Experience of using an open source clinical trials data management software system in Kenya.
Clinical trials data management (CTDM) remains one of the many challenges in running state of the art trials in resource-poor settings since most trials do not allocate, or have available, sufficient resources for CTDM and because of poor internet connectivity. Open-source software like OpenClinica could be a solution in such scenarios. In 2007, the KEMRI-Wellcome Trust Research Programme (KWTRP) adopted OpenClinica (OC) community edition, an open-source software system and we share our experience and lessons learnt since its adoption. We have used OC in three different modes; direct remote data entry from sites through Global System for Mobile Communications (GSM) modems, a centralized data centre approach where all data from paper records were entered at a central location and an off-line approach where data entry was done from a copy of database hosted on a field-site server laptop, then data uploaded to a centralized server later. We have used OC in eleven trials/studies with a cumulative number of participants in excess of 6000. These include large and complex trials, with multiple sites recruiting in different regions of East Africa. In the process, we have developed substantial local capacity through hands-on training and mentorship, which we have now begun to share with other institutions in the region. Our experience demonstrates that an open source data management system to manage trials' data can be utilized to international industry standards in resource-poor countries.


Dental fluorosis associated with hereditary diabetes insipidus.
Among the characteristics of hereditary pituitary diabetes insipidus are polydipsia and polyuria from early infancy. Drinking of large amounts of water, even with lower than accepted fluoride content, can produce fluorosis of the teeth. A mother and her four children affected by this disorder presented different degrees of fluorosis directly related to the stage at which hormonal therapy was introduced.


Endothelial chylomicron binding is altered by interaction with high-density lipoprotein in Heymann's nephritis.
Very-low-density lipoprotein (VLDL) catabolism is impaired in the nephrotic syndrome, partly as a result of structural changes that impair endothelial binding in the presence of lipoprotein lipase. Previous results suggested that postsynthetic modification of VLDL by high-density lipoprotein (HDL) in nephrotic syndrome rats causes their failure to bind endothelia normally. It is unknown (1) whether the structure of secreted lipoproteins is normal before exposure to nephrotic syndrome serum and (2) whether the same structural or functional defects are imparted to chylomicrons (CMs) through their interaction with HDL from nephrotic syndrome rats. CMs were isolated from thoracic duct lymph from rats with passive Heymann's nephritis (HN) and normal controls. CMs from control rats were incubated with HDL from either HN or control rats and reisolated, and apolipoprotein E (apo E) content and endothelial binding were determined. We found that CMs secreted by HN and control rats had similar apo E/B-48 ratios. HDL from HN rats had significantly lower apo E/A-I ratios than controls. Incubation of nascent control CMs with control HDL resulted in a 4-fold increase in CM apo E content, but binding was unaffected. Incubation with HDL from HN resulted in only a 50% increase in CM apo E content but reduced binding of these treated CMs by 50% compared either with nascent control CMs or with CMs incubated with control HDL. HDL from rats with HN alters CM binding to lipoprotein lipase by a mechanism that does not involve reducing the content of apo E already present on CMs at the time of secretion.


Multi-scale measurements show limited soil greenhouse gas emissions in Kenyan smallholder coffee-dairy systems.
Efforts have been made in recent years to improve knowledge about soil greenhouse gas (GHG) fluxes from sub-Saharan Africa. However, data on soil GHG emissions from smallholder coffee-dairy systems have not hitherto been measured experimentally. This study aimed to quantify soil GHG emissions at different spatial and temporal scales in smallholder coffee-dairy farms in Murang'a County, Central Kenya. GHG measurements were carried out for one year, comprising two cropping seasons, using vented static chambers and gas chromatography. Sixty rectangular frames were installed on two farms comprising the three main cropping systems found in the area: 1) coffee (Coffea arabica L.); 2) Napier grass (Pennisetum purpureum); and 3) maize intercropped with beans (Zea mays and Phaseolus vulgaris). Within these fields, chambers were allocated on fertilised and unfertilised locations to capture spatial variability. Cumulative annual fluxes in coffee plots ranged from 1 to 1.9kgN2O-Nha-1, 6.5 to 7.6MgCO2-Cha-1 and -3.4 to -2.2kgCH4-Cha-1, with 66% to 94% of annual GHG fluxes occurring during rainy seasons. Across the farm plots, coffee received most of the N inputs and had 56% to 89% higher emissions of N2O than Napier grass, maize and beans. Within farm plots, two to six times higher emissions were found in fertilised hotspots - around the perimeter of coffee trees or within planted maize rows - than in unfertilised locations between trees, rows and planting holes. Background and induced soil N2O emissions from fertiliser and manure applications in the three cropping systems were lower than hypothesized from previous studies and empirical models. This study supplements methods and underlying data for the quantification of GHG emissions at multiple spatial and temporal scales in tropical, smallholder farming systems. Advances towards overcoming the dearth of data will facilitate the understanding of synergies and tradeoffs of climate-smart approaches for low emissions development.


Environment, cancer and inequalities-The urgent need for prevention.
The proportion of total deaths attributable to environmental factors is estimated to be 23% of global deaths and 22% of global disability-adjusted life years (DALYs) according to one review. These estimates encompass all environmental agents including infectious agents but excluding behavioural factors. The authors of the review also estimated that 16% (95% CI: 7-41%) of cancer deaths are attributable to environmental risk factors (and 36% [95% CI: 17-52%] for lung cancer). In this article, we focus on the reasons why epidemiology is often unable to account for the whole burden of environmental carcinogens. The experience of air pollution is particularly instructive. While in the 1970s and early 1980s, air pollution was considered as a relatively marginal exposure in terms of attributable risks, the most recent estimate is that it accounts for 7.6% of global deaths and 4.2% of global DALYs world-wide (with East and South Asia accounting for 59% of the total). According to a review, ambient fine particulate matter air pollution contributed to 17.1% of ischaemic heart disease, 14.2% of cerebrovascular disease, 16.5% of lung cancer, 24.7% of low respiratory infections, and 27.1% of COPD mortality in 2015. Estimates for cancer as a whole are not available. The change in appreciation of the role of air pollution has been mainly due to the refinement of exposure assessment methods and the new generations of longitudinal studies. Mechanistic evidence via omic technologies is now rapidly increasing, thus lending credibility to previous epidemiological ('black box') associations. Much less is known about other environmental contaminants, some of which are widespread and pervasive, thus suggesting the need for the same rigourous methods as those applied to air pollution. Finally, a crucial issue remains inequality across different population groups, with uneven exposure to hazards and acquired susceptibilities due to multiple concomitant exposures and poorer health status.


Sustained and Long-Term Release of Doxorubicin from PLGA Nanoparticles for Eliciting Anti-Tumor Immune Responses.
Immunogenic cell death (ICD) is a powerful trigger eliciting strong immune responses against tumors. However, traditional chemoimmunotherapy (CIT) does not last long enough to induce sufficient ICD, and also does not guarantee the safety of chemotherapeutics. To overcome the disadvantages of the conventional approach, we used doxorubicin (DOX) as an ICD inducer, and poly(lactic-co-glycolic acid) (PLGA)-based nanomedicine platform for controlled release of DOX. The diameter of 138.7 nm of DOX-loaded PLGA nanoparticles (DP-NPs) were stable for 14 days in phosphate-buffered saline (PBS, pH 7.4) at 37 °C. Furthermore, DOX was continuously released for 14 days, successfully inducing ICD and reducing cell viability in vitro. Directly injected DP-NPs enabled the remaining of DOX in the tumor site for 14 days. In addition, repeated local treatment of DP-NPs actually lasted long enough to maintain the enhanced antitumor immunity, leading to increased tumor growth inhibition with minimal toxicities. Notably, DP-NPs treated tumor tissues showed significantly increased maturated dendritic cells (DCs) and cytotoxic T lymphocytes (CTLs) population, showing enhanced antitumor immune responses. Finally, the therapeutic efficacy of DP-NPs was maximized in combination with an anti-programmed death-ligand 1 (PD-L1) antibody (Ab). Therefore, we expect therapeutic efficacies of cancer CIT can be maximized by the combination of DP-NPs with immune checkpoint blockade (ICB) by achieving proper therapeutic window and continuously inducing ICD, with minimal toxicities.


Primary hyperoxaluria type 1: a cluster of new mutations in exon 7 of the AGXT gene.
Primary hyperoxaluria type 1 (PH1) is a severe autosomal recessive inborn error of glyoxylate metabolism caused by deficiency of the hepatic peroxisomal enzyme alanine:glyoxylate aminotransferase. This enzyme is encoded by the AGXT gene on chromosome 2q37.3. DNA samples from 79 PH1 patients were studied using single strand conformation polymorphism analysis to detect sequence variants, which were then characterised by direct sequencing and confirmed by restriction enzyme digestion. Four novel mutations were identified in exon 7 of AGXT: a point mutation T853C, which leads to a predicted Ile244Thr amino acid substitution, occurred in nine patients. Two other mutations in adjacent nucleotides, C819T and G820A, mutated the same codon at residue 233 from arginine to cysteine and histidine, respectively. The fourth mutation, G860A, introduced a stop codon at amino acid residue 246. Enzyme studies in these patients showed that AGT catalytic activity was either very low or absent and that little or no immunoreactive protein was present. Together with a new polymorphism in exon 11 (C1342A) these findings underline the genetic heterogeneity of the AGXT gene. The novel mutation T853C is the second most common mutation found to date with an allelic frequency of 9% and will therefore be of clinical importance for the diagnosis of PH1.


