Evaluation of the impact of the voucher and accreditation approach on improving reproductive health behaviors and status in Kenya.
Alternatives to the traditional 'supply-side' approach to financing service delivery are being explored. These strategies are termed results-based finance, demand-side health financing or output-based aid which includes a range of interventions that channel government or donor subsidies to the user rather than the provider. Initial pilot assessments of reproductive health voucher programs suggest that, they can increase access and use, reducing inequities and enhancing program efficiency and service quality. However, there is a paucity of evidence describing how the programs function in different settings, for various reproductive health services. Population Council, funded by the Bill and Melinda Gates Foundation, intends to generate evidence around the 'voucher and accreditation' approaches to improving the reproductive health of low income women in Kenya. A quasi-experimental study will investigate the impact of the voucher approach on improving reproductive health behaviors, reproductive health status and reducing inequities at the population level; and assessing the effect of vouchers on increasing access to, and quality of, and reducing inequities in the use of selected reproductive health services. The study comprises of four populations: facilities, providers, women of reproductive health age using facilities and women and men who have been pregnant and/or used family planning within the previous 12 months. The study will be carried out in samples of health facilities - public, private and faith-based in: three districts; Kisumu, Kiambu, Kitui and two informal settlements in Nairobi which are accredited to provide maternal and newborn health and family planning services to women holding vouchers for the services; and compared with a matched sample of non-accredited facilities. Health facility assessments (HFA) will be conducted at two stages to track temporal changes in quality of care and utilization. Facility inventories, structured observations, and client exit interviews will be used to collect comparable data across facilities. Health providers will also be interviewed and observed providing care. A population survey of about 3000 respondents will also be carried out in areas where vouchers are distributed and similar locations where vouchers are not distributed.


Trauma-induced coagulopathy: impact of the early coagulation support protocol on blood product consumption, mortality and costs.
Hemorrhage is the principal cause of death in the first few hours following severe injury. Coagulopathy is a frequent complication of critical bleeding. A network of Italian trauma centers recently developed a protocol to prevent and treat trauma-induced coagulopathy. A pre-post cohort multicenter study was conducted to assess the impact of the early coagulation support (ECS) protocol on blood products consumption, mortality and treatment costs. We prospectively collected data from all severely injured patients (Injury Severity Score (ISS) >15) admitted to two trauma centers in 2013 and compared these findings with the data for 2011. Patients transfused with at least 3 units of packed red blood cells (PRBCs) within 24 hours of an accident were included in the study. In 2011, patients with significant hemorrhaging were treated with early administration of plasma with the aim of achieving a high (≥1:2) plasma-to-PRBC ratio. In 2013, the ECS protocol was the treatment strategy. Outcome data, blood product consumption and treatment costs were compared between the two periods. The two groups were well matched for demographics, injury severity (ISS: 32.9 in 2011 versus 33.6 in 2013) and clinical and laboratory data on admission. In 2013, a 40% overall reduction in PRBCs was observed, together with a 65% reduction in plasma and a 52% reduction in platelets. Patients in the ECS group received fewer blood products: 6.51 units of PRBCs versus 8.14 units. Plasma transfusions decreased from 8.98 units to 4.21 units (P <0.05), and platelets fell from 4.14 units to 2.53 units (P <0.05). Mortality in 2013 was 13.5% versus 20% in 2011 (13 versus 26 hospital deaths, respectively) (nonsignificant). When costs for blood components, factors and point-of-care tests were compared, a €76,340 saving in 2013 versus 2011 (23%) was recorded. The introduction of the ECS protocol in two Italian trauma centers was associated with a marked reduction in blood product consumption, reaching statistical significance for plasma and platelets, and with a non-significant trend toward a reduction in early and 28-day mortality. The overall costs for transfusion and coagulation support (including point-of-care tests) decreased by 23% between 2011 and 2013.


An evidence-based approach to perioperative nutrition support in the elective surgery patient.
In surgical practice, great attention is given to the perioperative management of the elective surgical patient with regard to surgical planning, stratification of cardiopulmonary risk, and postoperative assessment for complication. However, growing evidence supports the beneficial role for implementation of a consistent and literature-based approach to perioperative nutrition therapy. Determining nutrition risk should be a routine component of the preoperative evaluation. As with the above issues, this concept begins with the clinician's first visit with the patient as risk is assessed and the severity of the surgical insult considered. If the patient is an appropriate candidate for benefit from preoperative support, a plan for initiation and reassessment should be implemented. Once appropriate nutrition end points have been achieved, special consideration should be given to beneficial practices the immediate day preceding surgery that may better prepare the patient for the intervention from a metabolic standpoint. In the operating room, consideration should be given to the potential placement of enteral access during the index operation as well as judicious and targeted intraoperative resuscitation. Immediately following the intervention, adequate resuscitation and glycemic control are key concepts, as is an evidence-based approach to the early advancement of an enteral/oral diet in the postoperative patient. Through the implementation of perioperative nutrition therapy plans in the elective surgery setting, outcomes can be improved.


The yeast carboxyl-terminal repeat domain kinase CTDK-I is a divergent cyclin-cyclin-dependent kinase complex.
Saccharomyces cerevisiae CTDK-I is a protein kinase complex that specifically and efficiently hyperphosphorylates the carboxyl-terminal repeat domain (CTD) of RNA polymerase II and is composed of three subunits of 58, 38, and 32 kDa. The kinase is essential in vivo for normal phosphorylation of the CTD and for normal growth and differentiation. We have now cloned the genes for the two smaller kinase subunits, CTK2 and CTK3, and found that they form a unique, divergent cyclin-cyclin-dependent kinase complex with the previously characterized largest subunit protein CTK1, a cyclin-dependent kinase homolog. The CTK2 gene encodes a cyclin-related protein with limited homology to cyclin C, while CTK3 shows no similarity to other known proteins. Copurification of the three gene products with each other and CTDK-I activity by means of conventional chromatography and antibody affinity columns has verified their participation in the complex in vitro. In addition, null mutations of each of the genes and all combinations thereof conferred very similar growth-impaired, cold-sensitive phenotypes, consistent with their involvement in the same function in vivo. These characterizations and the availability of all of the genes encoding CTDK-I and reagents derivable from them will facilitate investigations into CTD phosphorylation and its functional consequences both in vivo and in vitro.


Service providers' experiences of using a telehealth network 12 months after digitisation of a large Australian rural mental health service.
Despite evidence of benefits of telehealth networks in increasing access to, or providing, previously unavailable mental health services, care providers still prefer traditional approaches. For psychiatric assessment, digital technology can offer improvements over analog systems for the technical and, subsequently, the social quality of provider-client interaction. This is in turn expected to support greater provider uptake and enhanced patient benefits. Within the framework of Innovation Diffusion Theory, to study service providers' experiences of an existing regional telehealth network for mental health care practice twelve months after digitisation in order to identify the benefits of digital telehealth over an analog system for mental health care purposes in rural Australia. Qualitative interviews and focus groups were conducted with over 40 service providers from June to September 2013 in South Australia, ranging from the metropolitan central operations to health providers located up to 600km away in rural and remote areas of the same state. Participants included rural mental health teams, directors of nursing at rural hospitals, metropolitan-based psychiatrists and registrars, the metropolitan-based mental health team dedicated to rural provider support, rural GPs, administrative staff, and the executive group of the state rural health department. Fieldwork was conducted 12 months after the analog system was digitised. The interview and focus group data were analysed using thematic analysis, focusing on three key areas of innovation diffusion theory: relative advantage, technical complexity and technical compatibility. Five themes with 11 sub-themes were identified: (1) "Existing Uses", with three sub-themes: current mental health use, use by GPs, and use for staff support; (2) "Relative Advantage", with four sub-themes: improved technical quality, improved clinical practice, time and cost benefits for providers, and improved patient care; (3) "Technical Complexity"; (4) "Technical Compatibility" with two sub-themes: technical-clinical and technical-administrative; and (5) "Broader Organisational Culture", with two sub-themes: organizational policy support and 'digital telehealth' culture. The digitised telehealth network was generally well received by providers and adopted into clinical practice. Compared with the previous analog system, staff found advantages in better visual and audio quality, more technical stability with less "drop-out", less time delay to conversations and less confusion for clients. Despite these advantages, providers identified a range of challenges to starting or continuing use and they recommended improvements to increase uptake among mental health service providers and other providers (including GPs), and to clinical uses other than mental health. To further increase uptake and impact of telehealth-mediated mental health care in rural and remote areas, even with a high quality digital system, future research must design innovative care models, consider time and cost incentives for providers to use telehealth, and must focus not only on technical training but also how to best integrate technology with clinical practice and must develop an organization-wide digital telehealth culture.


The Ege Stroke Registry: a hospital-based study in the Aegean region, Izmir, Turkey. Analysis of 2,000 stroke patients.
We present the profile of risk factors, etiologic and clinical data of 2,000 consecutive patients with first-ever-in-a-lifetime stroke (cerebral infarction, cerebral hemorrhage and subarachnoid hemorrhage), admitted to the Ege University Hospital between January 1, 1991, and September 31, 1995. This hospital-based registry is the first systematic epidemiologic report on the stroke profile of Turkish people The Ege University Stroke Unit is the only tertiary medical care facility which is organized for patients with different stroke subtypes in Izmir, Turkey. A prospective hospital-based registry using systematic computer coding of data of all stroke patients has been used since January 1991. All patients were evaluated by clinical examination, CT and/or MRI, color duplex and specific cardiac investigations. They were followed up for at least 6 months. The mean age was 62.3 +/- 12 years, and 44.4% were females. Ischemic stroke was found in 77%, primary intracerebral hemorrhage in 19% and subarachnoid hemorrhage in 4%. The major risk factor of ischemic stroke was hypertension (63%), followed by hypercholesterolemia (37%), diabetes mellitus (35%), ischemic heart disease (23%), atrial fibrillation (20%) and smoking (17%). The main cause of primary intracerebral hemorrhage was hypertension (88%), and the principal localization was the thalamus (38%), followed by putamen (28%), lobar(16%), pons(6%), cerebellar(4%), primary intraventricular hemorrhage (4%) and multiple hemorrhages (2%). The over- all 30-day case-fatality rate was 19.7% and the higher mortality rate was found in patients with primary intracerebral hemorrhage (29%) than in those with ischemic stroke (17%). The Ege Stroke Registry allows to estimate the stroke-related problems in patients admitted to a stroke unit and to evaluate the risk factors, etiology and clinical manifestations of stroke in Turkey.


