-dimensional dynamical calculations showing that severe methane convective storms accompanied by intense precipitation may occur in Titan under the right environmental conditions. The strongest storms grow when the methane relative humidity in the middle troposphere is above 80 per cent, producing updrafts with maximum velocities of 20 m s(-1), able to reach altitudes of 30 km before dissipating in 5-8 h. Raindrops of 1-5 mm in radius produce precipitation rainfalls on the surface as high as 110 kg m(-2) and are comparable to flash flood events on Earth.


Pain in children with cerebral palsy: implications for pediatric physical therapy.
This literature review explores pain assessment tools and psychosocial pain management methods that are pertinent to physical therapy (PT) for children with cerebral palsy (CP). Children with CP experience considerable pain that affects quality of life and cooperation during healthcare procedures. Physical therapist-led research on interventions to address pain in this population is limited, despite evidence for the prevalence of pain during PT interventions, and the preponderance of research supporting the use of psychosocial pain management during other healthcare-related pain-inducing procedures. Research completed primarily by non-physical therapist healthcare professionals delineate assessment tools and psychosocial pain management techniques that hold promise for evaluating and reducing pain that occurs during PT procedures for children with CP.


Volume regulation and shape bifurcation in the cell nucleus.
Alterations in nuclear morphology are closely associated with essential cell functions, such as cell motility and polarization, and correlate with a wide range of human diseases, including cancer, muscular dystrophy, dilated cardiomyopathy and progeria. However, the mechanics and forces that shape the nucleus are not well understood. Here, we demonstrate that when an adherent cell is detached from its substratum, the nucleus undergoes a large volumetric reduction accompanied by a morphological transition from an almost smooth to a heavily folded surface. We develop a mathematical model that systematically analyzes the evolution of nuclear shape and volume. The analysis suggests that the pressure difference across the nuclear envelope, which is influenced by changes in cell volume and regulated by microtubules and actin filaments, is a major factor determining nuclear morphology. Our results show that physical and chemical properties of the extracellular microenvironment directly influence nuclear morphology and suggest that there is a direct link between the environment and gene regulation.


Hypofractionated stereotactic radiotherapy using intensity-modulated radiotherapy in patients with one or two brain metastases.
A small fraction of patients with 1-2 brain metastases will not be suitable candidates to either surgical resection or stereotactic radiosurgery (SRS) due to either their location or their size. The objective of this study was to determine the local control, survival, patterns of relapse and the incidence of brain injury following a course of hypofractionated stereotactic radiotherapy while avoiding upfront whole brain radiation therapy (WBRT) in this subgroup of patients. A Gill-Thomas removable head frame system was used for immobilization. Brain LAB software with dynamic multileaf collimator hardware was used to design and deliver an intensity-modulated radiation therapy treatment plan. A dose of 600 cGy was prescribed to the 100% isodose line that would encompass the lesion with a 3-mm margin. A total dose of 3,000 cGy was delivered in 5 fractions using 2 fractions per week. The patients were followed with neurological examination and serial MRI images done every 3 months following the procedure. Twenty patients have been treated using this fractionation schedule since April 2004. The 1-year local control at the site of original disease is 70%. The complete response, partial response and stable disease at the last follow-up were 15, 30 and 45%, respectively. Two patients had local recurrence at the site of original disease, while 5 had evidence of leptomeningeal disease. Two additional patients developed new brain metastases, resulting in a 1-year brain relapse-free survival of 36% following this approach. The median overall survival was 8.5 months. Three patients (15%) developed steroid dependency lasting 3 months or longer following the procedure. Four patients (20%) needed WBRT as salvage following this approach. The preliminary results of hypofractionated SRS are comparable to both surgery and SRS data for solitary brain metastases in terms of local control and overall survival with acceptable morbidity in this cohort of unfavorable patients.