A Golgi-targeting fluorescent probe for labile Fe(ii) to reveal an abnormal cellular iron distribution induced by dysfunction of VPS35.
Iron is involved in numerous physiologically essential processes in our body. However, excessive iron is a pathogenic factor in neurodegenerative diseases, causing aberrant oxidative stress. Divalent metal transporter 1 (DMT1) acts as a primary transporter of Fe(ii) ions. The intracellular delivery of DMT1 toward the cellular membrane via the trans-Golgi network during the endocytotic process is partially regulated by a retromer-mediated protein-sorting system comprising vacuolar protein-sorting proteins (VPSs). Thus, together with DMT1, the Golgi-apparatus acts as a hub organelle in the delivery system for intracellular Fe(ii) ions. Dysfunction of the VPS-relevant protein sorting system can induce the abnormal delivery of DMT1 toward lysosomes concomitantly with Fe(ii) ions. To explore this issue, we developed a fluorescent probe, Gol-SiRhoNox, for the Golgi-specific detection of Fe(ii) ions by integrating our original N-oxide-based Fe(ii)-specific chemical switch, a new Golgi-localizable chemical motif, and polarity-sensitive fluorogenic scaffold. Our synchronous imaging study using Gol-SiRhoNox and LysoRhoNox, a previously developed fluorescent probe for lysosomal Fe(ii), revealed that the intracellular distribution balance of Fe(ii) ions between the Golgi apparatus and lysosomes is normally Golgi-dominant, whereas the lysosome-specific elevation of Fe(ii) ions was observed in cells with induced dysfunction of VPS35, a member of the retromer complex. Treatment of cells with dysfunctional VPS35 with R55, a molecular chaperone, resulted in the restoration of the subcellular distribution of Fe(ii) ions to the Golgi-dominant state. These results indicate that the impairment of the DMT1 traffic machinery affects subcellular iron homeostasis, promoting Fe(ii) leakage at the Golgi and lysosomal accumulation of Fe(ii) through missorting of DMT1.


Photon-number-resolving detection based on InGaAs/InP avalanche photodiode in the sub-saturated mode.
We demonstrated a robust spike cancellation by virtue of optical balancing technique for the near-infrared single-photon detection based on InGaAs/InP avalanche photodiode. A 31 dB suppression of the spike noise provided an efficient technique to read out weak avalanche currents at the early built-up, allowing the study on the photon number resolving dynamics of the InGaAs/InP avalanche photodiode. With the detection efficiency varied from 1% to 36%, the avalanche gain was shown to vary from the linear mode to the saturated mode and evidenced as a sub-saturated avalanche state. Multi-photon avalanche saturation was observed at different photon numbers as the avalanche gain varied. A photon-number-resolving detection was achieved with the detection efficiency as high as 36%.


Pediatric cervicofacial necrotizing fasciitis: a case report and review of a 10-year national pediatric database.
To present a case of a pediatric cervicofacial necrotizing fasciitis (NF), a rapidly progressive infection, and a review of a 10-year pediatric inpatient database. Case report and review. Pediatric intensive care unit. A healthy 5-year-old male who developed NF of the lower lip 36 hours following minor trauma. International Classification of Diseases, Ninth Revision, code 728.86 (NF), was the inclusion criteria for the Kids' Inpatient Database (KID) in 1997 and 2006. A pediatric case is presented with a thorough photographic record demonstrating the need for rapid diagnosis and treatment. In a review of the KID from 1997 and 2006, the relative risk of being discharged with NF in 2006 vs 1997 was 1.4 (95% CI, 9.95-2.28). Age at diagnosis of NF was older in 2006 compared with 1997 (11.5 years vs 8.05 years; P < .001). Deaths with a diagnosis of NF increased from 1997 compared with 2006: from 3.9% to 5.4%. In 2006, the odds of death were 15.1 times higher in pediatric discharges with a diagnosis of NF compared with discharges without a diagnosis of NF (P < .001; 95% CI, 9.3-23.1). Even with the advent of new treatments and antibiotics, the incidence and death rates of NF have changed little over the past 10 years. While it is still a rare diagnosis, knowledge and awareness of necrotizing fasciitis with aggressive medical and surgical treatment are still the foundation in disease survival.


Breast Implant-Associated Anaplastic Large Cell Lymphoma in Australia and New Zealand: High-Surface-Area Textured Implants Are Associated with Increased Risk.
The association between breast implants and breast implant-associated anaplastic large cell lymphoma (ALCL) has been confirmed. Implant-related risk has been difficult to estimate to date due to incomplete datasets. All cases in Australia and New Zealand were identified and analyzed. Textured implants reported in this group were subjected to surface area analysis. Sales data from three leading breast implant manufacturers (i.e., Mentor, Allergan, and Silimed) dating back to 1999 were secured to estimate implant-specific risk. Fifty-five cases of breast implant-associated ALCL were diagnosed in Australia and New Zealand between 2007 and 2016. The mean age of patients was 47.1 years and the mean time of implant exposure was 7.46 years. There were four deaths in the series related to mass and/or metastatic presentation. All patients were exposed to textured implants. Surface area analysis confirmed that higher surface area was associated with 64 of the 75 implants used (85.3 percent). Biocell salt loss textured (Allergan, Inamed, and McGhan) implants accounted for 58.7 percent of the implants used in this series. Comparative analysis showed the risk of developing breast implant-associated ALCL to be 14.11 times higher with Biocell textured implants and 10.84 higher with polyurethane (Silimed) textured implants compared with Siltex textured implants. This study has calculated implant-specific risk of breast implant-associated ALCL. Higher-surface-area textured implants have been shown to significantly increase the risk of breast implant-associated ALCL in Australia and New Zealand. The authors present a unifying hypothesis to explain these observations.


Oncogenic KRAS confers chemoresistance by upregulating NRF2.
Oncogenic KRAS mutations found in 20% to 30% of all non-small cell lung cancers (NSCLC) are associated with chemoresistance and poor prognosis. Here we demonstrate that activation of the cell protective stress response gene NRF2 by KRAS is responsible for its ability to promote drug resistance. RNAi-mediated silencing of NRF2 was sufficient to reverse resistance to cisplatin elicited by ectopic expression of oncogenic KRAS in NSCLC cells. Mechanistically, KRAS increased NRF2 gene transcription through a TPA response element (TRE) located in a regulatory region in exon 1 of NRF2. In a mouse model of mutant KrasG12D-induced lung cancer, we found that suppressing the NRF2 pathway with the chemical inhibitor brusatol enhanced the antitumor efficacy of cisplatin. Cotreatment reduced tumor burden and improved survival. Our findings illuminate the mechanistic details of KRAS-mediated drug resistance and provide a preclinical rationale to improve the management of lung tumors harboring KRAS mutations with NRF2 pathway inhibitors.


T cells specific for different latent and lytic viral proteins efficiently control Epstein-Barr virus-transformed B cells.
Epstein-Barr virus (EBV)-associated post-transplant lymphoproliferative disorders (PTLD) belong to the most dreaded complications of immunosuppression. The efficacy of EBV-specific T-cell transfer for PTLD has been previously shown, yet the optimal choice of EBV-derived antigens inducing polyclonal CD4(+) and CD8(+) T cells that cover a wide range of human leukocyte antigen types and efficiently control PTLD remains unclear. A pool of 125 T-cell epitopes from seven latent and nine lytic EBV-derived proteins (EBVmix) and peptide pools of EBNA1, EBNA3c, LMP2a and BZLF1 were used to determine T-cell frequencies and to isolate T cells through the use of the interferon (IFN)-γ cytokine capture system. We further evaluated the phenotype and functionality of the generated T-cell lines in vitro. EBVmix induced significantly higher T-cell frequencies and allowed selecting more CD4(+)IFN-γ(+) and CD8(+)IFN-γ(+) cells than single peptide pools. T cells of all specificities expanded similarly in vitro, recognized cognate antigen, and, to a lower extent, EBV-infected cells, exerted moderate cytotoxicity and showed reduced alloreactivity. However, EBVmix-specific cells most efficiently controlled EBV-infected lymphoblastoid cell lines (LCLs). This control was mainly mediated by EBV-specific CD8(+) cells with an oligoclonal epitope signature covering both latent and lytic viral proteins. Notably, EBV-specific CD4(+) cells unable to control LCLs produced significantly less perforin and granzyme B, probably because of limited LCL epitope presentation. EBVmix induces a broader T-cell response, probably because of its coverage of latent and lytic EBV-derived proteins that may be important to control EBV-transformed B cells and might offer an improvement of T-cell therapies.


Role of the area postrema in the hypophagic effects of oleoylethanolamide.
The satiety-promoting action of oleoylethanolamide (OEA) has been associated to the indirect activation of selected brain areas, such as the nucleus of the solitary tract (NST) in the brainstem and the tuberomammillary (TMN) and paraventricular (PVN) nuclei in the hypothalamus, where noradrenergic, histaminergic and oxytocinergic neurons play a necessary role. Visceral ascending fibers were hypothesized to mediate such effects. However, our previous findings demonstrated that the hypophagic action of peripherally administered OEA does not require intact vagal afferents and is associated to a strong activation of the area postrema (AP). Therefore, we hypothesized that OEA may exert its central effects through the direct activation of this circumventricular organ. To test this hypothesis, we subjected rats to the surgical ablation of the AP (APX rats) and evaluated the effects of OEA (10mgkg-1 i.p.) on food intake, Fos expression, hypothalamic oxytocin (OXY) immunoreactivity and on the expression of dopamine beta hydroxylase (DBH) in the brainstem and hypothalamus. We found that the AP lesion completely prevented OEA's behavioral and neurochemical effects in the brainstem and the hypothalamus. Moreover OEA increased DBH expression in AP and NST neurons of SHAM rats while the effect in the NST was absent in APX rats, thus suggesting the possible involvement of noradrenergic AP neurons. These results support the hypothesis of a necessary role of the AP in mediating OEA's central effects that sustain its pro-satiety action.


Food-cue affected motor response inhibition and self-reported dieting success: a pictorial affective shifting task.
Behavioral inhibition is one of the basic facets of executive functioning and is closely related to self-regulation. Impulsive reactions, that is, low inhibitory control, have been associated with higher body mass index (BMI), binge eating, and other problem behaviors (e.g., substance abuse, pathological gambling, etc.). Nevertheless, studies which investigated the direct influence of food-cues on behavioral inhibition have been fairly inconsistent. In the current studies, we investigated food-cue affected behavioral inhibition in young women. For this purpose, we used a go/no-go task with pictorial food and neutral stimuli in which stimulus-response mapping is reversed after every other block (affective shifting task). In study 1, hungry participants showed faster reaction times to and omitted fewer food than neutral targets. Low dieting success and higher BMI were associated with behavioral disinhibition in food relative to neutral blocks. In study 2, both hungry and satiated individuals were investigated. Satiation did not influence overall task performance, but modulated associations of task performance with dieting success and self-reported impulsivity. When satiated, increased food craving during the task was associated with low dieting success, possibly indicating a preload-disinhibition effect following food intake. Food-cues elicited automatic action and approach tendencies regardless of dieting success, self-reported impulsivity, or current hunger levels. Yet, associations between dieting success, impulsivity, and behavioral food-cue responses were modulated by hunger and satiation. Future research investigating clinical samples and including other salient non-food stimuli as control category is warranted.