Saccharomyces cerevisiae RAD5-encoded DNA repair protein contains DNA helicase and zinc-binding sequence motifs and affects the stability of simple repetitive sequences in the genome.
rad5 (rev2) mutants of Saccharomyces cerevisiae are sensitive to UV light and other DNA-damaging agents, and RAD5 is in the RAD6 epistasis group of DNA repair genes. To unambiguously define the function of RAD5, we have cloned the RAD5 gene, determined the effects of the rad5 deletion mutation on DNA repair, DNA damage-induced mutagenesis, and other cellular processes, and analyzed the sequence of RAD5-encoded protein. Our genetic studies indicate that RAD5 functions primarily with RAD18 in error-free postreplication repair. We also show that RAD5 affects the rate of instability of poly(GT) repeat sequences. Genomic poly(GT) sequences normally change length at a rate of about 10(-4); this rate is approximately 10-fold lower in the rad5 deletion mutant than in the corresponding isogenic wild-type strain. RAD5 encodes a protein of 1,169 amino acids of M(r) 134,000, and it contains several interesting sequence motifs. All seven conserved domains found associated with DNA helicases are present in RAD5. RAD5 also contains a cysteine-rich sequence motif that resembles the corresponding sequences found in 11 other proteins, including those encoded by the DNA repair gene RAD18 and the RAG1 gene required for immunoglobin gene arrangement. A leucine zipper motif preceded by a basic region is also present in RAD5. The cysteine-rich region may coordinate the binding of zinc; this region and the basic segment might constitute distinct DNA-binding domains in RAD5. Possible roles of RAD5 putative ATPase/DNA helicase activity in DNA repair and in the maintenance of wild-type rates of instability of simple repetitive sequences are discussed.


The 12/15-lipoxygenase pathway counteracts fibroblast activation and experimental fibrosis.
Idiopathic and inflammation-dependent fibrotic diseases such systemic sclerosis (SSc) impose a major burden on modern societies. Understanding endogenous mechanisms, which counteract fibrosis, may yield new therapeutic approaches. Lipoxins are highly potent lipid mediators, which have recently been found to be decreased in SSc. To determine the potential role of 12/15-lipoxygenase (12/15-LO), the key enzyme for the synthesis of lipoxins, in fibrosis. Two mouse models for experimental dermal fibrosis (bleomycin-induced dermal fibrosis and tight-skin 1 mouse model) together with bone marrow transfers were used in wildtype and 12/15-LO(-/-) mice to elucidate the role of this enzyme during dermal fibrosis. Primary dermal fibroblasts of wildtype and 12/15-LO(-/-) mice, and 12/15-LO-derived eicosanoids, were used to identify underlying molecular mechanisms In both models, 12/15-LO(-/-) mice exhibited a significant exacerbation of the fibrotic tissue response. Bone marrow transfer experiments disclosed a predominant role of mesenchymal cell-derived 12/15-LO in these antifibrotic effects. Indeed, 12/15-LO(-/-) fibroblasts showed an enhanced activation of the mitogen-activated protein-kinase pathway and an increased col 1a2 mRNA expression in response to stimulation with transforming growth factor β (TGFβ), whereas 12/15-LO-derived eicosanoids blocked these TGFβ-induced effects. These data indicate that 12/15-LO and its metabolites have a prominent antifibrotic role during dermal fibrosis. This opens new opportunities for therapeutic approaches in the treatment of fibrotic diseases.


Integrating dynamic stopping, transfer learning and language models in an adaptive zero-training ERP speller.
Most BCIs have to undergo a calibration session in which data is recorded to train decoders with machine learning. Only recently zero-training methods have become a subject of study. This work proposes a probabilistic framework for BCI applications which exploit event-related potentials (ERPs). For the example of a visual P300 speller we show how the framework harvests the structure suitable to solve the decoding task by (a) transfer learning, (b) unsupervised adaptation, (c) language model and (d) dynamic stopping. A simulation study compares the proposed probabilistic zero framework (using transfer learning and task structure) to a state-of-the-art supervised model on n = 22 subjects. The individual influence of the involved components (a)-(d) are investigated. Without any need for a calibration session, the probabilistic zero-training framework with inter-subject transfer learning shows excellent performance--competitive to a state-of-the-art supervised method using calibration. Its decoding quality is carried mainly by the effect of transfer learning in combination with continuous unsupervised adaptation. A high-performing zero-training BCI is within reach for one of the most popular BCI paradigms: ERP spelling. Recording calibration data for a supervised BCI would require valuable time which is lost for spelling. The time spent on calibration would allow a novel user to spell 29 symbols with our unsupervised approach. It could be of use for various clinical and non-clinical ERP-applications of BCI.


Liver stiffness measurement by transient elastography in clinical practice.
The AIM of our study was to evaluate the results of transient elastography assessment of liver stiffness (LS) in various categories of patients. We performed transient elastography in 986 patients. We evaluated: the percentage of cases in which valid measurements could be obtained; the values of LS in 40 patients with no history of chronic liver disease ("normal" patients); 44 inactive HBsAg carriers; 173 patients with proven liver cirrhosis; and the correlation between liver biopsy results and LS in 93 patients with chronic HCV hepatitis. We obtained valid measurements of LS in 94.6% of the 986 cases. Male gender, younger age and low BMI were positive predictive factors for obtaining valid measurements. The mean values of LS were: 5.2+/-1.3 kPa in "normal" patients, 5.8+/-2.6 kPa in inactive HBsAg carriers, 37.2+/-20.9 kPa in patients with liver cirrhosis. In patients with chronic HCV hepatitis, we found that the mean value of LS in those with METAVIR F>=2 was 8.5+/-4.2 kPa, higher than in those with F<2: 5.3+/-1.4 kPa (p=0.0017). In patients with F>=3, the mean value of LS was 11.1+/-4.3 kPa, significantly higher than in patients with F<3: 6.1+/-2.5 kPa (p<0.0001). Liver stiffness, as a marker of fibrosis, can be evaluated by means of transient elastography in a great majority of patients. It is a useful method for the exclusion of significant liver fibrosis and for predicting liver cirrhosis. As compared to liver biopsy, transient elastography can discern significant fibrosis from no or mild fibrosis.


When it comes to opiates, just say NO.
Repeated use of opiate analgesic drugs such as morphine for the relief of chronic pain may result in the development of opiate tolerance and dependence, leading to a narrowing of the drug's therapeutic index and increased side effects. Previous preclinical work has shown that interruption of a signaling cascade involving the N-methyl-D-aspartate receptor and NO prevents morphine tolerance. In this issue of the JCI, Muscoli and colleagues extend our understanding of the role of NO in tolerance by demonstrating that, in mice, tolerance to chronic morphine administration is associated with NO conversion to peroxynitrite, which accumulates and nitrates tyrosine moieties within various proteins in the spinal cord (see the related article beginning on page 3530). This and other data suggest that peroxynitrite plays a role in opiate tolerance and that regulation of peroxynitrite may be utilized for the management of opiate-induced tolerance.


Genetic analysis of viruses associated with emergence of Rift Valley fever in Saudi Arabia and Yemen, 2000-01.
The first confirmed Rift Valley fever outbreak outside Africa was reported in September 2000, in the Arabian Peninsula. As of February 2001, a total of 884 hospitalized patients were identified in Saudi Arabia, with 124 deaths. In Yemen, 1,087 cases were estimated to have occurred, with 121 deaths. Laboratory diagnosis of Rift Valley fever virus (RVFV) infections included virus genetic detection and characterization of clinical specimens by reverse transcription-polymerase chain reaction, in addition to serologic tests and virus isolation. Genetic analysis of selected regions of virus S, M, and L RNA genome segments indicated little genetic variation among the viruses associated with disease. The Saudi Arabia and Yemen viruses were almost identical to those associated with earlier RVF epidemics in East Africa. Analysis of S, M, and L RNA genome segment sequence differences showed similar phylogenetic relationships among these viruses, indicating that genetic reassortment did not play an important role in the emergence of this virus in the Arabian Peninsula. These results are consistent with the recent introduction of RVFV into the Arabian Peninsula from East Africa.


A functional and structural analysis of the Sex combs reduced locus of Drosophila melanogaster.
We have undertaken a developmental genetic analysis of the homeotic gene Sex combs reduced (Scr) of Drosophila melanogaster by examining embryonic and adult phenotypes of mutations affecting Scr gene function. Molecular mapping of Scr breakpoint lesions has defined a segment of greater than 70 kb of DNA necessary for proper Scr gene function. This region is split by the fushi tarazu (ftz) gene, with lesions affecting embryonic Scr function molecularly mapping to the region proximal (5') to ftz and those exhibiting polyphasic semilethality predominantly mapping distal (3') to ftz. Gain-of-function mutations are associated with genomic rearrangements and map throughout the Scr locus. Our analysis has revealed that the Scr locus encompasses genetic elements that are responsible for functions in both the embryonic and larval to adult periods of development. From these studies, we conclude that Scr is a complex genetic locus with an extensive regulatory region that directs functions required for normal head and thoracic development in both the embryo and the adult and that the regulation of Scr during these two periods is distinct.


Home blood pressure management and improved blood pressure control: results from a randomized controlled trial.
To determine which of 3 interventions was most effective in improving blood pressure (BP) control, we performed a 4-arm randomized trial with 18-month follow-up at the primary care clinics at a Veterans Affairs Medical Center. Eligible patients were randomized to either usual care or 1 of 3 telephone-based intervention groups: (1) nurse-administered behavioral management, (2) nurse- and physician-administered medication management, or (3) a combination of both. Of the 1551 eligible patients, 593 individuals were randomized; 48% were African American. The intervention telephone calls were triggered based on home BP values transmitted via telemonitoring devices. Behavioral management involved promotion of health behaviors. Medication management involved adjustment of medications by a study physician and nurse based on hypertension treatment guidelines. The primary outcome was change in BP control measured at 6-month intervals over 18 months. Both the behavioral management and medication management alone showed significant improvements at 12 months-12.8% (95% confidence interval [CI], 1.6%-24.1%) and 12.5% (95% CI, 1.3%-23.6%), respectively-but not at 18 months. In subgroup analyses, among those with poor baseline BP control, systolic BP decreased in the combined intervention group by 14.8 mm Hg (95% CI, -21.8 to -7.8 mm Hg) at 12 months and 8.0 mm Hg (95% CI, -15.5 to -0.5 mm Hg) at 18 months, relative to usual care. Overall intervention effects were moderate, but among individuals with poor BP control at baseline, the effects were larger. This study indicates the importance of identifying individuals most likely to benefit from potentially resource intensive programs. clinicaltrials.gov Identifier: NCT00237692.