Rapsyn may function as a link between the acetylcholine receptor and the agrin-binding dystrophin-associated glycoprotein complex.
The 43 kDa AChR-associated protein rapsyn is required for the clustering of nicotinic acetylcholine receptors (AChRs) at the developing neuromuscular junction, but the functions of other postsynaptic proteins colocalized with the AChR are less clear. Here we use a fibroblast expression system to investigate the role of the dystrophin-glycoprotein complex (DGC) in AChR clustering. The agrin-binding component of the DGC, dystroglycan, is found evenly distributed across the cell surface when expressed in fibroblasts. However, dystroglycan colocalizes with AChR-rapsyn clusters when these proteins are coexpressed. Furthermore, dystroglycan colocalizes with rapsyn clusters even in the absence of AChR, indicating that rapsyn can cluster dystroglycan and AChR independently. Immunofluorescence staining using a polyclonal antibody to utrophin reveals a lack of staining of clusters, suggesting that the immunoreactive species, like the AChR, does not mediate the observed rapsyndystroglycan interaction. Rapsyn may therefore be a molecular link connecting the AChR to the DGC. At the neuromuscular synapse, rapsyn-mediated linkage of the AChR to the cytoskeleton-anchored DGC may underlie AChR cluster stabilization.


Inactivation of endothelial ZEB1 impedes tumor progression and sensitizes tumors to conventional therapies.
Current antiangiogenic therapy is limited by its cytostatic property, scarce drug delivery to the tumor, and side toxicity. To address these limitations, we unveiled the role of ZEB1, a tumor endothelium-enriched zinc-finger transcription factor, during tumor progression. We discovered that the patients who had lung adenocarcinomas with high ZEB1 expression in tumor endothelium had increased prevalence of metastases and markedly reduced overall survival after the diagnosis of lung cancer. Endothelial ZEB1 deletion in tumor-bearing mice diminished tumor angiogenesis while eliciting persistent tumor vascular normalization by epigenetically repressing TGF-β signaling. This consequently led to improved blood and oxygen perfusion, enhanced chemotherapy delivery and immune effector cell infiltration, and reduced tumor growth and metastasis. Moreover, targeting vascular ZEB1 remarkably potentiated the anticancer activity of nontoxic low-dose cisplatin. Treatment with low-dose anti-programmed cell death protein 1 (anti-PD-1) antibody elicited tumor regression and markedly extended survival in ZEB1-deleted mice, conferring long-term protective anticancer immunity. Collectively, we demonstrated that inactivation of endothelial ZEB1 may offer alternative opportunities for cancer therapy with minimal side effects. Targeting endothelium-derived ZEB1 in combination with conventional chemotherapy or immune checkpoint blockade therapy may yield a potent and superior anticancer effect.


Activation of Metabotropic Glutamate Receptor 7 Is Required for Induction of Long-Term Potentiation at SC-CA1 Synapses in the Hippocampus.
Of the eight metabotropic glutamate (mGlu) receptor subtypes, only mGlu7 is expressed presynaptically at the Schaffer collateral (SC)-CA1 synapse in the hippocampus in adult animals. Coupled with the inhibitory effects of Group III mGlu receptor agonists on transmission at this synapse, mGlu7 is thought to be the predominant autoreceptor responsible for regulating glutamate release at SC terminals. However, the lack of mGlu7-selective pharmacological tools has hampered direct testing of this hypothesis. We used a novel, selective mGlu7-negative allosteric modulator (NAM), ADX71743, and a newly described Group III mGlu receptor agonist, LSP4-2022, to elucidate the role of mGlu7 in modulating transmission in hippocampal area CA1 in adult C57BL/6J male mice. Interestingly, although mGlu7 agonists inhibit SC-CA1 EPSPs, we found no evidence for activation of mGlu7 by stimulation of SC-CA1 afferents. However, LSP4-2022 also reduced evoked monosynaptic IPSCs in CA1 pyramidal cells and, in contrast to its effect on SC-CA1 EPSPs, ADX71743 reversed the ability of high-frequency stimulation of SC afferents to reduce IPSC amplitudes. Furthermore, blockade of mGlu7 prevented induction of LTP at the SC-CA1 synapse and activation of mGlu7 potentiated submaximal LTP. Together, these data suggest that mGlu7 serves as a heteroreceptor at inhibitory synapses in area CA1 and that the predominant effect of activation of mGlu7 by stimulation of glutamatergic afferents is disinhibition, rather than reduced excitatory transmission. Furthermore, this mGlu7-mediated disinhibition is required for induction of LTP at the SC-CA1 synapse, suggesting that mGlu7 could serve as a novel therapeutic target for treatment of cognitive disorders.