Ultrasonic decalcification offers new perspectives for rapid FISH, DNA, and RT-PCR analysis in bone marrow trephines.
The requisite analyses on bone marrow biopsies are increasing: Molecular analyses such as fluorescence in situ hybridization (FISH), polymerase chain reaction (PCR), and reverse transcriptase (RT)-PCR are demanded in addition to morphology and immunohistochemistry to improve diagnostic accuracy. Moreover, analysis of certain molecular prognostic or predictive biomarkers is increasingly mandatory in the assessment of hematologic diseases. In some circumstances, only formalin fixed, bone-containing tissue is available for molecular analysis. Because various fixation and decalcification procedures can impair DNA and RNA quality, there is an urgent need for standardized decalcification protocols which allow FISH and PCR analysis. In this study we developed a routinely applicable decalcification protocol to optimize the molecular analysis method although preserving morphology and immunohistochemical results. Therefore, we compared 2 different approaches including ultrasonic decalcification versus nonultrasonic procedures and ethylenediaminetetraacetate-based reagents versus acid-based ones. In our hands, the combined use of ultrasound and ethylenediaminetetraacetate-based reagents permits successful interphase FISH, PCR, and RT-PCR analysis whereas concomitantly preserving morphology and antigeneicity.


Assessing the quality of corporate social responsibility reports: the case of reporting practices in selected European Union member states.
The organization may communicate its engagement in sustainability and may presents results achieved in this field by creating and publishing corporate social responsibility (CSR) reports. Today, we can observe a growing number of companies issuing such reports as a part of their annual reports or as stand-alone CSR reports. Despite the increase in the number of such reports their quality is different. CSR reports do not always provide complete data that readers desire, which in turn intensifies the problem with the evaluation and comparison of the organization's results achieved in this scope. Differences also occur between reporting models used in different EU countries caused by, inter alia, differently applied EU legislation on the disclosure of non-financial information in different Member States. This paper is one of the first attempts to perform a quantitative and qualitative analysis of corporate sustainability reporting practices in several European Union countries. The purpose of this article is to present the current state of CSR reporting practices in selected EU Member States and identify the differences in the quality and level of this kind of practices, taking into account the mandatory and voluntary model of disclosure. The study included separate CSR reports as well as annual reports with CSR sections and integrated reports published in 2012 in six selected EU Member States. The authors have used a specific evaluation tool in the examination of the individual reports. The assessment questionnaire consists of seventeen criteria grouped into two categories (relevance and credibility of information). In order to assess the quality of examined reports, the authors aggregated the indicators related with the reporting practices. The findings show that the quality level of the studied reports is generally low. Referring to its components, the relevance of the information provided in the assessed reports is at the higher level than its credibility. The study also indicates that the legal obligation of CSR data disclosure has a positive effect on the quality of CSR reports.


Integrating DSM-IV factors to predict violence in high-risk psychiatric patients.
This study incorporated Axis-II and Axis-IV factors in DSM-IV to test the relationship between predicted risk for violence assessed in the psychiatric emergency room and actual violence during hospitalization. Psychiatric nurses lack an objective instrument to use during the acute psychiatric assessment. The retrospective study comprised consecutive psychiatric admissions (n = 161) in one tertiary veterans' hospital. Statistical testing for the predictive power of risk factors, relationships between variables, and violent events included nonparametric tests, factor analysis, and logistic regression. Of the 32 patients who committed violence during hospitalization, 12 had committed violence in the psychiatric emergency room. Statistical significance was shown for violent incidents and dementia, court-ordered admission, mood disorder, and for three or more risk factors. The 13-item Risk of Violence Assessment (ROVA) scale suggests validity and sensitivity for rating DSM-IV factors and psychosocial stressors to predict risk for violence during hospitalization. Replication studies are recommended to strengthen validity of the ROVA scale.


Using a Concept Inventory to Reveal Student Thinking Associated with Common Misconceptions about Antibiotic Resistance.
Misconceptions, also known as alternate conceptions, about key concepts often hinder the ability of students to learn new knowledge. Concept inventories (CIs) are designed to assess students' understanding of key concepts, especially those prone to misconceptions. Two-tiered CIs include prompts that ask students to explain the logic behind their answer choice. Such two-tiered CIs afford an opportunity for faculty to explore the student thinking behind the common misconceptions represented by their choice of a distractor. In this study, we specifically sought to probe the misconceptions that students hold prior to beginning an introductory microbiology course (i.e., preconceptions). Faculty-learning communities at two research-intensive universities used the validated Host-Pathogen Interaction Concept Inventory (HPI-CI) to reveal student preconceptions. Our method of deep analysis involved communal review and discussion of students' explanations for their CI answer choice. This approach provided insight valuable for curriculum development. Here the process is illustrated using one question from the HPI-CI related to the important topic of antibiotic resistance. The frequencies with which students chose particular multiple-choice responses for this question were highly correlated between institutions, implying common underlying misconceptions. Examination of student explanations using our analysis approach, coupled with group discussions within and between institutions, revealed patterns in student thinking to the participating faculty. Similar application of a two-tiered concept inventory by general microbiology instructors, either individually or in groups, at other institutions will allow them to better understand student thinking related to key concepts in their curriculum.


Intestinal involvement in progressive systemic sclerosis detected by increased unconjugated serum bile acids.
In patients with progressive systemic sclerosis, impaired motor function of the small intestine may lead to bacterial overgrowth causing diarrhoea, steatorrhoea and malabsorption. As unconjugated serum bile acids have been proposed as markers for small bowel bacterial overgrowth, we studied individual unconjugated serum bile acids in 36 patients with progressive systemic sclerosis. These patients had significantly higher serum concentrations of unconjugated cholic acid (median 0.18; range 0.05-30.75 v 0.09; 0.01-0.19 mumol/l, p less than 0.001) and chenodeoxycholic acid (0.10; 0.01-6.83 v 0.04; 0.01-0.39 mumol/l, p less than 0.025) than healthy controls (n = 16). This difference was mainly due to patients with diarrhoea (n = 10), who had significantly higher concentrations of unconjugated serum bile acids than patients with normal bowel habit (cholic acid median 0.55 v 0.16 mumol/l, p less than 0.001; chenodeoxycholic acid 0.75 v 0.07 mumol/l; p less than 0.005). All patients with raised unconjugated serum bile acids had oesophageal motility disorders. These results confirm a relationship between motility disorders and bacterial overgrowth in patients with progressive systemic sclerosis.


Beyond RCHOP: A Blueprint for Diffuse Large B Cell Lymphoma Research.
Diffuse large B cell lymphoma (DLBCL) comprises multiple molecular and biological subtypes, resulting in a broad range of clinical outcomes. With standard chemoimmunotherapy, there remains an unacceptably high treatment failure rate in certain DLBCL subsets: activated B cell (ABC) DLBCL, double-hit lymphoma defined by the dual translocation of MYC and BCL2, dual protein-expressing lymphomas defined by the overexpression of MYC and BCL2, and older patients and those with central nervous system involvement. The main research challenges for DLBCL are to accurately identify molecular subsets and to determine if specific chemotherapy platforms and targeted agents offer differential benefit. The ultimate goal should be to maximize initial cure rates to improve long-term survival while minimizing toxicity. In particular, a frontline trial should focus on biologically defined risk groups not likely to be cured with cyclophosphamide, doxorubicin, vincristine, and prednisone plus rituximab (R-CHOP). An additional challenge is to develop effective and personalized strategies in the relapsed setting, for which there is no current standard other than autologous stem cell transplantation, which benefits a progressively smaller proportion of patients. Relapsed/refractory DLBCL is the ideal setting for testing novel agents and new biomarker tools and will require a national call for biopsies to optimize discovery in this setting. Accordingly, the development of tools with both prognostic and predictive utility and the individualized application of new therapies should be the main priorities. This report identifies clinical research priorities for critical areas of unmet need in this disease.


Is Aortic Valve Leaflet Morphology Predictive of Outcome in Pediatric Aortic Valve Stenosis?
Initial palliative treatment of congenital aortic valve stenosis consists of either surgical commissurotomy or transcatheter balloon valvuloplasty. The basis for selection of primary approach usually is ill defined. It was hypothesized that aortic valve characteristics may be helpful in directing choice of intervention. This study assesses the impact of valve morphology on time to reintervention after catheter- or surgical-based therapy. A retrospective review of preprocedural echocardiographic aortic outflow characteristics was compared with outcomes of primary surgical or balloon valve interventions. Characteristics studied included (1) annular dimension; (2) leaflet number; (3) leaflet excursion; and (4) degree of leaflet coaptation. Patients included those <20 years with a primary diagnosis of aortic stenosis (AS) and no other hemodynamically significant lesions at our institutions from 2000 to 2011. A total of 102 patients were included, 31 classified as having critical and 71 as having noncritical aortic stenosis. Of the patients, 79 were male, and 50 underwent primary catheter intervention. Echo parameters were compared with procedural outcome as defined by death or need for reintervention. Receiver operator curves were utilized to determine the point within each morphologic feature where the greatest difference occurred. This was utilized as the distinguishing point within each the morphologic group. Analysis was conducted separately for critical and noncritical aortic stenosis. Kaplan-Meier analysis demonstrated no significant difference in time to reintervention or death whether initial palliation consisted of surgical commissurotomy or balloon valvuloplasty with respect to any of the morphologic characteristics studied. Patients with AS do equally well with surgical commissurotomy or balloon valvuloplasty as initial palliation. This holds true for those with either critical or noncritical aortic stenosis. Valve morphology did not help in selection of initial palliative strategy. Current technologies should enable an improved selection of initial palliative approach through thoughtful, randomized trials.


The Children's Respiratory and Environmental Workgroup (CREW) birth cohort consortium: design, methods, and study population.
Single birth cohort studies have been the basis for many discoveries about early life risk factors for childhood asthma but are limited in scope by sample size and characteristics of the local environment and population. The Children's Respiratory and Environmental Workgroup (CREW) was established to integrate multiple established asthma birth cohorts and to investigate asthma phenotypes and associated causal pathways (endotypes), focusing on how they are influenced by interactions between genetics, lifestyle, and environmental exposures during the prenatal period and early childhood. CREW is funded by the NIH Environmental influences on Child Health Outcomes (ECHO) program, and consists of 12 individual cohorts and three additional scientific centers. The CREW study population is diverse in terms of race, ethnicity, geographical distribution, and year of recruitment. We hypothesize that there are phenotypes in childhood asthma that differ based on clinical characteristics and underlying molecular mechanisms. Furthermore, we propose that asthma endotypes and their defining biomarkers can be identified based on personal and early life environmental risk factors. CREW has three phases: 1) to pool and harmonize existing data from each cohort, 2) to collect new data using standardized procedures, and 3) to enroll new families during the prenatal period to supplement and enrich extant data and enable unified systems approaches for identifying asthma phenotypes and endotypes. The overall goal of CREW program is to develop a better understanding of how early life environmental exposures and host factors interact to promote the development of specific asthma endotypes.