Analysis of waterpipe aerosol constituents in accordance with the ISO standard 22486.
This study analyzed commercial waterpipe tobacco products in accordance with the newly developed ISO 22486 as well as with commercial waterpipes and charcoals using the ISO 22486 puffing regime for comparison. The aerosols from these products were analyzed for their nicotine, humectant, tobacco specific nitrosamine, carbonyl, benzo[a]pyrene, and metal yields. Significant differences were observed among the waterpipe tobacco products when analyzed in accordance with the ISO standard 22486 and with different commercial waterpipes and charcoals. The concentrations of CO and benzo[a]pyrene observed in the consumers' configuration using the ISO 22486 puffing regime (with lit charcoal) were higher than those obtained with the ISO standard using electrical heating, with the yields for carbonyl compounds being lower or higher. The use of the recently published ISO standard for generating water pipe tobacco aerosols should be complemented with analysis by using the consumers' configuration. The necessity for this was demonstrated by the differences in CO and benzo[a]pyrene yields in the present work. It appears that the temperature (280°C) selected for electrical heating of waterpipe tobacco products in ISO 22486 is somewhat lower than that obtained with commercial charcoals, resulting in a generally lower yield of nicotine and total collected matter. In addition, there is a need to evaluate the contribution of commercial charcoals to the concentration of constituents in waterpipe aerosols. This is particularly true for compounds resulting from charcoal combustion, such as CO and benzo[a]pyrene.


Synthesis of corrugated C-based nanostructures by Br-corannulene oligomerization.
The structure and electronic properties of carbon-based nanostructures obtained by metal surface assisted synthesis is highly dependent on the nature of the precursor molecule. Here, we report on a combined scanning tunneling microscopy, soft X-ray spectroscopy and density functional theory investigation on the surface assisted polymerization of Br-corannulene at Ag(110) and on the possibility of building a mesh of π-conjugated polymers starting from buckyball shaped molecules. Indeed, the corannulene units form one-molecule-wide ribbons in which the natural concavity of the precursor molecule is maintained. These C-based nanostructures are corrugated and merge into a covalent network on the surface.


Biocompatibility and tolerability of a purely bicarbonate-buffered peritoneal dialysis solution.
Novel peritoneal dialysis solutions are characterized by a minimal content of glucose degradation products and a neutral pH. Many studies have shown the biocompatibility of neutral lactate-buffered solutions; however, until now, the effect of purely bicarbonate-buffered solutions has not been intensively studied in vivo. This study was an open label, prospective, crossover multicenter trial to investigate the biocompatibility of a purely bicarbonate-buffered solution (bicPDF) by measuring biocompatibility parameters such as cancer antigen 125 (CA125) in peritoneal effluent. 55 patients were enrolled in the study. After a 2-week run-in phase, 53 patients could be randomized into 2 groups, starting with either standard lactate-buffered peritoneal dialysis fluid (SPDF) for 12 weeks (phase 1) and then switching to bicPDF for 12 weeks (phase 2), or vice versa. Overnight peritoneal effluents were collected at baseline and at the end of phases 1 and 2 and were tested for CA125, hyaluronic acid, vascular endothelial growth factor (VEGF), tumor necrosis factor-alpha (TNF-alpha), interleukin 6 (IL-6), interferon gamma (IFNgamma), and transforming growth factor-beta(1) (TGF-beta1). Total ultrafiltration and residual renal function were also assessed. At the end of the study, pain during fluid exchange and dwell was evaluated using special questionnaires. 34 patients completed the study; 27 of them provided data for analysis of the biocompatibility parameters. CA125 levels in overnight effluent were significantly higher with bicPDF (61.9 +/- 33.2 U/L) than with SPDF (18.6 +/- 18.2 U/L, p < 0.001). Hyaluronic acid levels were significantly lower after the use of bicPDF (185.0 +/- 119.6 ng/mL) than after SPDF (257.4 +/- 174.0 ng/mL, p = 0.013). Both TNF-alpha and TGF-beta1 showed higher levels with the use of bicPDF than with SPDF. No differences were observed for IL-6, VEGF, or IFNgamma levels. We observed an improvement in the glomerular filtration rate with the use of bicPDF but no differences were observed for total fluid loss. Pain scores could be analyzed in 23 patients: there was no difference between the solutions. The use of a purely bicarbonate-buffered low-glucose degradation product solution significantly changes most of the peritoneal effluent markers measured, suggesting an improvement in peritoneal membrane integrity. Additionally, it seems to have a positive effect on residual renal function.


Rationale and design of the Hunting for the off-target propertIes of Ticagrelor on Endothelial function and other Circulating biomarkers in Humans (HI-TECH) trial.
Among the 3 approved oral P2Y12 inhibitors for the treatment for patients with acute coronary syndrome (ACS), ticagrelor, but not prasugrel or clopidogrel, has been associated with off-target properties, such as improved endothelial-dependent vasomotion and increased adenosine plasma levels. The HI-TECH study (NCT02587260) is a multinational, randomized, open-label, crossover study with a Latin squares design, conducted at 5 European sites, in which patients free from recurrent ischemic or bleeding events ≥30 days after a qualifying ACS were allocated to sequentially receive a 30 ± 5-day treatment with prasugrel, clopidogrel, and ticagrelor in random order. The primary objective was to evaluate whether ticagrelor, at treatment steady state (ie, after 30 ± 5 days of drug administration), as compared with both clopidogrel and prasugrel, is associated with an improved endothelial function, assessed with peripheral arterial tonometry. Thirty-six patients undergoing evaluable endothelial function assessment for each of the assigned P2Y12 inhibitor were needed to provide 90% power to detect a 10% relative change of the reactive hyperemia index in the ticagrelor group. The HI-TECH study is the first randomized, crossover study aiming to ascertain whether ticagrelor, when administered at approved regimen in post-ACS patients, improves endothelial function as compared with both clopidogrel and prasugrel.


Health diaries: strategies for compliance and relation to other measures.
This article described experience with the use of health diaries in a two-year prospective study of the influence of the psychosocial environment on the health status of 500 subjects in the Hamilton area. Three strategies were used to maintain compliance: 1) random sampling of three days within each two-week interval; 2) a lottery ticket incentive; and 3) telephone follow-up. The results of an initial telephone and lottery ticket study demonstrated a significant effect on compliance. The data from the two-year study were analyzed to characterize health change based on diary reports over successive six-month intervals and to determine the relationship of reported health to medical utilization data. The results indicated that subjects reported symptoms on about one third of the days surveyed but took no action on about one third of these symptom days. Only one quarter of the symptom days resulted in a change in usual activity, and fewer than one tenth of the symptom days resulted in time off from work or physician visits. The diary variable showed a low, positive correlation with health utilization.


Safety, effectiveness, and health care cost comparisons among elderly patients with venous thromboembolism prescribed warfarin or apixaban in the United States Medicare population.
Objective: To compare safety, effectiveness, and healthcare costs of major bleeding (MB), clinically relevant non-major (CRNM) bleeding, recurrent venous thromboembolism (VTE), and all-cause hospitalization among elderly Medicare VTE patients prescribed warfarin vs apixaban.Methods: Using 100% Medicare data, elderly patients prescribed apixaban or warfarin within 30 days after a VTE encounter were identified. Patients had continuous health plan enrollment and no parenteral or oral anticoagulant use ≤6 months preceding the VTE encounter. Cohorts were balanced using 1:1 propensity score matching (PSM). Cox proportional hazard models were used to assess the risk of MB, CRNM bleeding, recurrent VTE, and all-cause hospitalization. Generalized linear and two-part models were used to estimate MB-, recurrent VTE-, and all-cause related costs (per patient per month [PPPM]).Results: In the pre-matched cohort, 25,284 (66.9%) patients were prescribed warfarin and 12,515 (33.1%) apixaban. After 1:1 PSM, 11,363 matched pairs of apixaban-warfarin patients were included for a mean follow-up of 4.0 and 4.4 months, respectively. Matched cohorts had a mean age of 78 years and mean Charlson Comorbidity Index score of 2.9. Warfarin was associated with a higher risk of MB (hazard ratio [HR] = 1.31; 95% confidence interval [CI] = 1.10-1.57) and CRNM bleeding (HR = 1.31; 95% CI = 1.19-1.43) vs apixaban. The risks of recurrent VTE (HR = 0.96; 95% CI = 0.70-1.33) and all-cause hospitalization (HR = 1.05; 95% CI = 0.99-1.12) were similar among warfarin and apixaban patients. Warfarin patients had higher MB-related ($147 vs $75; p = .003) and all-cause costs PPPM ($3,267 vs $3,033; p < .001), but similar recurrent VTE-related medical costs PPPM ($30 vs $36; p = .516) vs apixaban patients.Conclusions: Warfarin was associated with significantly higher risk of MB and CRNM bleeding as well as higher MB-related and all-cause costs vs apixaban patients. Recurrent VTE risk and costs were similar among warfarin and apixaban patients.


Fish can encode order in their spatial map.
Animals must often orient through areas that are larger than their perceptual range. The blind Mexican cave fish, Astyanax fasciatus, depends on detecting self-induced near-field wave perturbations by objects via the use of its lateral line organ. Its perceptual range (less than or equal to 0.05 m) is greatly exceeded by its ecological ranging requirements (ca. 30 m). Although known to possess a spatial map of its environment, it is not known how this fish links places (or the area over which the perceptual range extends) together. Using the blind cave fish's propensity to accelerate when faced with objects or environments that are recognizably different, I used a behavioural assay to test whether fishes can learn and remember the order of a landmark sequence. I show, to my knowledge for the first time, that blind Mexican cave fish can encode order in their spatial map. The ability to represent the order in which a series of places are spatially linked is a powerful tool for animals that must orient beyond the limit of their perceptual range. The resulting spatial map would be analogous to a jigsaw puzzle, where each piece represents a place whose size is constrained by the animal's perceptual range.