KIR3DL01 upregulation on gut natural killer cells in response to SIV infection of KIR- and MHC class I-defined rhesus macaques.
Natural killer cells provide an important early defense against viral pathogens and are regulated in part by interactions between highly polymorphic killer-cell immunoglobulin-like receptors (KIRs) on NK cells and their MHC class I ligands on target cells. We previously identified MHC class I ligands for two rhesus macaque KIRs: KIR3DL01 recognizes Mamu-Bw4 molecules and KIR3DL05 recognizes Mamu-A1*002. To determine how these interactions influence NK cell responses, we infected KIR3DL01+ and KIR3DL05+ macaques with and without defined ligands for these receptors with SIVmac239, and monitored NK cell responses in peripheral blood and lymphoid tissues. NK cell responses in blood were broadly stimulated, as indicated by rapid increases in the CD16+ population during acute infection and sustained increases in the CD16+ and CD16-CD56- populations during chronic infection. Markers of proliferation (Ki-67), activation (CD69 & HLA-DR) and antiviral activity (CD107a & TNFα) were also widely expressed, but began to diverge during chronic infection, as reflected by sustained CD107a and TNFα upregulation by KIR3DL01+, but not by KIR3DL05+ NK cells. Significant increases in the frequency of KIR3DL01+ (but not KIR3DL05+) NK cells were also observed in tissues, particularly in the gut-associated lymphoid tissues, where this receptor was preferentially upregulated on CD56+ and CD16-CD56- subsets. These results reveal broad NK cell activation and dynamic changes in the phenotypic properties of NK cells in response to SIV infection, including the enrichment of KIR3DL01+ NK cells in tissues that support high levels of virus replication.


Equilibrium sampling for biomolecules under mechanical tension.
In the studies of force-induced conformational transitions of biomolecules, the large timescale difference from experiments presents the challenge of obtaining convergent sampling for molecular dynamics simulations. To circumvent this fundamental problem, an approach combining the replica-exchange method and umbrella sampling (REM-US) was developed to simulate mechanical stretching of biomolecules under equilibrium conditions. Equilibrium properties of conformational transitions can be obtained directly from simulations without further assumptions. To test the performance, we carried out REM-US simulations of atomic force microscope (AFM) stretching and relaxing measurements on the polysaccharide pustulan, a (1-->6)-beta-D-glucan, which undergoes well-characterized rotameric transitions in the backbone bonds. With significantly enhanced sampling convergence and efficiency, the REM-US approach closely reproduced the equilibrium force-extension curves measured in AFM experiments. Consistent with the reversibility in the AFM measurements, the new approach generated identical force-extension curves in both stretching and relaxing simulations-an outcome not reported in previous studies, proving that equilibrium conditions were achieved in the simulations. REM-US may provide a robust approach to modeling of mechanical stretching on polysaccharides and even nucleic acids.