Formation of hydroxyphenyl-pyranoanthocyanins in Grenache wines: precursor levels and evolution during aging.
Grenache red wines were produced following three different winemaking techniques, that is, small-scale standard experimental wines and industrial-scale wines by both double-mash fermentation and fermentation in Ganimede vats. Wines were analyzed for their color properties, as well as the anthocyanin, flavonol, hydroxycinnamic acid, and pyranoanthocyanin profiles following alcoholic and malolactic fermentation. The evolution of pyranoanthocyanins and their corresponding precursors in the experimental wines was monitored at 6 and 10 months of aging. Wines produced by double-mash fermentation exhibited superior color properties compared to Ganimede wines and the experimental red wines, due to better extraction of flavonols and anthocyanins as well as a lower degree of polymerization. Pyranoanthocyanin formation varied within the different classes of pigments. Vitisins A and B were formed only during alcoholic fermentation. Pinotin A (i.e., the reaction product from malvidin 3-glucoside and caffeic acid) formation took place only during the aging process, whereas formation of hydroxyphenyl-pyranoanthocyanins derived from p-coumaric and ferulic acid followed two different pathways, that is, an enzymatically assisted production during fermentation and a pure chemical formation during aging.


Stability study of sodium colistimethate-loaded lipid nanoparticles.
In the last decades, the encapsulation of antibiotics into nanoparticulate carriers has gained increasing attention for the treatment of infectious diseases. Sodium colistimethate-loaded solid lipid nanoparticles (Colist-SLNs) and nanostructured lipid carriers (Colist-NLCs) were designed aiming to treat the pulmonary infection associated to cystic fibrosis patients. The nanoparticles were freeze-dried using trehalose as cryoprotectant. The stability of both nanoparticles was analysed over one year according to the International Conference of Harmonisation (ICH) guidelines by determining the minimum inhibitory concentration (MIC) against clinically isolated Pseudomonas aeruginosa strains and by studying their physico-chemical characteristics. The results showed that Colist-SLNs lost their antimicrobial activity at the third month; on the contrary, the antibacterial activity of Colist-NLCs was maintained throughout the study within an adequate range (MIC ≤16 μg/mL). In addition, Colist-NLCs exhibited suitable physico-chemical properties at 5 °C and 25 °C/60% relative humidity over one year. Altogether, Colist-NLCs proved to have better stability than Colist-SLNs.


Seminal fluid excretion of cytomegalovirus related to immunosuppression in homosexual men.
Seminal fluid samples from 84 Danish homosexual men were successfully cultured to determine the prevalence of cytomegalovirus excretion. Ten (15%) out of 66 men positive for the antibody were found to be excreting the virus. Although the proportion excreting was inversely related to age (p less than 0.01), three men aged over 30 and with many years of homosexual experience excreted the virus. In addition, a 50 year old man with Kaposi's sarcoma excreted the virus. A further study of the ratio of T cell helpers to suppressors in the men aged over 30 and a series of age matched non-excreting homosexual control or heterosexual men showed that those excreting cytomegalovirus in their seminal fluid had statistically lower ratios (all less than 0.77) than the controls (p less than 0.05). Excretion of cytomegalovirus may be related to re-emergence of latent infection in immunosuppressed homosexual men.


Mass-Spectrometry-Based Method To Quantify in Parallel Tau and Amyloid β 1-42 in CSF for the Diagnosis of Alzheimer's Disease.
Alzheimer's disease (AD), the most common form of dementia, afflicts about 50 million people worldwide. Currently, AD diagnosis is primarily based on psychological evaluation and can only be confirmed post-mortem. Reliable and objective biomarkers for prognosis and diagnosis have been sought for years. Together, tau and amyloid β 1-42 (Aβ42) in cerebrospinal fluid (CSF) have been shown to provide good diagnostic sensitivity and specificity. Additionally, phosphorylated forms of tau, such as tau pS181, have also shown promising results. However, the measurement of such markers currently relies on antibody-based immunoassays that have shown variability, leading to discrepant results across laboratories. To date, mass spectrometry methods developed to evaluate CSF tau and Aβ42 are not compatible. We present in this article the development of a mass-spectrometry-based method of quantification for CSF tau and Aβ42 in parallel. The absolute concentrations of tau and Aβ42 we measured are on average 50 ng/mL (7-130 ng/mL) and 7.1 ng/mL (3-13 ng/mL), respectively. Analyses of CSF tau and Aβ42, in a cohort of patients with AD, mild cognitive impairment, and healthy controls (30 subjects), provide significant group differences evaluated with ROC curves (AUC(control-AD) and AUC(control-MCI) = 1, AUC(MCI-AD) = 0.76), with at least equivalent diagnostic utility to immunoassay measurements in the same sample set. Finally, a significant and negative correlation was found between the tau and Aβ peptides ratio and the disease severity.


Ginsenoside Rg5 induces apoptosis and autophagy via the inhibition of the PI3K/Akt pathway against breast cancer in a mouse model.
Breast cancer is the most frequently diagnosed cancer and has become the main cause of cancer-related death among women worldwide. Traditional chemotherapy for breast cancer has serious side effects for patients, such as the first-line drug docetaxel. Ginsenoside Rg5, a rare ginsenoside and the main ingredient extracted from fine black ginseng, has been proved to have anti-breast cancer efficacy in vitro. Here, the in vivo anti-breast cancer efficacy, side effects and potential molecular mechanisms of Rg5 were investigated on a BALB/c nude mouse model of human breast cancer. The tumor growth inhibition rate of high dose Rg5 (20 mg kg-1) was 71.4 ± 9.4%, similar to that of the positive control docetaxel (72.0 ± 9.1%). Compared to docetaxel, Rg5 showed fewer side effects in the treatment of breast cancer. Treatment with Rg5 induced apoptosis and autophagy in breast cancer tissues. Rg5 was proved to induce caspase-dependent apoptosis via the activation of the extrinsic death receptor and intrinsic mitochondrial signaling pathways. The autophagy induction was related to the formation of an autophagosome and accumulation of LC3BII, P62 and critical Atg proteins. Further studies showed that Rg5 in a dose-dependent manner induced apoptosis and autophagy through the inhibition of the PI3K/Akt signaling pathway as indicated by the reduced phosphorylation level of PI3K and Akt. Taken together, Rg5 could be a novel and promising clinical antitumor drug targeting breast cancer.


Disruption of CEP290 microtubule/membrane-binding domains causes retinal degeneration.
Mutations in the gene centrosomal protein 290 kDa (CEP290) cause an array of debilitating and phenotypically distinct human diseases, ranging from the devastating blinding disease Leber congenital amaurosis (LCA) to Senior-Løken syndrome, Joubert syndrome, and the lethal Meckel-Gruber syndrome. Despite its critical role in biology and disease, very little is known about CEP290's function. Here, we have identified 4 functional domains of the protein. We found that CEP290 directly binds to cellular membranes through an N-terminal domain that includes a highly conserved amphipathic helix motif and to microtubules through a domain located within its myosin-tail homology domain. Furthermore, CEP290 activity was regulated by 2 autoinhibitory domains within its N and C termini, both of which were found to play critical roles in regulating ciliogenesis. Disruption of the microtubule-binding domain in a mouse model of LCA was sufficient to induce significant deficits in cilium formation, which led to retinal degeneration. These data implicate CEP290 as an integral structural and regulatory component of the cilium and provide insight into the pathological mechanisms of LCA and related ciliopathies. Further, these data illustrate that disruption of particular CEP290 functional domains may lead to particular disease phenotypes and suggest innovative strategies for therapeutic intervention.


Prognostic value of bleeding after percutaneous coronary intervention in patients with diabetes.
The aim of this study was to assess the impact of bleeding after percutaneous coronary intervention (PCI) on the outcome of patients with type 2 diabetes. This study included 4,329 diabetic patients who underwent PCI. Bleeding was assessed using the Bleeding Academic Research Consortium criteria. The primary outcome was one-year mortality. Bleeding events occurred in 474 patients (10.9%). Access-site and non-access-site bleeds occurred in 274 patients (58%) and 200 patients (42%), respectively. Within the first year after PCI there were 198 deaths: 45 deaths (9.6%) among patients with bleeding and 153 deaths (4.0%) among patients without bleeding (adjusted hazard ratio=2.04 [95% confidence interval 1.38-3.00], p<0.001). There were 25 deaths (12.7%) among patients with non-access-site bleeding and 20 deaths (7.4%) among patients with access-site bleeding (odds ratio [OR]=3.45 [2.20-5.41], p<0.001 for non-access-site bleeding vs. no bleeding and OR=1.90 [1.17-3.01], p=0.008 for access-site bleeding vs. no bleeding). Bleeding improved the discriminatory power of the multivariable model for mortality prediction (p=0.002). In patients with diabetes undergoing PCI, occurrence of bleeding within the first 30 days after PCI was associated with a significant increase in the risk of one-year mortality.


Nonlocal propagation and tunnelling of surface plasmons in metallic hourglass waveguides.
The nanofocusing performance of hourglass plasmonic waveguides is studied analytically and numerically. Nonlocal effects in the linearly tapered metal-air-metal stack that makes up the device are taken into account within a hydrodynamical approach. Using this hourglass waveguide as a model structure, we show that spatial dispersion drastically modifies the propagation of surface plasmons in metal voids, such as those generated between touching particles. Specifically, we investigate how nonlocal corrections limit the enormous field enhancements predicted by local electromagnetic treatments of geometric singularities. Finally, our results also indicate the emergence of nonlocality assisted tunnelling of plasmonic modes across hourglass contacts as thick as 0.5 nm.