Molecular Subtype-Specific Expression of MicroRNA-29c in Breast Cancer Is Associated with CpG Dinucleotide Methylation of the Promoter.
Basal-like breast cancer is a molecularly distinct subtype of breast cancer that is highly aggressive and has a poor prognosis. MicroRNA-29c (miR-29c) has been shown to be significantly down-regulated in basal-like breast tumors and to be involved in cell invasion and sensitivity to chemotherapy. However, little is known about the genetic and regulatory factors contributing to the altered expression of miR-29c in basal-like breast cancer. We here report that epigenetic modifications at the miR-29c promoter, rather than copy number variation of the gene, may drive the lower expression of miR-29c in basal-like breast cancer. Bisulfite sequencing of CpG sites in the miR-29c promoter region showed higher methylation in basal-like breast cancer cell lines compared to luminal subtype cells with a significant inverse correlation between expression and methylation of miR-29c. Analysis of primary breast tumors using The Cancer Genome Atlas (TCGA) dataset confirmed significantly higher levels of methylation of the promoter in basal-like breast tumors compared to all other subtypes. Furthermore, inhibition of CpG methylation with 5-aza-CdR increases miR-29c expression in basal-like breast cancer cells. Flourescent In Situ Hybridization (FISH) revealed chromosomal abnormalities at miR-29c loci in breast cancer cell lines, but with no correlation between copy number variation and expression of miR-29c. Our data demonstrated that dysregulation of miR-29c in basal-like breast cancer cells may be in part driven by methylation at CpG sites. Epigenetic control of the miR-29c promoter by epigenetic modifiers may provide a potential therapeutic target to overcome the aggressive behavior of these cancers.


Individual differences in the neural signature of subjective value among older adults.
Some healthy older adults show departures from standard decision-making patterns exhibited by younger adults. We asked if such departures are uniform or if heterogeneous aging processes can designate which older adults show differing decision patterns. Thirty-three healthy older adults with varying decision-making patterns on a complex decision task (the Iowa Gambling Task) completed an intertemporal choice task while undergoing functional magnetic resonance imaging. We examined whether value representation in the canonical valuation network differed across older adults based on complex decision-making ability. Older adults with advantageous decision patterns showed increased activity in the valuation network, including the ventromedial prefrontal cortex (VMPFC) and striatum. In contrast, older adults with disadvantageous decision patterns showed reduced or absent activation in the VMPFC and striatum, and these older adults also showed greater blood oxygen level dependent signal temporal variability in the striatum. Our results suggest that a reduced representation of value in the brain, possibly driven by increased neural noise, relates to suboptimal decision-making in a subset of older adults, which could translate to poor decision-making in many aspects of life, including finance, health and long-term care. Understanding the connection between suboptimal decision-making and neural value signals is a step toward mitigating age-related decision-making impairments.


Effect of surrounding environment on atomic structure and equilibrium shape of growing nanocrystals: gold in/on SiO2.
We report on the equilibrium shape and atomic structure of thermally-processed Au nanocrystals (NCs) as determined by high resolution transmission electron microscopy (TEM). The NCs were either deposited on SiO2surface or embedded in SiO2layer. Quantitative data on the NCs surface free energy were obtained via the inverse Wulff construction. Nanocrystals inside the SiO2layer are defect-free and maintain a symmetrical equilibrium shape during the growth. Nanocrystals on SiO2surface exhibit asymmetrical equilibrium shape that is characterized by the introduction of twins and more complex atomic defects above a critical size. The observed differences in the equilibrium shape and atomic structure evolution of growing NCs in and on SiO2is explained in terms of evolution in isotropic/anisotropic environment making the surface free energy function angular and/or radial symmetric/asymmetric affecting the rotational/translational invariance of the surface stress tensor.


Betweenness centrality as predictor for forces in granular packings.
A load applied to a jammed frictional granular system will be localized into a network of force chains making inter-particle connections throughout the system. Because such systems are typically under-constrained, the observed force network is not unique to a given particle configuration, but instead varies upon repeated formation. In this paper, we examine the ensemble of force chain configurations created under repeated assembly in order to develop tools to statistically forecast the observed force network. In experiments on a gently suspended 2D layer of photoelastic particles, we subject the assembly to hundreds of repeated cyclic compressions. As expected, we observe the non-unique nature of the force network, which differs for each compression cycle, by measuring all vector inter-particle contact forces using our open source PeGS software. We find that total pressure on each particle in the system correlates to its betweenness centrality value extracted from the geometric contact network. Thus, the mesoscale network structure is a key control on individual particle pressures.


Mobile health devices: will patients actually use them?
Although mobile health (mHealth) devices offer a unique opportunity to capture patient health data remotely, it is unclear whether patients will consistently use multiple devices simultaneously and/or if chronic disease affects adherence. Three healthy and three chronically ill participants were recruited to provide data on 11 health indicators via four devices and a diet app. The healthy participants averaged overall weekly use of 76%, compared to 16% for those with chronic illnesses. Device adherence declined across all participants during the study. Patients with chronic illnesses, with arguably the most to benefit from advanced (or increased) monitoring, may be less likely to adopt and use these devices compared to healthy individuals. Results suggest device fatigue may be a significant problem. Use of mobile technologies may have the potential to transform care delivery across populations and within individuals over time. However, devices may need to be tailored to meet the specific patient needs.


Antioxidant Activity and Total Phenolic and Flavonoid Content of Various Solvent Extracts from In Vivo and In Vitro Grown Trifolium pratense L. (Red Clover).
In the present study the extracts of in vivo and in vitro grown plants as well as callus tissue of red clover were tested for their antioxidant activities, using different extraction solvent and different antioxidant assays. The total flavonoid and phenolic contents as well as extraction yield of the extracts were also investigated to determine their correlation with the antioxidant activity of the extracts. Among all the tested extracts the highest amounts of total phenolic and total flavonoids content were found in methanol extract of in vivo grown plants. The antioxidant activity of tested samples followed the order in vivo plant extract > callus extract > in vitro extract. The highest reducing power, 2,2-azino-bis-(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS) radical scavenging, and chelating power were found in methanol extracts of in vivo grown red clover, while the chloroform fraction of in vivo grown plants showed the highest 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging, superoxide anion radical scavenging and hydrogen peroxide scavenging compared to the other tested extracts. A significant correlation was found between the antioxidant activity of extracts and their total phenolic and total flavonoid content. According to the findings, the extract of in vitro culture of red clover especially the callus tissue possesses a comparable antioxidant activity to the in vivo cultured plants' extract.


Using an engineered glutamate-gated chloride channel to silence sensory neurons and treat neuropathic pain at the source.
See Basbaum (doi:10.1093/brain/awx227) for a scientific commentary on this article. Peripheral neuropathic pain arises as a consequence of injury to sensory neurons; the development of ectopic activity in these neurons is thought to be critical for the induction and maintenance of such pain. Local anaesthetics and anti-epileptic drugs can suppress hyperexcitability; however, these drugs are complicated by unwanted effects on motor, central nervous system and cardiac function, and alternative more selective treatments to suppress hyperexcitability are therefore required. Here we show that a glutamate-gated chloride channel modified to be activated by low doses of ivermectin (but not glutamate) is highly effective in silencing sensory neurons and reversing neuropathic pain-related hypersensitivity. Activation of the glutamate-gated chloride channel expressed in either rodent or human induced pluripotent stem cell-derived sensory neurons in vitro potently inhibited their response to both electrical and algogenic stimuli. We have shown that silencing is achieved both at nerve terminals and the soma and is independent of membrane hyperpolarization and instead likely mediated by lowering of the membrane resistance. Using intrathecal adeno-associated virus serotype 9-based delivery, the glutamate-gated chloride channel was successfully targeted to mouse sensory neurons in vivo, resulting in high level and long-lasting expression of the channel selectively in sensory neurons. This enabled reproducible and reversible modulation of thermal and mechanical pain thresholds in vivo; analgesia was observed for 3 days after a single systemic dose of ivermectin. We did not observe any motor or proprioceptive deficits and noted no reduction in cutaneous afferent innervation or upregulation of the injury marker ATF3 following prolonged glutamate-gated chloride channel expression. Established mechanical and cold pain-related hypersensitivity generated by the spared nerve injury model of neuropathic pain was reversed by ivermectin treatment. The efficacy of ivermectin in ameliorating behavioural hypersensitivity was mirrored at the cellular level by a cessation of ectopic activity in sensory neurons. These findings demonstrate the importance of aberrant afferent input in the maintenance of neuropathic pain and the potential for targeted chemogenetic silencing as a new treatment modality in neuropathic pain.


Pregnancy-associated breast cancer.
The frequency of pregnancy-associated breast cancer, a rare but serious occurrence, may increase in light of the secular trends for lower parity in general and for older age at first full-term delivery in particular Data on PABC in individuals who are at high risk for breast cancer are limited. A computerized search of Pubmed showed that the reported incidence of PABC is 1:3000 pregnancies; it is often diagnosed at an advanced stage and its prognosis is inferior compared to non-PABC Carriers of mutations in the genes BRCA1/2 may present a specific high risk group for PABC especially at younger ages. Women treated with fertility treatment drugs may be at a higher risk for PABC as well.


An HIT Solution for Clinical Care and Disaster Planning: How One health Center in Joplin, MO Survived a Tornado and Avoided a Health Information Disaster.
Since taking office, President Obama has made substantial investments in promoting the diffusion of health information technology (IT). The objective of the national health IT program is, generally, to enable health care providers to better manage patient care through secure use and sharing of health information. Through the use of technologies including electronic health records, providers can better maintain patient care information and facilitate communication, often improving care outcomes. The recent tornado in Joplin, MO highlights the importance of health information technology in the health center context, and illustrates the importance of secure electronic health information systems as a crucial element of disaster and business continuity planning. This article examines the experience of a community health center in the aftermath of the major tornado that swept through the American Midwest in the spring of 2011, and provides insight into the planning for disaster survival and recovery as it relates to patient records and health center data.