Effects of feeding dry-rolled corn-based diets with and without wet distillers grains with solubles and zilpaterol hydrochloride on performance, carcass characteristics, and heat stress in finishing beef steers.
Zilpaterol hydrochloride (ZH) has been approved for use since 2006; however, there is no research on any interactions between ZH and coproducts. Additionally, there is no published information on the potential effects of ZH on heat stress in feedlot cattle. Therefore, an experiment was conducted to determine the effects of feeding dry-rolled corn (DRC)-based diets with and without wet distillers grains with solubles (WDGS) and ZH on performance, carcass characteristics, and heat stress in feedlot cattle. Four hundred thirty-eight steers were used in a randomized complete block design with a 2 × 2 factorial arrangement of treatments in 16 pens with 26 to 28 steers in each pen. Factors consisted of inclusion of 0 or 30% (on a DM basis) WDGS and inclusion of ZH at 0 or 84 mg/steer daily for 21 d at the end of the finishing period. Therefore, cattle were blocked by BW and randomly assigned to 1 of the resulting 4 treatment combinations: 1) DRC-based diet with 0% WDGS and 84 mg/steer ZH, 2) DRC-based diet with 0% WDGS and no ZH, 3) DRC-based diet with 30% WDGS and 84 mg/steer of ZH, and 4) DRC-based diet with 30% WDGS and no ZH. Final live BW, carcass-adjusted BW, ADG, and G:F were greater for cattle fed ZH than non-ZH-fed cattle (P < 0.01). Additionally, cattle fed ZH consumed 7.4% less DM than cattle not fed ZH (P < 0.01). Cattle fed ZH for 21 d also had a 2.9% greater HCW (P < 0.01), a 1.1% greater dressing percentage (P < 0.01), 7.3% greater LM area (P < 0.01), and an 8.4% improvement in yield grade (P < 0.01) than cattle not fed ZH. For the main effect of WDGS inclusion, ADG was greater for cattle fed 0 vs. 30% WDGS (P = 0.04) and G:F also tended to be greater for cattle fed 0 vs. 30% WDGS (P = 0.07) for the 21-d ZH feeding period. However, when evaluated over the entire experiment, cattle fed 30 vs. 0% WDGS had a greater ADG and G:F (P < 0.01). Furthermore, cattle fed 30 vs. 0% WDGS had a greater dressing percentage and tended to have a greater amount of 12th rib fat (P < 0.07). Heat stress measurements were collected during the time cattle were fed ZH, from May 31 to July 12, 2013. The slopes for change in respiration rate and panting score per day were positive but were not different across dietary treatments (P > 0.71); in addition, the slopes for change in respiration rate and panting score when accounting for environmental conditions were positive but were not different across dietary treatments (P > 0.32).


Antimicrobial and antibiofilm activity of pleurocidin against cariogenic microorganisms.
Dental caries is a common oral bacterial infectious disease of global concern. Prevention and treatment of caries requires control of the dental plaque formed by pathogens such as Streptococcus mutans and Streptococcus sobrinus. Pleurocidin, produced by Pleuronectes americanus, is an antimicrobial peptide that exerts broad-spectrum activity against pathogenic bacteria and fungi. Moreover, pleurocidin shows less hemolysis and is less toxic than other natural peptides. In the present study, we investigated whether pleurocidin is an effective antibiotic peptide against common cariogenic microorganisms and performed a preliminary study of the antimicrobial mechanism. We assayed minimal inhibitory concentration (MIC), minimal bactericide concentration (MBC) and bactericidal kinetics and performed a spot-on-lawn assay. The BioFlux system was used to generate bacterial biofilms under controllable flow. Fluorescence microscopy and confocal laser scanning microscopy (CLSM) were used to analyze and observe biofilms. Scanning electron microscopy was used to observe the bacterial membrane. MIC and MBC results showed that pleurocidin had different antimicrobial activities against the tested oral strains. Although components of saliva could affect antimicrobial activity, pleurocidin dissolved in saliva still showed antimicrobial effects against oral microorganisms. Furthermore, pleurocidin showed a favorable killing effect against BioFlux flow biofilms in vitro. Our findings suggest that pleurocidin has the potential to kill dental biofilms and prevent dental caries.


CD47 functions as a molecular switch for erythrocyte phagocytosis.
CD47 on erythrocytes inhibits phagocytosis through interaction with the inhibitory immunoreceptor SIRPα expressed by macrophages. Thus, the CD47-SIRPα interaction constitutes a negative signal for erythrocyte phagocytosis. However, we report here that CD47 does not only function as a "do not eat me" signal for uptake but can also act as an "eat me" signal. In particular, a subset of old erythrocytes present in whole blood was shown to bind and to be phagocytosed via CD47-SIRPα interactions. Furthermore, we provide evidence that experimental aging of erythrocytes induces a conformational change in CD47 that switches the molecule from an inhibitory signal into an activating one. Preincubation of experimentally aged erythrocytes with human serum before the binding assay was required for this activation. We also demonstrate that aged erythrocytes have the capacity to bind the CD47-binding partner thrombospondin-1 (TSP-1) and that treatment of aged erythrocytes with a TSP-1-derived peptide enabled their phagocytosis by human red pulp macrophages. Finally, CD47 on erythrocytes that had been stored for prolonged time was shown to undergo a conformational change and bind TSP-1. These findings reveal a more complex role for CD47-SIRPα interactions in erythrocyte phagocytosis, with CD47 acting as a molecular switch for controlling erythrocyte phagocytosis.