Cross Sectional and Longitudinal Associations between Cardiovascular Risk Factors and Age Related Macular Degeneration in the EPIC-Norfolk Eye Study.
To examine the cross sectional and longitudinal relationship between cardiovascular risk factors and age-related macular degeneration (AMD) in a large British cohort study. The EPIC Norfolk Eye study is nested in a larger prospective cohort study. Data on cardiovascular risk factors were collected at baseline (1993-1997) and follow up (2006-2011) via clinical examination, validated lifestyle questionnaires and serum blood samples. AMD was ascertained using standardised grading of fundus photographs at the follow up. Logistic regression was used to examine associations between baseline and follow up risk factors with AMD. 5,344 pairs (62.0% of total 8623) of fundus photographs were of sufficient quality for grading of AMD in participants with mean age of 67.4 years old (range 44-91) at diagnosis. There were 28 cases of late AMD (0.5%, 95% confidence interval (CI)=0.3-0.8%) and 645 cases of early AMD (12.1%, 95%CI=11.2-13.0.%). In multivariable analysis, older people with higher levels of baseline high density lipoprotein- cholesterol (HDL-C ) and C-reactive protein (CRP) were more likely to have any signs of AMD, after adjusting for sex, education, smoking, and systolic blood pressure. In cross sectional analysis, only older age and higher HDL were significantly associated with AMD. We have found that older age and higher levels of CRP and HDL-C were associated with increased odds of AMD in this population in the longitudinal analysis, but older age and HDL-C, not CRP was significantly associated with AMD in the cross sectional analysis. The prevalence of AMD in this cohort was low compared to other cohorts in Europe, the US and Australia, and probably reflects the some selection biases in follow up participation as well as the low rate of smoking among our healthy participants.


Current progress in black phosphorus materials and their applications in electrochemical energy storage.
Recently, a new two-dimensional material, single- or few-layered black phosphorus (BP), has attracted considerable attention for applications in electronics, optoelectronics, and batteries due to its unique properties, including large specific surface area, anisotropy, and tunable and direct band gaps. In particular, contributions to electrochemical energy storage devices, such as lithium and sodium ion batteries and supercapacitors, have emerged. However, critical issues remain to be explored before scaled-up commercial production of BP, such as preparation, stability, and performance. Herein, we present the first review of recent progress in BP-based electrochemical energy storage device. The preparation and electrochemical properties of black phosphorus, recent advances, potential challenges, and relevant perspectives in electrochemical energy storage, and the potential of BP are discussed in this work.


Hyperglycemia-induced transcriptional regulation of ROCK1 and TGM2 expression is involved in small artery remodeling in obese diabetic Göttingen Minipigs.
Obesity and diabetes in humans are associated with hypertrophic remodeling and increased media:lumen ratio of small resistance arteries, which is an independent predictor of cardiovascular events. In order to minimize increases in media:lumen ratio, hypertrophic remodeling should be accompanied by outward remodeling. We aimed to investigate the mechanisms of structural remodeling in small pial arteries (PAs) and terminal mesenteric arteries (TMAs) from obese Göttingen Minipigs with or without diabetes. Göttingen Minipigs received either control diet (lean control (LC)), high fat/high fructose/high cholesterol diet (FFC), or FFC diet with streptozotocin (STZ)-induced diabetes (FFC/STZ) for 13 months. At the end of the study (20 months), we assessed body weight, fasting plasma biochemistry, passive vessel dimensions, mRNA expression (matrix metallopeptidases 2/9 (MMP2, MMP9), tissue inhibitor of metallopeptidase 1 (TIMP1), transglutaminase 2 (TGM2), Rho-kinase 1 (ROCK1), TGFβ-receptor 2 (TGFBR2), and IGF1-receptor (IGFR1) genes), and immunofluorescence in PAs and TMAs. We performed multiple linear correlation analyses using plasma values, structural data, and gene expression data. We detected outward hypertrophic remodeling in TMAs and hypertrophic remodeling in PAs from FFC/STZ animals. ROCK1 and TGM2 genes were up-regulated in PAs and TMAs from the FFC/STZ group. Passive lumen diameter (PLD) of TMAs was correlated with plasma values of glucose (GLU), fructosamine (FRA), total cholesterol (TC), and triglycerides (TGs). ROCK1 and TGM2 expressions in TMAs were correlated with PLD, plasma GLU, fructosamine, and TC. ROCK1 and TGM2 proteins were immunolocalized in the media of PAs and TMAs, and their fluorescence levels were increased in the FFC/STZ group. Hyperglycemia/hyperlipidemia is involved in regulation of ROCK1 and TGM2 expression leading to outward remodeling of small resistance arteries in obese diabetic Göttingen Minipigs.


Interactions of Fc receptors with antibodies against Ia antigens and other cell surface components.
Two Fc receptor-dependent tests were investigated to study the question of a relationship between Fc receptors and known cell surface antigens, in particular I region-associated (Ia) antigens: (a) a rosette assay with antibody-coated erythrocytes (EA) as indicator cells and normal mouse lymphoid cells as source of rosette-forming cells, and (b) a cytotoxicity test with antibody-coated erythrocytes as target cells and normal mouse spleen cells as a source of cytotoxic cells (K cells). EA rosettes were specifically inhibited by antibodies reacting with Ia antigens. Various other antisera reacting with antigens on B lymphocytes, like anti-Ly 4.2 (raised in H-2 identical mice), rabbit antimouse B-cell serum, or rabbit antimouse immunoglobulin, also specifically inhibited the rosettes. No inhibition occurred in the presence of allogeneic or xenogeneic antisera reacting with T lymphocytes. K-cell cytotoxicity was specifically inhibited by each of the antisera (reacting with either B cells or T cells). F(ab')2 fragments of anti-Ia antibodies could still specifically inhibit EA rosettes but they could not inhibit K-cell cytotoxicity. Similar results were obtained with F(ab')2 fragments of anti-immunoglobulin antibodies. These results indicate that the mechanism of inhibition of Fc receptors in the two tests was different. In neither of the tests could we find any evidence for a unique association between the Fc receptors and Ia antigens. The Fc receptors on K cells did not seem to be associated at all with Ia antigens.


Structures of neutral and anionic Au(16) clusters revisited.
Using the density functional theory and generalized gradient approximation for exchange and correlation potential, we have performed an extensive search to obtain the ground state geometries of both neutral and anionic Au(16) cluster by considering over 200 low lying isomers. For the neutral Au(16) cluster we found a new T(d) compact structure to be the lowest energy configuration, which is nearly degenerate in total energy with the previously reported C(s) and C(2v) noncage structures. While the Au(16) (-) cluster, in agreement with previous calculations, is found to have a T(d) hollow cage structure, an isomer with a planar structure is found to be lower in energy. The photoelectron spectra from all the nine lowest energy isomers are calculated and compared with experiment to determine the possibility of their existence. Molecular dynamics simulations on both neutral and anionic Au(16) clusters are carried out to provide further insight into the origin and stability of these structures. Our comprehensive study allows us to answer the following questions: (1) Why are the adiabatic and vertical detachment energies of Au(16) cluster nearly identical when the lowest energy structures of the anion and the neutral are so very different? (2) How is Au(16) (-) formed? Is it born neutral and the extra electron attaches afterwards or is it born anionic and the structure evolves during the electron attachment process?


Accessing semantic person knowledge: temporal dynamics of nonstrategic categorical and associative priming.
Recent theories of semantic memory suggest a subdivision into several separate domains of knowledge. The present study examined the structure of semantic person knowledge by analyzing both behavioral and ERP correlates of associative priming (via co-occurrence and/or shared semantic information) versus purely categorical priming (via shared occupational information). Participants performed familiarity decisions for target faces, which were preceded by sandwich-masked prime names at either short (33 msec) or long (1033 msec) SOAs. Although masking effectively prevented explicit prime recognition, faster RTs were generally observed for both associative and categorical priming (relative to an unrelated prime-target condition). At the short SOA, both associatively and categorically primed targets similarly elicited more positive going ERPs compared with unrelated targets in the N400 time range (N400 priming effect), suggesting a common initial mechanism mediating both forms of priming. By contrast, at the long SOA, a typical N400 priming effect was observed for associative priming only, whereas the corresponding effect for categorical priming was small and restricted to a left parietal site. This hitherto unreported interaction of relatedness, and SOA in the N400 suggests an initial fast spreading of activation to a wide range of related targets, which subsequently focuses to more closely related people at longer SOAs. This ability of ERPs to trace the neural dynamics of activation for different forms of prime/target relatedness can be exploited for testing different models of semantic priming.


Paraventricular--suprachiasmatic lesions prevent salt-induced hypertension in Dahl rats.
1. We studied the effects that lesions produced in the paraventricular and suprachiasmatic nuclei and intervening periventricular area had on 24 h mean circadian blood pressures in Dahl salt-sensitive and -resistant rats and their sham-operated controls. We measured blood pressures while the animals were on a low salt diet and after 1, 5 and 13 weeks of 8% NaCl diet. 2. Salt-sensitive rats with lesions had lower blood pressures than salt-sensitive sham-operated controls at all points of the study. In contrast, identical lesions in salt-resistant rats produced a transient pressor response to the diet. Twenty-four hour mean heart rate, determined after 13 weeks of 8% NaCl intake, was low only in salt-sensitive rats with lesions. Sodium intake and excretion per kg of body weight, as well as plasma sodium concentrations, were similar in all groups. 3. We conclude that the anteromedial hypothalamic area, which includes the paraventricular nucleus, the suprachiasmatic nucleus and the intervening periventricular area, participates in the development of Dahl hypertension. We suggest that a multifactorial mechanism is involved: (a) the facilitatory role of this region in ACTH release, (b) this region's participation in the baroreceptor reflex via vasopressinergic efferents to the nucleus of the tractus solitarius, and (c) the roles of the paraventricular and suprachiasmatic nuclei in the regulation of salt and water balance.


Heart Rate and Heart Rate Variability Correlate with Clinical Reasoning Performance and Self-Reported Measures of Cognitive Load.
Cognitive load is a key mediator of cognitive processing that may impact clinical reasoning performance. The purpose of this study was to gather biologic validity evidence for correlates of different types of self-reported cognitive load, and to explore the association of self-reported cognitive load and physiologic measures with clinical reasoning performance. We hypothesized that increased cognitive load would manifest evidence of elevated sympathetic tone and would be associated with lower clinical reasoning performance scores. Fifteen medical students wore Holter monitors and watched three videos depicting medical encounters before completing a post-encounter form and standard measures of cognitive load. Correlation analysis was used to investigate the relationship between cardiac measures (mean heart rate, heart rate variability and QT interval variability) and self-reported measures of cognitive load, and their association with clinical reasoning performance scores. Despite the low number of participants, strong positive correlations were found between measures of intrinsic cognitive load and heart rate variability. Performance was negatively correlated with mean heart rate, as well as single-item cognitive load measures. Our data signify a possible role for using physiologic monitoring for identifying individuals experiencing high cognitive load and those at risk for performing poorly during clinical reasoning tasks.