Spanish Translation, Cross-Cultural Adaptation, and Validation of the American Academy of Orthopaedic Surgeons Foot and Ankle Outcomes Questionnaire in Mexican-Americans With Traumatic Foot and Ankle Injuries.
Hispanics represent the largest minority group within the US population accounting for an estimated 55.4 million individuals. Enrolling Hispanics into clinical outcome studies is important in order for study populations to be externally valid and representative of the US population. Inclusion of Mexican-Americans in clinical studies is frequently limited by the lack of validated outcome measures. The goal of this study was to validate a Spanish version of the American Academy of Orthopaedic Surgeons Foot and Ankle Outcomes Questionnaire (AAOS-FAOQ) in Mexican-Americans with traumatic foot and ankle injuries. The translation and cross-cultural adaptation procedure was performed by a committee of bilingual speakers using the following steps: (1) forward translation and adaptation, (2) synthesis, (3) back translation, (4) committee review, and (5) pilot testing. The validation was performed in 100 Mexican-Americans with traumatic foot and ankle injuries. A total of 41 females and 59 males were enrolled in this study. The mean age was 42.98 years (range 18-88). The Spanish version of the Global Foot and Ankle Scale of the AAOS-FAOQ showed statistically significant correlations with all 8 subscales of the Spanish SF-36 as well as the Physical Component Summary scale and the Mental Component Summary scale (P < 0.05). The Global Foot and Ankle scale of the Spanish AAOS-FAOQ demonstrated a test-retest reliability of 0.68. We provide a Spanish translation and cross-cultural adaptation of the AAOS-FAOQ. The instrument demonstrates appropriate psychometric properties in Mexican-Americans with traumatic foot and ankle injuries.


The abts and sulp families of anion transporters from Caenorhabditis elegans.
The slc4 and slc26 gene families encode two distinct groups of gene products that transport HCO(3)(-) and other anions in mammalian cells. The SLC4 and SLC26 proteins are important contributors to transepithelial movement of fluids and electrolytes and to cellular pH and volume regulation. Herein we describe the cDNA cloning from the nematode Caenorhabditis elegans of four anion bicarbonate transporter (abts) homologs of slc4 cDNA and eight sulfate permease (sulp) homologs of slc26 cDNA. Analysis of transgenic nematode strains carrying promoter::GFP fusions suggests relatively restricted expression patterns for many of these genes. At least three genes are expressed primarily in the intestine, three are expressed primarily in the excretory cell, and one is expressed in both of these polarized cell types. One of the genes is also expressed exclusively in the myoepithelium-like cells of the pharynx. Many of the sulp gene products localize to the basolateral membrane rather than to the apical membrane. Several ABTS and SULP proteins exhibited anion transport function in Xenopus oocytes. The strongest Cl(-) transporter among these also mediated Cl(-)/HCO(3)(-) exchange. These findings encourage exploitation of the genetic strengths of the nematode model system in the study of the physiological roles of anion transport by the proteins of these two highly conserved gene families.


Vitamin d in the general population of young adults with autism in the faroe islands.
Vitamin D deficiency has been proposed as a possible risk factor for developing autism spectrum disorder (ASD). 25-Hydroxyvitamin D3 (25(OH)D3) levels were examined in a cross-sectional population-based study in the Faroe Islands. The case group consisting of a total population cohort of 40 individuals with ASD (aged 15-24 years) had significantly lower 25(OH)D3 than their 62 typically-developing siblings and their 77 parents, and also significantly lower than 40 healthy age and gender matched comparisons. There was a trend for males having lower 25(OH)D3 than females. Effects of age, month/season of birth, IQ, various subcategories of ASD and Autism Diagnostic Observation Schedule score were also investigated, however, no association was found. The very low 25(OH)D3 in the ASD group suggests some underlying pathogenic mechanism.


Constructing a semantic predication gold standard from the biomedical literature.
Semantic relations increasingly underpin biomedical text mining and knowledge discovery applications. The success of such practical applications crucially depends on the quality of extracted relations, which can be assessed against a gold standard reference. Most such references in biomedical text mining focus on narrow subdomains and adopt different semantic representations, rendering them difficult to use for benchmarking independently developed relation extraction systems. In this article, we present a multi-phase gold standard annotation study, in which we annotated 500 sentences randomly selected from MEDLINE abstracts on a wide range of biomedical topics with 1371 semantic predications. The UMLS Metathesaurus served as the main source for conceptual information and the UMLS Semantic Network for relational information. We measured interannotator agreement and analyzed the annotations closely to identify some of the challenges in annotating biomedical text with relations based on an ontology or a terminology. We obtain fair to moderate interannotator agreement in the practice phase (0.378-0.475). With improved guidelines and additional semantic equivalence criteria, the agreement increases by 12% (0.415 to 0.536) in the main annotation phase. In addition, we find that agreement increases to 0.688 when the agreement calculation is limited to those predications that are based only on the explicitly provided UMLS concepts and relations. While interannotator agreement in the practice phase confirms that conceptual annotation is a challenging task, the increasing agreement in the main annotation phase points out that an acceptable level of agreement can be achieved in multiple iterations, by setting stricter guidelines and establishing semantic equivalence criteria. Mapping text to ontological concepts emerges as the main challenge in conceptual annotation. Annotating predications involving biomolecular entities and processes is particularly challenging. While the resulting gold standard is mainly intended to serve as a test collection for our semantic interpreter, we believe that the lessons learned are applicable generally.


The cell adhesion molecule M-cadherin is specifically expressed in developing and regenerating, but not denervated skeletal muscle.
The spatiotemporal distribution of M-cadherin mRNA has been determined by in situ hybridization in the mouse embryo and in adult skeletal muscle following experimental regeneration and denervation. M-cadherin mRNA is highly tissue specific and is found only in developing skeletal muscle. In contrast, N-cadherin mRNA has a broader tissue distribution in the embryo, being found on both neural elements and skeletal and cardiac muscle. M-cadherin is expressed in the myotomes shortly after they form, along with the myogenic regulatory factor myogenin. M-cadherin is expressed in muscles derived from the myotomes and is detected in forelimb bud precursor cells at embryonic day 11.5. In the latter case M-cadherin expression appears co-ordinately with that of myogenin and cardiac alpha-actin. Shortly before birth, M-cadherin expression is down regulated. M-cadherin can, however, be re-expressed following experimental regeneration of skeletal muscle. Here M-cadherin is transiently expressed on regenerating myoblasts but not myotubes. Following muscle denervation no evidence was found for re-expression of M-cadherin under conditions where there was strong expression of the nicotinic acetylcholine receptor on myofibres. The highly specific tissue distribution and unique developmental profile distinguishes M-cadherin from other cadherins and suggests a role in cell surface events during early myogenesis.


Controlled outcome of Hirschsprung's disease beyond adolescence: a single center experience.
The aim of this study was to assess the function and quality of life of Hirschsprung's Disease (HD) beyond adolescence and relate it to matched controls. All 203 patients diagnosed with HD at our department from 1961 to 1995 were identified. 21 had died, 43 had unclear diagnosis and 16 could not be traced. The remaining 123 patients were sent bowel function and SF-36 quality of life questionnaires. 69 patients (mean age 37.8, range 22-58, 13 female) responded and were matched with 138 age and sex-matched controls. Function: HD-patients had significantly higher number of bowel movements per week, higher incidence of soiling, urgency, permanent stomas, use of laxatives, enemas and loperamide. HD-patients also scored significantly lower in their satisfaction with their bowel function. There was, however, no significant difference in Miller Incontinence score. QOL: HD-patients reported a significantly higher incidence of negative impact by their bowel function on daily life, social interaction and ability to go on vacation. There were no significant differences in SF-36-scores. Bowel function has a lifelong negative impact on the lives of patients with HD. This strongly indicates a need for structured follow-up beyond adolescence.


Detecting depressive and anxiety disorders in distressed patients in primary care; comparative diagnostic accuracy of the Four-Dimensional Symptom Questionnaire (4DSQ) and the Hospital Anxiety and Depression Scale (HADS).
Depressive and anxiety disorders often go unrecognized in distressed primary care patients, despite the overtly psychosocial nature of their demand for help. This is especially problematic in more severe disorders needing specific treatment (e.g. antidepressant pharmacotherapy or specialized cognitive behavioural therapy). The use of a screening tool to detect (more severe) depressive and anxiety disorders may be useful not to overlook such disorders. We examined the accuracy with which the Four-Dimensional Symptom Questionnaire (4DSQ) and the Hospital Anxiety and Depression Scale (HADS) are able to detect (more severe) depressive and anxiety disorders in distressed patients, and which cut-off points should be used. Seventy general practitioners (GPs) included 295 patients on sick leave due to psychological problems. They excluded patients with recognized depressive or anxiety disorders. Patients completed the 4DSQ and HADS. Standardized diagnoses of DSM-IV defined depressive and anxiety disorders were established with the Composite International Diagnostic Interview (CIDI). Receiver Operating Characteristic (ROC) analyses were performed to obtain sensitivity and specificity values for a range of scores, and area under the curve (AUC) values as a measure of diagnostic accuracy. With respect to the detection of any depressive or anxiety disorder (180 patients, 61%), the 4DSQ and HADS scales yielded comparable results with AUC values between 0.745 and 0.815. Also with respect to the detection of moderate or severe depressive disorder, the 4DSQ and HADS depression scales performed comparably (AUC 0.780 and 0.739, p 0.165). With respect to the detection of panic disorder, agoraphobia and social phobia, the 4DSQ anxiety scale performed significantly better than the HADS anxiety scale (AUC 0.852 versus 0.757, p 0.001). The recommended cut-off points of both HADS scales appeared to be too low while those of the 4DSQ anxiety scale appeared to be too high. In general practice patients on sick leave because of psychological problems, the 4DSQ and the HADS are equally able to detect depressive and anxiety disorders. However, for the detection of cases severe enough to warrant specific treatment, the 4DSQ may have some advantages over the HADS, specifically for the detection of panic disorder, agoraphobia and social phobia.


Emerging Developments in Microbiome and Microglia Research: Implications for Neurodevelopmental Disorders.
From immunology to neuroscience, interactions between the microbiome and host are increasingly appreciated as potent drivers of health and disease. Epidemiological studies previously identified compelling correlations between perinatal microbiome insults and neurobehavioral outcomes, the mechanistic details of which are just beginning to take shape thanks to germ-free and antibiotics-based animal models. This review summarizes parallel developments from clinical and preclinical research that suggest neuroactive roles for gut bacteria and their metabolites. We also examine the nascent field of microbiome-microglia crosstalk research, which includes pharmacological and genetic strategies to inform functional capabilities of microglia in response to microbial programming. Finally, we address an emerging hypothesis behind neurodevelopmental disorders, which implicates microbiome dysbiosis in the atypical programming of neuroimmune cells, namely microglia.