Sexual Risk-Taking in HIV-Negative Gay and Bisexual Men Increases with Depression: Results from a U.S. National Study.
The link between depression and sexual risk-taking has received mixed findings in the literature. The current study analyzed the links between depression and recent condomless anal sex (CAS) with casual partners among 1033 HIV-negative, non-PrEP-using, gay and bisexual men. When CAS was dichotomized as either none or some, depression was not associated with the odds of CAS (with receptive and insertive combined) or insertive CAS only, but was positively associated with the odds of receptive CAS. When CAS was tallied as a count variable of events, depression was positively associated with total CAS, receptive CAS, and insertive CAS. With the addition of a quadratic term for depression, a positive quadratic effect was only found for total CAS and receptive CAS, but not for insertive CAS. These findings highlight the utility of using count data for CAS events and treating CAS separately with regard to receptive and insertive positioning when considering the role of depression among gay and bisexual men.


Sensory stimulation activates both motor and sensory components of the swallowing system.
Volitional swallowing in humans involves the coordination of both brainstem and cerebral swallowing control regions. Peripheral sensory inputs are necessary for safe and efficient swallowing, and their importance to the patterned components of swallowing has been demonstrated. However, the role of sensory inputs to the cerebral system during volitional swallowing is less clear. We used four conditions applied during functional magnetic resonance imaging to differentiate between sensory, motor planning, and motor execution components for cerebral control of swallowing. Oral air pulse stimulation was used to examine the effect of sensory input, covert swallowing was used to engage motor planning for swallowing, and overt swallowing was used to activate the volitional swallowing system. Breath-holding was also included to determine whether its effects could account for the activation seen during overt swallowing. Oral air pulse stimulation, covert swallowing and overt swallowing all produced activation in the primary motor cortex, cingulate cortex, putamen and insula. Additional regions of the swallowing cerebral system that were activated by the oral air pulse stimulation condition included the primary and secondary somatosensory cortex and thalamus. Although air pulse stimulation was on the right side only, bilateral cerebral activation occurred. On the other hand, covert swallowing minimally activated sensory regions, but did activate the supplementary motor area and other motor regions. Breath-holding did not account for the activation during overt swallowing. The effectiveness of oral-sensory stimulation for engaging both sensory and motor components of the cerebral swallowing system demonstrates the importance of sensory input in cerebral swallowing control.


Differential Feedback Regulation of Δ4-3-Oxosteroid 5β-Reductase Expression by Bile Acids.
Δ4-3-oxosteroid 5β-reductase is member D1 of the aldo-keto reductase family 1 (AKR1D1), which catalyzes 5β-reduction of molecules with a 3-oxo-4-ene structure. Bile acid intermediates and most of the steroid hormones carry the 3-oxo-4-ene structure. Therefore, AKR1D1 plays critical roles in both bile acid synthesis and steroid hormone metabolism. Currently our understanding on transcriptional regulation of AKR1D1 under physiological and pathological conditions is very limited. In this study, we investigated the regulatory effects of primary bile acids, chenodeoxycholic acid (CDCA) and cholic acid (CA), on AKR1D1 expression. The expression levels of AKR1D1 mRNA and protein in vitro and in vivo following bile acid treatments were determined by real-time PCR and Western blotting. We found that CDCA markedly repressed AKR1D1 expression in vitro in human hepatoma HepG2 cells and in vivo in mice. On the contrary, CA significantly upregulated AKR1D1 expression in HepG2 cells and in mice. Further mechanistic investigations revealed that the farnesoid x receptor (FXR) signaling pathway was not involved in regulating AKR1D1 by bile acids. Instead, CDCA and CA regulated AKR1D1 through the mitogen-activated protein kinases/c-Jun N-terminal kinases (MAPK/JNK) signaling pathway. Inhibition of the MAPK/JNK pathway effectively abolished CDCA and CA-mediated regulation of AKR1D1. It was thus determined that AKR1D1 expression was regulated by CDCA and CA through modulating the MAPK/JNK signaling pathway. In conclusion, AKR1D1 expression was differentially regulated by primary bile acids through negative and positive feedback mechanisms. The findings indicated that both bile acid concentrations and compositions play important roles in regulating AKR1D1 expression, and consequently bile acid synthesis and steroid hormone metabolism.