Hydrophobic Patch of Ubiquitin is Important for its Optimal Activation by Ubiquitin Activating Enzyme E1.
Protein ubiquitination plays a role in essentially every process in eukaryotic cells. The attachment of ubiquitin (Ub) or Ub-like (UBL) proteins to target proteins is achieved by parallel but distinct cascades of enzymatic reactions involving three enzymes: E1, E2, and E3. The E1 enzyme functions at the apex of this pathway and plays a critical role in activating the C-terminus of ubiquitin or UBL, which is an essential step that triggers subsequent downstream transfer to their cognate E2s resulting in the fidelity of the Ub/UBL conjugation machinery. Despite the central role of the E1 enzyme in protein modification, a quantitative method to measure Ub/UBL activation by E1 is lacking. Here, we present a mass spectrometry-based assay to accurately measure the activation of Ub/UBL by E1 independent of the E2/E3 enzymes. Our method does not require radiolabeling of any components and therefore can be used in any biochemical laboratory having access to a mass spectrometer. This method allowed us to dissect the concerted process of E1-E2-catalyzed Ub conjugation in order to separately characterize the process of Ub activation and how it is affected by select mutations and other factors. We found that the hydrophobic patch of Ub is important for the optimal activation of Ub by E1. We further show that the blockers of the Ub-proteasome system such as ubistatin and fullerenol inhibit Ub activation by E1. Interestingly, our data indicate that the phosphorylation of Ub at the S65 position augments its activation by the E1 enzyme.


A morphologic study of intrahepatic portal-vein islet isografts.
Isologous pancreatic islets were implanted into the portal vein of rats with streptozotocin-induced diabetes. At intervals of from one to 32 days after transplantation, the intrahepatic islet grafts were examined histologically and ultrastructurally, and their vascular supply was determined by later perfusion studies. Implanted islets were found widely dispersed throughout the liver in peripheral interlobular portal venules and surrounded by vacuolated liver cells containing large stores of glycogen. The endocrine cells were structurally normal in each interval examined. By the third day after transplantation the beta cells were depleted of secretory granules in aldehyde-fuchsin preparations. Regranulation returned by the 14th day and was associated with secretory organelle hypertrophy and hyperplasia. Islet cells were found outside the portal areas in direct apposition to hepatocytes forming distinct desmosomes by the first day. While hemoperfusion of the grafts occurred from the moment of implantation into the portal venule, a dual vascular supply derived from periportal arterial and venous sources developed by the 11th day after transplantation, establishing full vascularization of the grafts. Preliminary work is presented to show that an active ingrowth of nerves in the islet graft occurs in association with the process of vascularization.


Visual attention modulates brain activation to angry voices.
In accordance with influential models proposing prioritized processing of threat, previous studies have shown automatic brain responses to angry prosody in the amygdala and the auditory cortex under auditory distraction conditions. However, it is unknown whether the automatic processing of angry prosody is also observed during cross-modal distraction. The current fMRI study investigated brain responses to angry versus neutral prosodic stimuli during visual distraction. During scanning, participants were exposed to angry or neutral prosodic stimuli while visual symbols were displayed simultaneously. By means of task requirements, participants either attended to the voices or to the visual stimuli. While the auditory task revealed pronounced activation in the auditory cortex and amygdala to angry versus neutral prosody, this effect was absent during the visual task. Thus, our results show a limitation of the automaticity of the activation of the amygdala and auditory cortex to angry prosody. The activation of these areas to threat-related voices depends on modality-specific attention.


Development of toxicity values and exposure estimates for tetrabromobisphenol A: application in a margin of exposure assessment.
Tetrabromobisphenol A (TBBPA) is used in a diverse array of products to improve fire safety. The National Toxicology Program (NTP) recently completed a 2-year bioassay for TBBPA. The objective of the present study was to develop a cancer-based and a non-cancer based toxicity value and to compare such to appropriate estimates of human exposure. Data from the NTP 2-year and 13-week studies were selected to develop candidate toxicity values. Benchmark dose modeling and subsequent evaluation of candidate values resulted in selection of an oral reference dose (RfD) of 0.6 mg kg(-1) day(-1) based on uterine hyperplasia in rats and an oral cancer slope factor (OSF) of 0.00315 per mg kg(-1) day(-1) based on an increased incidence of uterine tumors in rats. Lifetime average daily dose (LADD) estimates ranged from 2.2 E(-7) to 3.9 E(-6) mg kg(-1) day(-1) based on age-adjusted exposures to TBBPA via breast milk consumption, dietary intake, soil/dust ingestion and drinking water ingestion in infants, young children, older children and adults. Average daily dose (ADD) estimates ranged from 3.2 E (-7) to 8.4 E(-5) mg kg(-1) day(-1). Resulting margin of exposure (MOE) values were > 800 000 for non-cancer endpoints and > 32,000,000 for cancer-based endpoints. These data collectively indicate a low level of health concern associated with exposures to TBBPA based on current data. It is anticipated that the exposure estimates, along with the toxicity values described within, should be informative for understanding human health hazards associated with TBBPA.


Results from the UK cohort of SOLVE: providing insights into the timing of insulin initiation in people with poorly controlled type 2 diabetes in routine clinical practice.
SOLVE was a large observational study of more than 17,000 insulin-naïve patients with type 2 diabetes, investigating basal insulin analogue initiation in a primary care setting across a diverse geographical area. The current analysis aimed to compare and contrast the results of the UK cohort with the previously published global population results. This analysis compares the UK cohort of SOLVE (n=761) with the global population (n=17,374). Patients eligible for the study were those for whom a clinical decision had been made to initiate treatment with a basal insulin analogue once daily as an add-on to existing OAD therapy. The UK cohort had a higher baseline HbA1c compared to the global population of SOLVE (9.8% vs. 8.9%, respectively) despite a shorter duration of disease, indicating that strict glycaemic targets set by international organisations are not being achieved in the UK. Following 24 weeks' treatment with insulin detemir, patients in the UK achieved a reduction in HbA1c of -1.3%, the same as the reduction achieved in the global population; however, a higher dose of insulin detemir was required in the UK than in the global population. Findings from the UK cohort of SOLVE show that it is possible to improve glycaemic control and reduce HbA1c in patients previously uncontrolled with oral antidiabetic drug therapy, in a primary setting, despite clinical inertia.


Genetic destabilization of Candida albicans by hydroxyurea.
Candida albicans is a commensal component of the normal human microflora, but frequently causes infections in persons undergoing treatment for malignancies. The cytotoxicity and genotoxicity of the antineoplastic agent hydroxyurea (HU) for the yeast is demonstrated. Cultivation of the organism on defined complete medium in the presence of HU induced growth inhibition or cell death, gene mutations, segregations of heterozygous loci through reciprocal and nonreciprocal mitotic recombinations, and a special heritable system for high frequency switching between phenotypes reflecting cellular growth characteristics and susceptibilities to HU. Each of these responses is influenced differently by variations in drug concentration and temperature. The biochemical complexity underlying cytotoxic and genetic effects of HU, and the implications for the likelihood of HU induced changes occurring in indigenous yeast populations of persons undergoing therapy with the drug, are discussed.


Interpreting international governance standards for health IT use within general medical practice.
General practices in Australia recognise the importance of comprehensive protective security measures. Some elements of information security governance are incorporated into recommended standards, however the governance component of information security is still insufficiently addressed in practice. The International Organistion for Standardisation (ISO) released a new global standard in May 2013 entitled, ISO/IEC 27014:2013 Information technology - Security techniques - Governance of information security. This standard, applicable to organisations of all sizes, offers a framework against which to assess and implement the governance components of information security. The standard demonstrates the relationship between governance and the management of information security, provides strategic principles and processes, and forms the basis for establishing a positive information security culture. An analysis interpretation of this standard for use in Australian general practice was performed. This work is unique as such interpretation for the Australian healthcare environment has not been undertaken before. It demonstrates an application of the standard at a strategic level to inform existing development of an information security governance framework.


Vortex-assisted DNA delivery.
Electroporation is one of the most widely used methods to deliver exogenous DNA payloads into cells, but a major limitation is that only a small fraction of the total membrane surface is permeabilized. Here we show how this barrier can be easily overcome by harnessing hydrodynamic effects associated with Dean flows that occur along curved paths. Under these conditions, cells are subjected to a combination of transverse vortex motion and rotation that enables the entire membrane surface to become uniformly permeabilized. Greatly improved transfection efficiencies are achievable with only a simple modification to the design of existing continuous flow electroporation systems.


Diversity and distribution of freshwater amphipod species in Switzerland (Crustacea: Amphipoda).
Amphipods are key organisms in many freshwater systems and contribute substantially to the diversity and functioning of macroinvertebrate communities. Furthermore, they are commonly used as bioindicators and for ecotoxicological tests. For many areas, however, diversity and distribution of amphipods is inadequately known, which limits their use in ecological and ecotoxicological studies and handicaps conservation initiatives. We studied the diversity and distribution of amphipods in Switzerland (Central Europe), covering four major drainage basins, an altitudinal gradient of>2,500 m, and various habitats (rivers, streams, lakes and groundwater). We provide the first provisional checklist and detailed information on the distribution and diversity of all amphipod species from Switzerland. In total, we found 29 amphipod species. This includes 16 native and 13 non-native species, one of the latter (Orchestia cavimana) reported here for the first time for Switzerland. The diversity is compared to neighboring countries. We specifically discuss species of the genus Niphargus, which are often receiving less attention. We also found evidence of an even higher level of hidden diversity, and the potential occurrence of further cryptic species. This diversity reflects the biogeographic past of Switzerland, and suggests that amphipods are ideally suited to address questions on endemism and adaptive radiations, post-glaciation re-colonization and invasion dynamics as well as biodiversity-ecosystem functioning relationships in aquatic systems.