Making an IMPAKT; Improving care of Chronic Kidney Disease patients in the community through collaborative working and utilizing Information Technology.
Chronic kidney disease (CKD) is a serious long-term condition, which if left untreated causes significant cardiovascular sequele. It is well recognized management of modifiable risk factors, such as blood pressure (BP), can lead to improved long-term outcomes. A novel information technology (IT) solution presents a possible solution to help clinicians in the community identify and manage at risk patients more efficiently. The IMproving Patient care and Awareness of Kidney disease progression Together (IMPAKT) IT tool was used to identify patients with CKD and uncontrolled hypertension in the community. A CKD nurse utilized the tool at primary care practices to identify patients who warranted potential intervention and disseminated this information to clinical staff. Blood pressure management targets and incidence of coded CKD were used to evaluate the project. Altogether 48 practices participated in an 18 month project from April 2014, and data from 20 practices, with a total adult population of 121,362, was available for analysis. Two full consecutive QI (Quality Improvement) audit cycles were completed. There was an increase in the mean recorded prevalence of coded CKD patients over the course of the project. Similarly, there was an increase in the percentage of patients with BP been recorded and importantly there was an accompanying significant increase in CKD patients achieving BP targets. At the end of the project an additional 345 individuals with CKD achieved better blood pressure control. This could potentially prevent 9 cardiovascular events in the CKD group, translating to a cost saving of £320,000 for the 20 practices involved. The most significant change in clinical markers occurred during cycle 1 of the audit, the improvement was maintained throughout cycle 2 of the audit. Our results show the real-life clinical impact of a relatively simple and easy to implement QI project, to help improve outcomes in patients with CKD. This was achieved through more efficient working by targeting of high-risk groups, and improved communication between primary/secondary care. The project could be adapted for other chronic disease conditions. Despite the recorded improvements in blood pressure management, a large proportion of high-risk patients remained above ideal blood pressure, additional interventions in this area need to be explored. Through collaborative and multi-professional working and utilizing IT resources, we have shown it is possible to deliver measurable and sustainable improvements in blood pressure control for patients with CKD in a real life clinical setting.


Cannabis legalisation and testing for cannabis use in safety- and risk-sensitive environments.
The legalisation of cannabis by the High Court of South Africa, which was confirmed by the Constitutional Court, imposes challenges to occupational medical practitioners acting as medical review officers in compliance testing and fit-for-service medical examinations. The lipophilic character of the psychoactive component of cannabis, delta-9-tetrahydrocannabinol (Δ9-THC), and its prolonged elimination half-life, create challenges for the ethically and scientifically correct management of the legal use of cannabis in risk-sensitive environments. Important issues to consider in testing for cannabis use are: the stance of 'zero tolerance'; screening and confirmation cut-off concentrations; and the bio-matrices used for testing. Constitutional rights relate to privacy, freedom, autonomy, freedom of religion and the equal enjoyment of rights and privileges, which must be balanced against the health and safety of others.


The accessory foramen ovale of the skull: an osteological study.
The sphenoid bone is known to have several foramina and the foramen ovale is one amongst them. The foramen ovale transmits the mandibular nerve, accessory meningeal artery, lesser petrosal nerve and the emissary veins. There have been past reports on the variations of the different foramina present in the skull but there are no reports on the variations of the skull foramina from any of the South-East Asian countries. The present study aims to highlight the presence of an accessory foramen ovale in the skull in Malaysian population. Both sides of fifteen adult skulls (n = 30) were taken for observation of any variations in the foramen ovale. We observed the presence of accessory foramen ovale on the left side of a single skull (3.33%). The minute accessory foramen ovale was located 0.1 cm medial to the normal foramen ovale. The anomalous accessory foramen ovale was circular in shape and measured 0.1 cm in diameter. Anatomical knowledge of the foramen ovale is important for all neurosurgical procedures involving the trigeminal nerve and administration of anaesthesia in the mandibular nerve. Interestingly, the percutaneous biopsy of the cavernous sinus is also performed through the foramen ovale. Prior knowledge of the presence of an accessory foramen ovale may be important for academic, anthropological, forensic and clinical purpose and the present study aims to highlight such.


Effects of Gender-Affirming Hormones on Lipid, Metabolic, and Cardiac Surrogate Blood Markers in Transgender Persons.
Gender-affirming hormonal therapy consists of testosterone in transgender men and estrogens and antiandrogens in transgender women. Research has concluded that gender-affirming therapy generally leads to high satisfaction rates, increased quality of life, and higher psychological well-being. However, given the higher incidence of cardiometabolic morbidity and mortality in cisgender men compared with cisgender women, concerns about the cardiometabolic risk of androgen therapy have been raised. A literature research was conducted on PubMed, Embase, and Scopus, searching for relevant articles on the effects of gender-affirming hormone therapy on cardiometabolic risk and thrombosis. After screening 734 abstracts, 77 full text articles were retained, of which 11 were review articles. Studies describing a higher risk for cardiometabolic and thromboembolic morbidity and/or mortality in transgender women (but not transgender men) mainly covered data on transgender women using the now obsolete ethinyl estradiol and, therefore, are no longer valid. Currently, most of the available literature on transgender people adhering to standard treatment regimens consists of retrospective cohort studies of insufficient follow-up duration. When assessing markers of cardiometabolic disease, the available literature is inconclusive, which may be ascribed to relatively short follow-up duration and small sample size. The importance of ongoing large-scale prospective studies/registries and of optimal management of conventional risk factors cannot be overemphasized.


Identification of bone morphogenetic protein 7 (BMP7) as an instructive factor for human epidermal Langerhans cell differentiation.
Human Langerhans cell (LC) precursors populate the epidermis early during prenatal development and thereafter undergo massive proliferation. The prototypic antiproliferative cytokine TGF-β1 is required for LC differentiation from human CD34(+) hematopoietic progenitor cells and blood monocytes in vitro. Similarly, TGF-β1 deficiency results in LC loss in vivo. However, immunohistology studies revealed that human LC niches in early prenatal epidermis and adult basal (germinal) keratinocyte layers lack detectable TGF-β1. Here we demonstrated that these LC niches express high levels of bone morphogenetic protein 7 (BMP7) and that Bmp7-deficient mice exhibit substantially diminished LC numbers, with the remaining cells appearing less dendritic. BMP7 induces LC differentiation and proliferation by activating the BMP type-I receptor ALK3 in the absence of canonical TGF-β1-ALK5 signaling. Conversely, TGF-β1-induced in vitro LC differentiation is mediated via ALK3; however, co-induction of ALK5 diminished TGF-β1-driven LC generation. Therefore, selective ALK3 signaling by BMP7 promotes high LC yields. Within epidermis, BMP7 shows an inverse expression pattern relative to TGF-β1, the latter induced in suprabasal layers and up-regulated in outer layers. We observed that TGF-β1 inhibits microbial activation of BMP7-generated LCs. Therefore, TGF-β1 in suprabasal/outer epidermal layers might inhibit LC activation, resulting in LC network maintenance.


Adaptation of stress-induced mucosal pathophysiology in rat colon involves opioid pathways.
Acute stress increases ion secretion and permeability of rat colonic epithelium. However, it is not known if stress-induced mucosal changes are subject to adaptation. Wistar-Kyoto rats were exposed to either continuous water-avoidance stress (CS) for 60 min or intermittent stress (IS) for three 20-min periods. Distal colonic segments were mounted in Ussing Chambers, and ion-transport [short-circuit current (I(sc))] and permeability [conductance and flux of horseradish peroxidase (HRP)] parameters were measured. CS significantly increased I(sc), conductance, and HRP flux compared with control values. In contrast, in IS rats these variables were similar to those in nonstressed controls. To study the pathways involved in IS-induced adaptation, rats were pretreated intraperitoneally with the opioid antagonists naloxone or methylnaloxone. Opioid antagonists had no effect on values in control or CS rats. However, in the IS group, naloxone and methylnaloxone reversed the adaptive responses, and all variables increased to CS values. We conclude that stress-induced colonic mucosal pathophysiology is subject to rapid adaptation, which involves opioid pathways.


Membrane-induced folding and structure of membrane-bound annexin A1 N-terminal peptides: implications for annexin-induced membrane aggregation.
Annexins constitute a family of calcium-dependent membrane-binding proteins and can be classified into two groups, depending on the length of the N-terminal domain unique for each individual annexin. The N-terminal domain of annexin A1 can adopt an alpha-helical conformation and has been implicated in mediating the membrane aggregation behavior of this protein. Although the calcium-independent interaction of the annexin A1 N-terminal domain has been known for some time, there was no structural information about the membrane interaction of this secondary membrane-binding site of annexin A1. This study used circular dichroism spectroscopy to show that a rat annexin A1 N-terminal peptide possesses random coil structure in aqueous buffer but an alpha-helical structure in the presence of small unilamellar vesicles. The binding of peptides to membranes was confirmed by surface pressure (Langmuir film balance) measurements using phosphatidylcholine/phosphatidylserine monolayers, which show a significant increase after injection of rat annexin A1 N-terminal peptides. Lamellar neutron diffraction with human and rat annexin A1 N-terminal peptides reveals an intercalation of the helical peptides with the phospholipid bilayer, with the helix axis lying parallel to the surface of membrane. Our findings confirm that phospholipid membranes assist the folding of the N-terminal peptides into alpha-helical structures and that this conformation enables favorable direct interactions with the membrane. The results are consistent with the hypothesis that the N-terminal domain of annexin A1 can serve as a secondary membrane binding site in the process of membrane aggregation by providing a peripheral membrane anchor.