ON BIMOLECULAR LAYERS OF LIPOIDS ON THE CHROMOCYTES OF THE BLOOD.
We have examined the blood of man and of the rabbit, dog, guinea pig, sheep, and goat. There exists a great difference in the size of the red blood cells of these animals, but the total surfaces of the chromocytes See PDF for Structure from 0.1 cc. blood do not show a similarly great divergence, because animals having very small cells (goat and sheep) have much greater quantities of these cells in their blood than animals with blood cells of larger dimensions (dog and rabbit). We give all the results of our experiments, omitting only those in which we were unable to avoid losses in the procedure of evaporation of the acetone. It is clear that all our results fit in well with the supposition that the chromocytes are covered by a layer of fatty substances that is two molecules thick.


Animal suffering should not trump environmental stewardship.
Andrew Linzey contends that our treatment of children should act as a model for our treatment of animals: just as we use our power to prevent the suffering of children, so should we restrict our behavior to protect animals from human-originated suffering. While not ignoring the role theology and emotion play in his ethical view, Linzey endeavors to provide a rational argument for the moral consideration of animals. In addition, Linzey explains how humans have created institutions to help them justify the continuance of animal suffering, followed by a plan to replace those institutions with animal-friendly ones. Linzey then applies his thinking to three contemporary institutions he believes cause animal suffering in an unjustifiable manner, namely hunting with dogs, fur farming, and commercial sealing. This review offers a detailed account of several significant weaknesses of Linzey's argument, ranging from the theological to the scientific, that should be considered before adopting his views.


Cerebral vasospasm affects arterial critical closing pressure.
The effect of cerebral vasospasm (CVS) after aneurysmal subarachnoid hemorrhage (SAH) on critical closing pressure (CrCP) has not been fully delineated. Using cerebral impedance methodology, we sought to assess the behavior of CrCP during CVS. As CrCP expresses the sum of intracranial pressure (ICP) and vascular wall tension, we also explored its role in reflecting changes in vascular tone occurring in small vessels distal to spasm. This retrospective analysis was performed using recordings from 52 patients, diagnosed with CVS through transcranial Doppler measurements. Critical closing pressure was calculated noninvasively using arterial blood pressure and blood flow velocity. Outcome was assessed at both discharge and 3 months after ictus with the Glasgow Outcome Scale. The onset of CVS caused significant decreases in CrCP (P=0.025), without any observed significant changes in ICP (P=0.134). Vasospasm induced asymmetry, with CrCP ipsilateral to CVS becoming significantly lower than contralateral (P=0.025). Unfavorable outcomes were associated with a significantly lower CrCP after the onset of CVS (discharge: P=0.014; 3 months after SAH: P=0.020). Critical closing pressure is reduced in the presence of CVS in both temporal and spatial assessments. As ICP remained unchanged during CVS, reduced CrCP most probably reflects a lower wall tension in dilated small vessels distal to spasm.


The Drosophila miti-mere gene, a member of the POU family, is required for the specification of the RP2/sibling lineage during neurogenesis.
The Drosophila POU gene miti-mere (previously known as pdm2) has a complex spatial and temporal pattern of expression during early development; initially it is expressed in gap-gene-like pattern, then in 14 stripes and finally in a subset of the cells in the developing CNS and PNS. To study the function of this gene during development, we generated a 'synthetic anti-morphic mutation' by expressing a truncated version of the miti protein from a constitutive hsp83 and an inducible hsp70 promoter. We show that these delta miti transgenes behave like classical antimorphic mutations. Using these dominant negative transgenes, together with deletions and a duplication for the gene, we show that miti is required during segmentation and neurogenesis. We have also used temperature-shift experiments with the hsp70 delta miti transgene to demonstrate that miti function in segmentation is distinct and separable from its function during neurogenesis. In segmentation, miti appears to be required in the specification of the segments A2 and A6. In the CNS, miti is required for the elaboration of the NB4-2-->GMC-1-->RP2/sib lineage. miti is initially required in this lineage to establish the identity of the parental ganglion mother cell, GMC-1. miti must then be down-regulated to allow the asymmetric division of GMC-1 into the RP2 and its sibling cell.