Possible role of ILK-affixin complex in integrin-cytoskeleton linkage during platelet aggregation.
Integrin-mediated adhesion induces the formation of focal adhesions that link the extracellular matrix and intracellular actin cytoskeletal networks. We previously showed that integrin-linked kinase (ILK), which can interact with beta1 and beta3 integrins, and its interacting protein, affixin, play an essential role in the initial assembly of focal adhesion structures and actin stress fibers. Although the relevant structures are also observed in integrin alphaIIbbeta3 in platelets, the precise underlying molecular mechanism remains unclarified. Here, we found that ILK stably forms a complex with ss-affixin in platelets. Thrombin stimulation induces their association with integrin beta3, which is followed by their incorporation into the Triton-insoluble membrane-cytoskeletal fraction. During the course of thrombin-induced platelet aggregation, ILK activity was enhanced within 90s to 2.1-fold of the basal level, independent of phosphatidylinositol 3-kinase. Taken together with the observation that the treatment with an anti-integrin beta3 antibody stimulates ILK activity without inducing platelet aggregation, these results suggest that the outside-in signaling induced by fibrinogen binding to integrin enhances ILK activity and results in the initial phase to reorganize the actin cytoskeleton.


Nomogram for Predicting Individual Survival After Recurrence of Advanced-Stage, High-Grade Ovarian Carcinoma.
To analyze clinical prognostic factors for survival after recurrence of high-grade, advanced-stage ovarian-peritoneal-tubal carcinoma and to develop a nomogram to predict individual survival after recurrence. We retrospectively analyzed patients treated in multicenter Gynecologic Oncology Group protocols for stage III and IV ovarian-peritoneal-tubal carcinoma who underwent primary debulking surgery, received chemotherapy with paclitaxel and a platinum compound, and subsequently developed recurrence. Prognostic factors affecting survival were identified and used to develop a nomogram, which was both internally and externally validated. There were 4,739 patients included in this analysis, of whom, 84% had stage III and 16% had stage IV ovarian carcinoma. At a median follow-up of 88.8 months (95% CI 86.2-92.0 months), the vast majority of patients (89.4%) had died. The median survival after recurrence was 21.4 months (95% CI 20.5-21.9 months). Time to recurrence after initial chemotherapy, clear cell or mucinous histology, performance status, stage IV disease, and age were significant variables used to develop a nomogram for survival after recurrence, which had a concordance index of 0.67. The time to recurrence alone accounted for 85% of the prognostic information. Similar results were found for patients who underwent second look laparotomy and had a complete pathologic response or received intraperitoneal chemotherapy. For individuals with advanced-stage ovarian carcinoma who recur after standard first-line therapy, estimated survivals after recurrence are closely related to the time to recurrence after chemotherapy and prognostic variables can be used to predict subsequent survival. ClinialTrials.gov, NCT00002568, NCT00837993, NCT00002717, NCT01074398, and NCT00011986.


The color purple: analyzing alkaline phosphatase expression in experimentally manipulated sea urchin embryos in an undergraduate developmental biology course.
In these laboratory exercises, developed for a sophomore/junior-level undergraduate course in Developmental Biology, students explore the processes of differentiation and morphogenesis in sea urchin embryos by monitoring the spatio-temporal expression pattern of the endoderm marker, alkaline phosphatase. Once students have determined the normal alkaline phosphatase expression pattern, they are asked to treat sea urchin embryos in some way that perturbs normal morphogenesis. Their task is to discover whether the chosen treatment perturbs both morphogenesis and differentiation of the gut or only morphogenesis. The ease with which sea urchin embryos can be cultured and manipulated provide the Developmental Biology instructor with a powerful system for inviting students to explore questions regarding differentiation and morphogenesis.