Potential climate change effects on the habitat of antarctic krill in the weddell quadrant of the southern ocean.
Antarctic krill is a cold water species, an increasingly important fishery resource and a major prey item for many fish, birds and mammals in the Southern Ocean. The fishery and the summer foraging sites of many of these predators are concentrated between 0° and 90°W. Parts of this quadrant have experienced recent localised sea surface warming of up to 0.2°C per decade, and projections suggest that further widespread warming of 0.27° to 1.08°C will occur by the late 21(st) century. We assessed the potential influence of this projected warming on Antarctic krill habitat with a statistical model that links growth to temperature and chlorophyll concentration. The results divide the quadrant into two zones: a band around the Antarctic Circumpolar Current in which habitat quality is particularly vulnerable to warming, and a southern area which is relatively insensitive. Our analysis suggests that the direct effects of warming could reduce the area of growth habitat by up to 20%. The reduction in growth habitat within the range of predators, such as Antarctic fur seals, that forage from breeding sites on South Georgia could be up to 55%, and the habitat's ability to support Antarctic krill biomass production within this range could be reduced by up to 68%. Sensitivity analysis suggests that the effects of a 50% change in summer chlorophyll concentration could be more significant than the direct effects of warming. A reduction in primary production could lead to further habitat degradation but, even if chlorophyll increased by 50%, projected warming would still cause some degradation of the habitat accessible to predators. While there is considerable uncertainty in these projections, they suggest that future climate change could have a significant negative effect on Antarctic krill growth habitat and, consequently, on Southern Ocean biodiversity and ecosystem services.


The validity of spot urine samples for low-level occupational mercury exposure assessment and relationship to porphyrin and creatinine excretion rates.
Hg and porphyrin levels in single void urine specimens (spot samples) were compared with calculated 24-hr urine levels in 35 (20 [correction of 25] male and 15 female) practicing dentists who had been occupationally exposed to low levels of elemental Hg. The study aimed to: 1) determine the individual variability for Hg and porphyrin concentrations in spot samples over a 24-hr period; 2) test for the presence of diurnal variation in urinary Hg and porphyrin concentrations; and 3) determine the time of day at which a spot sample would give a Hg concentration closest to the 24-hr average concentration. Results confirmed previous reports of a first-order diurnal pattern with a mid-morning peak for Hg concentration (P < .001). A second-order model best described creatinine excretion (P = .0089), with peaks at about 5:00 and 19:00. The use of creatinine adjustment for Hg concentration significantly reduced the intraindividual variation around the diurnal curve. No diurnal patterns were found for any of the porphyrins examined. We recommend that, for small clinical studies using urinary Hg concentration, 24-hr sampling would be ideal, but that for mass screenings and cross-sectional studies, spot samples may be useful because they correlate fairly well with 24-hr averages (creatinine adjusted, r = 0.61; unadjusted, r = 0.74). Because of the existence of diurnal variation, for all cases using serial sampling attention should be paid to time of day.


Phylogeographic patterns in the Philippine archipelago influence symbiont diversity in the bobtail squid-Vibrio mutualism.
Marine microbes encounter a myriad of biotic and abiotic factors that can impact fitness by limiting their range and capacity to move between habitats. This is especially true for environmentally transmitted bacteria that cycle between their hosts and the surrounding habitat. As geologic history, biogeography, and other factors such as water temperature, salinity, and physical barriers can inhibit bacterial movement to novel environments, we chose to examine the genetic architecture of Euprymna albatrossae (Mollusca: Cephalopoda) and their Vibrio fischeri symbionts in the Philippine archipelago using a combined phylogeographic approach. Eleven separate sites in the Philippine islands were examined using haplotype estimates that were examined via nested clade analysis to determine the relationship between E. albatrossae and V. fischeri populations and their geographic location. Identical analyses of molecular variance (AMOVA) were used to estimate variation within and between populations for host and symbiont genetic data. Host animals demonstrated a significant amount of variation within island groups, while symbiont variation was found within individual populations. Nested clade phylogenetic analysis revealed that hosts and symbionts may have colonized this area at different times, with a sudden change in habitat. Additionally, host data indicate restricted gene flow, whereas symbionts show range expansion, followed by periodic restriction to genetic flow. These differences between host and symbiont networks indicate that factors "outside the squid" influence distribution of Philippine V. fischeri. Our results shed light on how geography and changing environmental factors can impact marine symbiotic associations at both local and global scales.


Fabrication, characterization, and functionalization of dual carbon electrodes as probes for scanning electrochemical microscopy (SECM).
Dual carbon electrodes (DCEs) are quickly, easily, and cheaply fabricated by depositing pyrolytic carbon into a quartz theta nanopipet. The size of DCEs can be controlled by adjusting the pulling parameters used to make the nanopipet. When operated in generation/collection (G/C) mode, the small separation between the electrodes leads to reasonable collection efficiencies of ca. 30%. A three-dimensional finite element method (FEM) simulation is developed to predict the current response of these electrodes as a means of estimating the probe geometry. Voltammetric measurements at individual electrodes combined with generation/collection measurements provide a reasonable guide to the electrode size. DCEs are employed in a scanning electrochemical microscopy (SECM) configuration, and their use for both approach curves and imaging is considered. G/C approach curve measurements are shown to be particularly sensitive to the nature of the substrate, with insulating surfaces leading to enhanced collection efficiencies, whereas conducting surfaces lead to a decrease of collection efficiency. As a proof-of-concept, DCEs are further used to locally generate an artificial electron acceptor and to follow the flux of this species and its reduced form during photosynthesis at isolated thylakoid membranes. In addition, 2-dimensional images of a single thylakoid membrane are reported and analyzed to demonstrate the high sensitivity of G/C measurements to localized surface processes. It is finally shown that individual nanometer-size electrodes can be functionalized through the selective deposition of platinum on one of the two electrodes in a DCE while leaving the other one unmodified. This provides an indication of the future versatility of this type of probe for nanoscale measurements and imaging.


Lactobacillus gasseri SBT2055 reduces infection by and colonization of Campylobacter jejuni.
Campylobacter is a normal inhabitant of the chicken gut. Pathogenic infection with this organism in humans is accompanied by severe inflammation of the intestinal mucosal surface. The aim of this study was to evaluate the ability of Lactobacillus gasseri SBT2055 (LG2055) to inhibit the adhesion and invasion of Campylobacter jejuni in vitro and to suppress C. jejuni colonization of chicks in vivo. Pretreatment with LG2055 significantly reduced adhesion to and invasion of a human epithelial cell line, Intestine 407, by C. jejuni 81-176. Methanol (MeOH)-fixed LG2055 also reduced infection by C. jejuni 81-176. However, proteinase K (ProK)-treated LG2055 eliminated the inhibitory effects. Moreover, LG2055 co-aggregated with C. jejuni 81-176. ProK treatment prevented this co-aggregation, indicating that the co-aggregation phenotype mediated by the proteinaceous cell-surface components of LG2055 is important for reducing C. jejuni 81-176 adhesion and invasion. In an in vivo assay, oral doses of LG2055 were administered to chicks daily for 14 days after oral inoculation with C. jejuni 81-176. At 14 days post-inoculation, chicks treated with LG2055 had significantly reduced cecum colonization by C. jejuni. Reduction in the number of C. jejuni 81-176 cells adhering to and internalized by human epithelial cells demonstrated that LG2055 is an organism that effectively and competitively excludes C. jejuni 81-176. In addition, the results of the chick colonization assay suggest that treatment with LG2055 could be useful in suppressing C. jejuni colonization of the chicks at early growth stages.


An information-theoretic approach to evaluating the size and temperature dependence of metabolic rate.
The effects of body mass and temperature on metabolic rate (MR) are among the most widely examined physiological relationships. Recently, these relationships have been incorporated into the metabolic theory of ecology (MTE) that links the ecology of populations, communities and ecosystems to the MR of individual organisms. The fundamental equation of MTE derives the relation between mass and MR using first principles and predicts the temperature dependence of MR based on biochemical kinetics. It is a deliberately simple, zeroth-order approximation that represents a baseline against which variation in real biological systems can be examined. In the present study, we evaluate the fundamental equation of MTE against other more parameter-rich models for MR using an information-theoretic approach to penalize the inclusion of additional parameters. Using a comparative database of MR measurements for 1359 species, from 11 groups ranging from prokaryotes to mammals, and spanning 16 orders of magnitude in mass and a 59°C range in body temperature, we show that differences between taxa in the mass and temperature dependence of MR are sufficiently large as to be retained in the best model for MR despite the requirement for estimation of 22 more parameters than the fundamental equation of MTE.


Exploring the Gap: Food Insecurity and Resource Engagement.
Pediatric health care institutions are increasingly implementing food insecurity (FI) screens, but there is limited information about participant interest in referral and engagement with resources provided. In this descriptive cross-sectional study, we recruited participants from a consecutive sample of adult caregivers arriving with pediatric patients in the emergency department at an urban, freestanding children's hospital. Caregivers completed a validated, 2-question screen for FI. All participants received a list of food access resources. Direct referral to a partnered community food resource agency was offered to those who screened positive for FI; that agency completed a phone call to the participant for resource provision within 2 weeks. Among the 1818 participants recruited, 20.6% (375) screened positive for FI, consistent with the area's reported child FI rate. Of those who screened positive, 54.9% (206) opted to receive a direct-referral via phone call to a food resource agency, and 35.9% (74) of these were reached by phone. About 31.1% (23) of those contacted were no longer interested in food resource referrals, 10.8% (8) were signed up for the Supplemental Nutrition Assistance Program, and 59.5% (44) were referred to local food pantries. Through hospital-community partnership in an initial attempt to screen and offer direct-referral for FI, we elicited considerable interest among families for connection to resource agencies. However, there was a substantial gap between referral acceptance and ultimate connection with the resource agency stemming from 2 major sources: inability to re-contact and loss of interest after contact.


Being a palliative nurse for persons with severe congestive heart failure in advanced homecare.
Advanced homecare for persons with congestive heart failure is a 'new' challenge for palliative nurses. The aim of this study is to illuminate the meaning of being a palliative nurse for persons with severe congestive heart failure in advanced homecare. Narrative interviews with 11 nurses were conducted, tape-recorded, and transcribed verbatim. A phenomenological-hermeneutic method was used to interpret the text. One meaning of being a palliative nurse is being firmly rooted and guided by the values of palliative culture. Being adaptable to the patient's way of life carries great weight. On one hand nurses live out this value, facilitating for the patients to live their everyday life as good as possible. Being a facilitator is revealed as difficult, challenging, but overall positive. On the other hand nurses get into a tight corner when values of palliative culture clash and do not correspond with the nurses interpretation of what is good for the person with congestive heart failure. Being in such a tight corner is revealed as frustrating and giving rise to feelings of inadequacy. Thus, it seems important to reflect critical on the values of palliative culture.