Synthesis of kappa light chains by cell lines containing an 8;22 chromosomal translocation derived from a male homosexual with Burkitt's lymphoma.
Three cell lines were derived from a homosexual patient with probable acquired immunodeficiency syndrome and Burkitt's lymphoma. The cell lines produce an unusual strain of Epstein-Barr virus which will both transform cord blood lymphocytes and induce early antigens in Raji cells. Translocations between chromosomes 8 and 22 have occurred in all three lines, but the cells synthesize immunoglobulin M with light chains of the kappa type, in contrast to the usual concordance between a translocation involving chromosome 22 and lambda chain synthesis. Both kappa genes and one lambda gene are rearranged. These findings indicate either that translocation may occur as a separate event from immunoglobulin gene rearrangement or that the proposed hierarchical sequence of immunoglobulin gene rearrangements is not always adhered to. The data also imply that in cells containing a translocation between the long arm of chromosome 8 and a chromosome bearing an immunoglobulin gene, alteration of cellular myc expression may occur regardless of the immunoglobulin gene that is expressed.


River Blindness: Mathematical Models for Control and Elimination.
Human onchocerciasis (river blindness) is one of the few neglected tropical diseases (NTDs) whose control strategies have been informed by mathematical modelling. With the change in focus from elimination of the disease burden to elimination of Onchocerca volvulus, much remains to be done to refine, calibrate and validate existing models. Under the impetus of the NTD Modelling Consortium, the teams that developed EPIONCHO and ONCHOSIM have joined forces to compare and improve these frameworks to better assist ongoing elimination efforts. We review their current versions and describe how they are being used to address two key questions: (1) where can onchocerciasis be eliminated with current intervention strategies by 2020/2025? and (2) what alternative/complementary strategies could help to accelerate elimination where (1) cannot be achieved? The control and elimination of onchocerciasis from the African continent is at a crucial crossroad. The African Programme for Onchocerciasis Control closed at the end of 2015, and although a new platform for support and integration of NTD control has been launched, the disease will have to compete with a myriad of other national health priorities at a pivotal time in the road to elimination. However, never before had onchocerciasis control a better arsenal of intervention strategies as well as diagnostics. It is, therefore, timely to present two models of different geneses and modelling traditions as they come together to produce robust decision-support tools. We start by describing the structural and parametric assumptions of EPIONCHO and ONCHOSIM; we continue by summarizing the modelling of current treatment strategies with annual (or biannual) mass ivermectin distribution and introduce a number of alternative strategies, including other microfilaricidal therapies (such as moxidectin), macrofilaricidal (anti-wolbachial) treatments, focal vector control and the possibility of an onchocerciasis vaccine. We conclude by discussing challenges, opportunities and future directions.


A Pilot Randomized, Controlled Study of Nanocrystalline Silver, Manuka Honey, and Conventional Dressing in Healing Diabetic Foot Ulcer.
Nanocrystalline silver (nAg) and Manuka honey (MH) dressing have increasing popularity for treating diabetic foot ulcer (DFU). This study was an open-label randomized controlled trial with three parallel groups' design in examining the preliminary effectiveness of nAg against MH and conventional dressing in healing DFU in terms of ulcer healing, ulcer infection, and inflammation. 31 participants (11 in the nAg group, 10 in the MH group, and 10 in the convention group) diagnosed with type 2 diabetes were enrolled. Wound cleaning, debridement, and topical dressing application were performed according to the group allocation in each visit at weeks 1, 2, 3, 4, 6, 8, 10, and 12. The results found that the proportions of complete ulcer healing were 81.8%, 50%, and 40% in the nAg, MH, and conventional groups, respectively. The ulcer size reduction rate was potentially higher in the nAg group (97.45%) than the MH group (86.21%) and the conventional group (75.17%). In bacteriology, nAg showed a greater rate of microorganism reduction although it was not significant. To conclude, nAg alginate was potentially superior to MH and conventional dressing in healing diabetic foot ulcer in terms of ulcer size reduction rate.


Spiral organisms in endoscopic biopsies of the human stomach.
A retrospective light microscopic study of 310 consecutive endoscopic gastric biopsy specimens was performed. Spiral bacteria were found in 42% of cases and, apart from occasional organisms in parietal cell canaliculi, were confined to the surface of the glands and epithelium. Electron microscopic study of selected cases showed the bacteria to be approximately 6 micron maximum length and 0.7 micron diameter with a spiral periodicity of 1.2 micron. A significant association between the occurrence of spiral bacteria and gastritis was noted but not with carcinoma, peptic ulceration, or high pH of the gastric aspirate.


Time-series analysis to study the impact of an intersection on dispersion along a street canyon.
This paper presents data analysis from the Brooklyn Traffic Real-Time Ambient Pollutant Penetration and Environmental Dispersion (B-TRAPPED) study to assess the transport of ultrafine particulate matter (PM) across urban intersections. Experiments were performed in a street canyon perpendicular to a highway in Brooklyn, NY, USA. Real-time ultrafine PM samplers were positioned on either side of an intersection at multiple locations along a street to collect time-series number concentration data. Meteorology equipment was positioned within the street canyon and at an upstream background site to measure wind speed and direction. Time-series analysis was performed on the PM data to compute a transport velocity along the direction of the street for the cases where background winds were parallel and perpendicular to the street. The data were analyzed for sampler pairs located (1) on opposite sides of the intersection and (2) on the same block. The time-series analysis demonstrated along-street transport, including across the intersection when background winds were parallel to the street canyon and there was minimal transport and no communication across the intersection when background winds were perpendicular to the street canyon. Low but significant values of the cross-correlation function (CCF) underscore the turbulent nature of plume transport along the street canyon. The low correlations suggest that flow switching around corners or traffic-induced turbulence at the intersection may have aided dilution of the PM plume from the highway. This observation supports similar findings in the literature. Furthermore, the time-series analysis methodology applied in this study is introduced as a technique for studying spatiotemporal variation in the urban microscale environment.


Mortality from oral and pharyngeal cancer in Brazil: trends and regional patterns, 1979-2002.
To investigate the trends and regional patterns in mortality from oral cancer and pharyngeal cancer in Brazil from 1979 through 2002. Data were obtained from the Mortality Information System (Sistema de Informações sobre Mortalidade) database, which is compiled by the Ministry of Health of Brazil. Mortality rates were adjusted by gender and age. The Prais-Winsten generalized linear regression procedure was used to calculate the annual increase or decrease in mortality rates. The time trends for mortality due to oral cancer and to pharyngeal cancer were analyzed by specific anatomical site and by region of the country (North, Northeast, South, Southeast, and Center-West). In all five regions of Brazil over the period studied, oral cancer mortality remained stable for both genders, but pharyngeal cancer mortality increased for both genders. Mortality from cancer affecting the lips, tongue, gums, mouth floor, palate, other parts of the mouth, and tonsils showed a statistically significant decrease over the period. However, mortality from cancer affecting the oropharynx, hypopharynx, and ill-defined and undefined sites of the oral cavity and the pharynx showed a significant increase. Mortality rates for both oral cancer and pharyngeal cancer were higher in the South and Southeast regions of the country than in Brazil's three other regions. The relatively larger decrease in mortality from cancer affecting the lips, gums, and other anatomical sites more easily accessible to clinical inspection suggests a possible link between oral and pharyngeal cancer survival and an improved provision of health care services in Brazil in recent decades.


Regenerative medicine of pancreatic islets.
The pancreas became one of the first objects of regenerative medicine, since other possibilities of dealing with the pancreatic endocrine insufficiency were clearly exhausted. The number of people living with diabetes mellitus is currently approaching half a billion, hence the crucial relevance of new methods to stimulate regeneration of the insulin-secreting β-cells of the islets of Langerhans. Natural restrictions on the islet regeneration are very tight; nevertheless, the islets are capable of physiological regeneration via β-cell self-replication, direct differentiation of multipotent progenitor cells and spontaneous α- to β- or δ- to β-cell conversion (trans-differentiation). The existing preclinical models of β-cell dysfunction or ablation (induced surgically, chemically or genetically) have significantly expanded our understanding of reparative regeneration of the islets and possible ways of its stimulation. The ultimate goal, sufficient level of functional activity of β-cells or their substitutes can be achieved by two prospective broad strategies: β-cell replacement and β-cell regeneration. The "regeneration" strategy aims to maintain a preserved population of β-cells through in situ exposure to biologically active substances that improve β-cell survival, replication and insulin secretion, or to evoke the intrinsic adaptive mechanisms triggering the spontaneous non-β- to β-cell conversion. The "replacement" strategy implies transplantation of β-cells (as non-disintegrated pancreatic material or isolated donor islets) or β-like cells obtained ex vivo from progenitors or mature somatic cells (for example, hepatocytes or α-cells) under the action of small-molecule inducers or by genetic modification. We believe that the huge volume of experimental and clinical studies will finally allow a safe and effective solution to a seemingly simple goal-restoration of the functionally active β-cells, the innermost hope of millions of people globally.


Mutation in glycerol-3-phosphate dehydrogenase 1 like gene (GPD1-L) decreases cardiac Na+ current and causes inherited arrhythmias.
Brugada syndrome is a rare, autosomal-dominant, male-predominant form of idiopathic ventricular fibrillation characterized by a right bundle-branch block and ST elevation in the right precordial leads of the surface ECG. Mutations in the cardiac Na+ channel SCN5A on chromosome 3p21 cause approximately 20% of the cases of Brugada syndrome; most mutations decrease inward Na+ current, some by preventing trafficking of the channels to the surface membrane. We previously used positional cloning to identify a new locus on chromosome 3p24 in a large family with Brugada syndrome and excluded SCN5A as a candidate gene. We used direct sequencing to identify a mutation (A280V) in a conserved amino acid of the glycerol-3-phosphate dehydrogenase 1-like (GPD1-L) gene. The mutation was present in all affected individuals and absent in >500 control subjects. GPD1-L RNA and protein are abundant in the heart. Compared with wild-type GPD1-L, coexpression of A280V GPD1-L with SCN5A in HEK cells reduced inward Na+ currents by approximately 50% (P<0.005). Wild-type GPD1-L localized near the cell surface to a greater extent than A280V GPD1-L. Coexpression of A280V GPD1-L with SCN5A reduced SCN5A cell surface expression by 31+/-5% (P=0.01). GPD1-L is a novel gene that may affect trafficking of the cardiac Na+ channel to the cell surface. A GPD1-L mutation decreases SCN5A surface membrane expression, reduces inward Na+ current, and causes Brugada syndrome.