An internal thioester in a pathogen surface protein mediates covalent host binding.
To cause disease and persist in a host, pathogenic and commensal microbes must adhere to tissues. Colonization and infection depend on specific molecular interactions at the host-microbe interface that involve microbial surface proteins, or adhesins. To date, adhesins are only known to bind to host receptors non-covalently. Here we show that the streptococcal surface protein SfbI mediates covalent interaction with the host protein fibrinogen using an unusual internal thioester bond as a 'chemical harpoon'. This cross-linking reaction allows bacterial attachment to fibrin and SfbI binding to human cells in a model of inflammation. Thioester-containing domains are unexpectedly prevalent in Gram-positive bacteria, including many clinically relevant pathogens. Our findings support bacterial-encoded covalent binding as a new molecular principle in host-microbe interactions. This represents an as yet unexploited target to treat bacterial infection and may also offer novel opportunities for engineering beneficial interactions.


Biodegradation of 2-nitrotoluene by Pseudomonas sp. strain JS42.
A strain of Pseudomonas sp. was isolated from nitrobenzene-contaminated soil and groundwater on 2-nitrotoluene as the sole source of carbon, energy, and nitrogen. Bacterial cells growing on 2-nitrotoluene released nitrite into the growth medium. The isolate also grew on 3-methylcatechol, 4-methylcatechol, and catechol. 2-Nitrotoluene, 3-methylcatechol, and catechol stimulated oxygen consumption by intact cells regardless of the growth substrate. Crude extracts from the isolate contained catechol 2,3-dioxygenase and 2-hydroxy-6-oxohepta-2,4-dienoate hydrolase activity. The results suggest that 2-nitrotoluene is subject to initial attack by a dioxygenase enzyme that forms 3-methylcatechol with concomitant release of nitrite. The 3-methylcatechol is subsequently degraded via the meta ring fission pathway.


Endocytosis of cholera toxin in GERL-like structures of murine neuroblastoma cells pretreated with GM1 ganglioside. Cholera toxin internalization into Neuroblastoma GERL.
Cholera toxin (CT), covalently attached to horseradish peroxidase (HRP), is a specific cytochemical marker for GM1 ganglioside (GM1) and retains the ability of the native toxin to raise levels of cyclic AMP in avian erythrocytes. Using a cytochemical stain for HRP, we found that 9% of control cultured murine neuroblastoma cells bound cholera toxin-horseradish peroxidase conjugates (CT-HRP) on their surfaces after incubations for 1 h at 4 degrees C. Exogenous GM1, the natural receptor of CT, becomes associated in the culture medium with the plasma membranes of these cells so that 96% of cells are stained. Cells preincubated with GM1 at 4 degrees C were exposed to CT-HRP for 1 h at 4 degrees C. After washing, cells were incubated at 37 degrees C for 30 min-24 h. Endocytosis of CT-HRP occurred within 30 min and CT-HRP remained, throughout the 24-h period, in tubules, vesicles, and cisternae often found near the Golgi apparatus; this aggregate of peroxidase-positive elements probably corresponds to Golgi apparatus-endoplasmic reticulum-lysosomes (GERL) of neurons. In metaphase cells, CT-HRP was observed in aggregates of vesicles and tubules clustered near the centriole. Conjugates of HRP with subunit B, the GM1 binding component of CT, were internalized by cells pretreated with GM1 as was CT-HRP. The 9% of neuroblastoma cells binding CT-HRP in the absence of exogenous GM1 internalized the ligand in a manner indistinguishable from that of the treated cells. These findings indicate that, in neuroblastoma cells, a system of vesicles, tubules, and cisternae, analogous to GERL of neurons, is the primary recipient of adsorptive endocytosis of CT bound to endogenous or exogenously introduced GM1.


Spikes, synchrony, and attentive learning by laminar thalamocortical circuits.
This article develops the Synchronous Matching Adaptive Resonance Theory (SMART) neural model to explain how the brain may coordinate multiple levels of thalamocortical and corticocortical processing to rapidly learn, and stably remember, important information about a changing world. The model clarifies how bottom-up and top-down processes work together to realize this goal, notably how processes of learning, expectation, attention, resonance, and synchrony are coordinated. The model hereby clarifies, for the first time, how the following levels of brain organization coexist to realize cognitive processing properties that regulate fast learning and stable memory of brain representations: single-cell properties, such as spiking dynamics, spike-timing-dependent plasticity (STDP), and acetylcholine modulation; detailed laminar thalamic and cortical circuit designs and their interactions; aggregate cell recordings, such as current source densities and local field potentials; and single-cell and large-scale inter-areal oscillations in the gamma and beta frequency domains. In particular, the model predicts how laminar circuits of multiple cortical areas interact with primary and higher-order specific thalamic nuclei and nonspecific thalamic nuclei to carry out attentive visual learning and information processing. The model simulates how synchronization of neuronal spiking occurs within and across brain regions, and triggers STDP. Matches between bottom-up adaptively filtered input patterns and learned top-down expectations cause gamma oscillations that support attention, resonance, learning, and consciousness. Mismatches inhibit learning while causing beta oscillations during reset and hypothesis testing operations that are initiated in the deeper cortical layers. The generality of learned recognition codes is controlled by a vigilance process mediated by acetylcholine.


Src tyrosine kinase activity down-regulates Rho-dependent responses during Shigella entry into epithelial cells and stress fibre formation.
Invasion of epithelial cells by Shigella, the causative agent of bacillary dysentery, is dependent upon the formation of characteristic membrane ruffles that engulf the bacteria in a macropinocytic-like process. We show here that Cdc42 and Rac GTPases, but not Rho;, are critical for actin polymerisation, whereas Rho; is necessary for the recruitment of ezrin and Src at the site of entry. Remarkably, cells expressing constitutively active Src did not show ezrin recruitment at Shigella entry foci. In these cells, formation of stress fibres induced by LPA stimulation, or microinjection of activated Rho; (V14Rho), was inhibited. Src-mediated tyrosyl-phosphorylation of p190RhoGAP correlated with changes in the ability of p190RhoGAP to interact with Rho;, suggesting that Src regulates Rho; function via p190RhoGAP. We propose that Rho; activation is required for proper organisation of Shigella entry foci and for Src recruitment, and that Src tyrosine kinase activity, in turn, down-regulates the function of Rho; at the site of Shigella entry. The significance of this negative regulatory loop on Rho;-dependent responses is discussed.


Assessment of left atrial appendage function by transesophageal echocardiography. Implications for the development of thrombus.
The predilection of the left atrial appendage (LAA) for thrombus formation has long been known. We prospectively studied the two-dimensional echocardiographic and Doppler patterns of LAA function in 82 patients by transesophageal echocardiography. In the 63 patients in sinus rhythm, LAA area was measured during LAA diastole at the onset of the electrocardiographic (ECG) P wave (LAAmax) and after LAA systole at the ECG R wave (LAAmin) and LAA ejection fraction was calculated as (LAAmax-LAAmin)/LAAmax; peak Doppler velocity was recorded from the LAA outlet. The 58 patients in sinus rhythm without LAA thrombus were grouped according to left atrial size on transthoracic echocardiography; 39 patients had a left atrial size of less than 40 mm (group 1) and 19 had a left atrial size of 40 mm or greater (group 2). Five patients in sinus rhythm had LAA thrombus. In the 19 patients with atrial fibrillation or flutter LAAmax was measured independent of the ECG; three of these patients had LAA spontaneous contrast, four had thrombus, and one had both. Patients in sinus rhythm without LAA thrombus demonstrated a characteristic pattern of a contractile LAA apex and a noncontractile base with color flow and pulsed Doppler evidence of LAA emptying that coincided with the P wave. Patients in sinus rhythm with LAA thrombus had a mean +/- SD LAAmax (8.0 +/- 1.5 cm2) larger than that in group 1 (5.0 +/- 1.9 cm2) (p less than 0.01) but not group 2 (6.7 +/- 3.1 cm2), LAAmin (6.5 +/- 1.0 cm2) larger than that in both group 1 (2.3 +/- 1.5 cm2) and group 2 (4.2 +/- 2.7 cm2) (p less than 0.01), and LAA ejection fraction (17 +/- 11%) and LAA velocity (0.24 +/- 0.10 m/sec) less than those in both group 1 (55 +/- 21% and 0.48 +/- 0.24 m/sec, respectively) and group 2 (45 +/- 27% and 0.46 +/- 0.24 m/sec, respectively) (p less than 0.01). Patients with atrial fibrillation or flutter with LAA spontaneous contrast and/or thrombus had LAAmax (10.4 +/- 6.6 cm2) greater than that in patients with atrial fibrillation or flutter without LAA contrast and/or thrombus (6.8 +/- 3.0 cm2) (p less than 0.05). The LAA appeared as a static pouch in seven of eight of the former compared with in two of 11 of the latter. When attempted, Doppler demonstrated a recognizable fibrillatory LAA outflow velocity pattern in none of three in the former versus four of seven in the latter group. We conclude that the LAA has a characteristic pattern of emptying in sinus rhythm. LAA thrombus formation in sinus rhythm and atrial fibrillation is associated with both poor LAA contraction and LAA dilation.


Multiple carrier-transfer pathways in a flower-like In2S3/CdIn2S4/In2O3 ternary heterostructure for enhanced photocatalytic hydrogen production.
A novel flower-like In2S3/CdIn2S4/In2O3 (ICS) ternary heterostructure (HS) is rationally constructed for the first time by a series of carefully designed procedures. In2O3 nanoflakes are the main constituent units which assemble into a flower-like skeleton structure, and CdIn2S4 nanoparticles are in situ generated on the surface of In2O3 nanoflakes through the transformation of CdS quantum dots (QDs) while In2S3 nanoparticles are in situ produced at the region between CdIn2S4 nanoparticles and In2O3 nanoflakes resulting from a synchronous sulfuration procedure. As expected, the rationally designed ICS ternary HSs display significantly enhanced photocatalytic H2 production, especially ICS5 (sulfurized for 5 h) with the highest H2 evolution rate of 20.04 μmol h-1 (10 mg catalyst is used for photocatalytic reaction), which is 26.7 times and 2.6 times higher than that of pure In2O3 (0.75 μmol h-1) and In2S3/In2O3 binary HS (7.88 μmol h-1), respectively. The enhanced photocatalytic activity can be attributed to the multiple interfaces formed in the ICS HSs, including the CdIn2S4-In2O3 interface, the In2S3-In2O3 interface, and the CdIn2S4-In2O3-In2S3 interface, which construct multiple pathways for the transfer of photogenerated charge carriers, effectively promoting the photocatalytic hydrogen production.