The value of sensitive imaging modalities in rheumatoid arthritis.
X-ray evaluation of rheumatoid joints is relatively inexpensive, is widely available and has standardised methods for interpretation. It also has limitations, including the inability to reliably determine structural change in less than 6-12 months, the need for experienced readers to interpret images and the limited acceptance of this technique in routine clinical practice. High-frequency ultrasound, with or without power Doppler, and magnetic resonance imaging of rheumatoid joints permit an increasingly refined analysis of anatomic detail. However, further research using these sensitive imaging technologies is required to delineate pathophysiological correlates of imaging abnormalities and to standardise methods for assessment.


Synthetic approaches towards alkaloids bearing α-tertiary amines.
Alkaloids account for some of the most beautiful and biologically active natural products. Although they are usually classified along biosynthetic criteria, they can also be categorized according to certain structural motifs. Amongst these, the α-tertiary amine (ATA), i.e. a tetrasubstituted carbon atom surrounded by three carbons and one nitrogen, is particularly interesting. A limited number of methods have been described to access this functional group and fewer still are commonly used in synthesis. Herein, we review some approaches to asymmetrically access ATAs and provide an overview of alkaloid total syntheses where those have been employed.


Controlled fabrication of mesoporous TiO2 hierarchical structures as scattering layers to enhance the power conversion efficiency of dye-sensitized solar cells.
To meet the nanofabrication requirements, such as control of structure and scalability, we investigated an electrospray-based method to manufacture scattering layers (SLs) for dye-sensitized solar cells (DSSCs). TiO2 spherical and disk-shaped particles with a large surface area, high crystallinity, uniform nanostructure and good light scattering properties were fabricated via a simple electrospray method. We showed how the morphology and structure of the resulting films can be controlled by varying the droplet evaporation rates before impact on the substrate. Thus, by tuning the process conditions, high-quality TiO2 spheres and disks were obtained. Then, these mesoporous TiO2 particles were used as the SLs in photoelectrodes, which resulted in enhanced power conversion efficiency (PCE). Compared with conventional SLs (8.45%), DSSCs based on spherical and disk-shaped particle SLs yield higher PCEs of 9.0% and 9.53%, respectively. This is because the generated TiO2 spheres and disks provide a large surface area and exhibit excellent light scattering capabilities, allowing a low total internal resistance and a long electron lifetime.


The range of the golden-mantle tamarin, Saguinus tripartitus (Milne-Edwards, 1878): distributions and sympatry of four tamarins in Colombia, Ecuador, and northern Peru [corrected].
A detailed understanding of the range of the golden-mantle tamarin, Saguinus tripartitus (Milne Edwards, 1878), in Amazonian Peru and Ecuador is of particular relevance, not only because it is poorly known but also because it was on the basis of its supposed sympatry with the saddleback tamarin (S. fuscicollis lagonotus) that Thorington (Am J Primatol 15:367-371, 1988) argued that it is a distinct species rather than a saddleback tamarin subspecies, as was believed by Hershkovitz (Living new world monkeys, vol I. The University of Chicago Press, Chicago, 1977). A number of surveys have been carried out since 1988 in the supposed range of S. tripartitus, in both Ecuador and Peru. Here we summarize and discuss these issues and provide a new suggestion for the geographic range of this species; that is, between the ríos Napo and Curaray in Peru and extending east into Ecuador. We also review current evidence for the distributions of Spix's black-mantle tamarin (S. nigricollis nigricollis), Graells' black-mantle tamarin (S. n. graellsi), and the saddleback tamarin (S. fuscicollis lagonotus), which are also poorly known, and examine the evidence regarding sympatry between them. We conclude that despite the existence of a number of specimens with collecting localities that indicate overlap in their geographic ranges, the fact that the four tamarins are [corrected] of similar size and undoubtedly very similar in their feeding habits militates strongly against the occurrence of sympatry among them.


The relationship between paired associate learning and phonological skills in normally developing readers.
Seventy-five 6- to 11-year-old children were administered tests of phonological awareness, verbal short term memory (STM), and visual-verbal paired associate learning (PA learning) to investigate their relationship with word recognition and decoding skills. Phonological awareness was a stronger concurrent predictor of word recognition than verbal STM, and phonological awareness but not verbal STM was a predictor of learning in the PA learning task. Importantly, measures of phonological awareness and PA learning both accounted for independent variance in word reading, even when decoding skill was controlled. The results suggest that PA learning and phonological awareness tasks tap two separate mechanisms involved in learning to read. The results are discussed in relation to current theories of reading development.


Community-based prevention leads to an increase in condom use and a reduction in sexually transmitted infections (STIs) among men who have sex with men (MSM) and female sex workers (FSW): the Frontiers Prevention Project (FPP) evaluation results.
India has an estimated 2.0 million to 3.1 million people living with HIV; it has the highest number of HIV-positive people in Asia and ranks third in the world. The Frontiers Prevention Project (FPP) was implemented in 2002 to conduct targeted prevention intervention geared towards female sex workers (FSW) and men who have sex with men (MSM) in the state of Andhra Pradesh (AP). This paper reports the overall changes in behaviour and STI outcomes between 2003/4 and 2007 and also describes the changes attributed to the FPP. The evaluation used two cross-sectional surveys among MSM and FSW at 24 sites in AP. Surveys were implemented using a similar methodology. Univariate analyses were conducted by comparing means: baseline vs. four-year follow-up and FPP vs. non-FPP. For both MSM and FSW, random and fixed-effects logit regression models at the site level were estimated for condom use with last partner, syphilis sero-positivity and HSV 2 sero-positivity. In addition, for FSW we estimated models for condom use with regular partner, and for MSM we estimated models for condom use with last female partner. Among MSM, fixed-effects analysis revealed that FPP was positively correlated with the probability of condom use with last female sexual partner and negatively correlated with the individual probability of sero-positivity to syphilis and HSV 2. Among FSW, the FPP intervention was significantly correlated with increased condom use with regular partners and with lower probability of STI sero-positivity. Important changes in behaviours related to an increase in prevention activities translated to reductions in STI sero-prevalence in AP, India. In contrast with non-FPP sites, the FPP sites experienced an intense community approach as part of the FPP intervention, and the general increase in condom use and its effect on STI sero-prevalence reflected the efficacy of these intense prevention activities focused on key populations in AP.


A Screening Strategy for HIV-Associated Neurocognitive Disorders That Accurately Identifies Patients Requiring Neurological Review.
Human immunodeficiency virus (HIV)-associated neurocognitive disorders (HAND) are not routinely assessed due to the lack of an adequate screening strategy. We aimed to develop a clinically relevant screening procedure for symptomatic HAND, validated against a gold standard neuropsychological (NP) test battery. Representative HIV-infected (HIV+) and demographically matched HIV-uninfected (HIV-) participants in an observational study completed a standard evaluation for mood, drug and/or alcohol use, and activities of daily living and a newly designed 20-minute computerized CogState battery that assessed 5 cognitive domains. A subset completed standard NP assessment for 8 cognitive domains. HAND definition on screening and gold standard NP was determined using demographically corrected z scores and the global deficit score (≥ 0.5), applying the Frascati criteria. Participants were blinded to screening results, and the NP examiner was blinded to screening and HIV status. A total of 254 HIV+ participants were enrolled-mean age, 48.9 ± 10.2 years; median nadir CD4, 270 cells/mL; tertiary educated, 54%; and HIV- controls, 72. HIV+ HAND screening prevalence was 30.7% (HIV-associated dementia, 3.2%; mild neurocognitive disorder, 12.6%; and asymptomatic neurocognitive disorder, 15.0%; HIV- group: 13.9%; P = .004). Of the 75 participants who completed the NP battery, the HAND rate in the HIV+ group was 50.9% vs 43.4% by screening (P > .50). HAND screening vs gold standard NP sensitivity was 76% and specificity was 71%. Clinically relevant HIV-associated dementia and mild neurocognitive disorder sensitivity was 100% and specificity was 98% (positive predictive value 0.92). Symptomatic HAND warranting neurological review was accurately predicted using a CogState-based screening procedure.


COVID-19: Neuroimaging Features of a Pandemic.
The ongoing Coronavirus Disease 2019 (COVID-19) pandemic is caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). COVID-19 is occasionally associated with manifold diseases of the central nervous system (CNS). We sought to present the neuroimaging features of such CNS involvement. In addition, we sought to identify typical neuroimaging patterns that could indicate possible COVID-19-associated neurological manifestations. In this systematic literature review, typical neuroimaging features of cerebrovascular diseases and inflammatory processes associated with COVID-19 were analyzed. Reports presenting individual patient data were included in further quantitative analysis with descriptive statistics. We identified 115 studies reporting a total of 954 COVID-19 patients with associated neurological manifestations and neuroimaging alterations. A total of 95 (82.6%) of the identified studies were single case reports or case series, whereas 660 (69.2%) of the reported cases included individual information and were thus included in descriptive statistical analysis. Ischemia with neuroimaging patterns of large vessel occlusion event was revealed in 59.9% of ischemic stroke patients, whereas 69.2% of patients with intracerebral hemorrhage exhibited bleeding in a location that was not associated with hypertension. Callosal and/or juxtacortical location was identified in 58.7% of cerebral microbleed positive images. Features of hemorrhagic necrotizing encephalitis were detected in 28.8% of patients with meningo-/encephalitis. Manifold CNS involvement is increasingly reported in COVID-19 patients. Typical and atypical neuroimaging features have been observed in some disease entities, so that familiarity with these imaging patterns appears reasonable and may assist clinicians in the differential diagnosis of COVID-19 CNS manifestations.


Epidemiological evidences from China assume that psychiatric-related diseases may be associated with Toxoplasma gondii infection.
In recent years, the effect of Toxoplasma gondii infection on psychiatric-related aspects has been increasingly recognized. T. gondii has a high affinity for brain tissue where tachyzoites may form tissue cysts and persist life long. In recent years, 15 serological surveys about T. gondii infection and psychiatric diseases have been carried out in different areas in China. Studies showed that the prevalence of antibodies against T. gondii in psychotic patients was much higher than in normal persons; statistically differences were significant. Studies also reported that raising cats or enjoying the habit of eating raw or under cooked meet were potential risk factors for the infection of T. gondii. The epidemiological and serological evidence support the hypothesis that some psychiatric diseases such as schizophrenia or mental retardation might be linked to T. gondii infection.