Role of communication content and frequency in enabling evidence-based practices.
Many hospitals are unable to successfully implement evidence-based practices. For example, implementation of the central line bundle (CLB), proven to prevent catheter-related bloodstream infections (CRBSIs), is often challenging. This problem is broadly characterized as a "change implementation failure." A prospective study was conducted in 2 intensive care units (ICUs), a medical ICU (MICU) and a pediatric ICU (PICU), within an academic health center. Both units had low baseline adherence to CLB and higher-than-expected CRBSIs. The study sought to promote CLB implementation in both units through periodic quality improvement (QI) interventions over a 52-week period. Simultaneously, it examined (1) the content and frequency of communication related to CLB through weekly "communication logs" completed by physicians, nurses, and managers, and (2) outcomes, that is, CLB adherence rates through weekly medical record reviews. The aim of the study was 2-fold: (1) to examine associations between QI interventions and communication content and frequency at the unit level, and (2) to examine associations between communication content and frequency and outcomes at the unit level. The periodic QI interventions were expected to increase CLB adherence and reduce CRBSIs through their influence on communication content and frequency. A total of 2638 instances of communication were analyzed. Both units demonstrated a statistically significant increase in "proactive" communications-that is, communication intended to reduce infection risk between physicians and nurses over time. Proactive communications increased by 68% in the MICU (P < .05) and 61% in the PICU (P < .05). During the same timeframe, both units increased CLB adherence to 100%. Both units also demonstrated statistically significant declines in (1) catheter days: 34% decline in the MICU (P < .05) and 30% in the PICU (P < .05); and (2) CRBSI rates: 63% decline in the MICU (P < .05) and 100% in the PICU (P < .10). Direct costs savings from reduced CRBSIs in 1 year were estimated to be at least $840 000. Periodic QI interventions were effective in reframing interprofessional communication dynamics and enabling practice change. The prospective design provides insights into communication content and frequency associated with collective learning and culture change. The study identifies evidence-based management strategies for positive practice change at the unit level.


Portion weights of food served in English schools: have they changed following the introduction of nutrient-based standards?
Mandatory food-based and nutrient-based standards for the food provided in English schools were introduced in 2008 (primary) and 2009 (secondary) and have had a positive impact on pupils' food choice and nutrient intake at school. There are no recommendations for portion sizes in England, although anecdotal evidence suggests that portions of food and drink sold in schools have decreased since the standards were introduced. Data were collected from 136 primary and 80 secondary schools in 2009 and 2010/11, respectively. All food and drink items provided at lunchtime were weighed on five consecutive days at each school. The mean and median weight, SD, and 25th and 75th centile for each individual food were calculated. Data were compared with the results obtained from similar surveys in 2004 and 2005, as well as with portion size recommendations for Scottish schools. The proportion of food items that differed in weight since 2004/05 varied from 13% in primary schools to 29% in secondary schools. Changes in weight were equally likely to be positive or negative, with the exception of portions of fruit and vegetables, which had decreased. Primary schools were more likely to meet portion size recommendations than secondary schools. Of the items that were directly comparable over time, a limited number showed a significant change in portion size since the standards for school food were introduced. Portion weight recommendations are based on a balanced healthy diet, and pupils should eat all the components of meals offered by schools to meet dietary recommendations.


The Future of Direct Cardiac Reprogramming: Any GMT Cocktail Variety?
Direct cardiac reprogramming has emerged as a novel therapeutic approach to treat and regenerate injured hearts through the direct conversion of fibroblasts into cardiac cells. Most studies have focused on the reprogramming of fibroblasts into induced cardiomyocytes (iCMs). The first study in which this technology was described, showed that at least a combination of three transcription factors, GATA4, MEF2C and TBX5 (GMT cocktail), was required for the reprogramming into iCMs in vitro using mouse cells. However, this was later demonstrated to be insufficient for the reprogramming of human cells and additional factors were required. Thereafter, most studies have focused on implementing reprogramming efficiency and obtaining fully reprogrammed and functional iCMs, by the incorporation of other transcription factors, microRNAs or small molecules to the original GMT cocktail. In this respect, great advances have been made in recent years. However, there is still no consensus on which of these GMT-based varieties is best, and robust and highly reproducible protocols are still urgently required, especially in the case of human cells. On the other hand, apart from CMs, other cells such as endothelial and smooth muscle cells to form new blood vessels will be fundamental for the correct reconstruction of damaged cardiac tissue. With this aim, several studies have centered on the direct reprogramming of fibroblasts into induced cardiac progenitor cells (iCPCs) able to give rise to all myocardial cell lineages. Especially interesting are reports in which multipotent and highly expandable mouse iCPCs have been obtained, suggesting that clinically relevant amounts of these cells could be created. However, as of yet, this has not been achieved with human iCPCs, and exactly what stage of maturity is appropriate for a cell therapy product remains an open question. Nonetheless, the major concern in regenerative medicine is the poor retention, survival, and engraftment of transplanted cells in the cardiac tissue. To circumvent this issue, several cell pre-conditioning approaches are currently being explored. As an alternative to cell injection, in vivo reprogramming may face fewer barriers for its translation to the clinic. This approach has achieved better results in terms of efficiency and iCMs maturity in mouse models, indicating that the heart environment can favor this process. In this context, in recent years some studies have focused on the development of safer delivery systems such as Sendai virus, Adenovirus, chemical cocktails or nanoparticles. This article provides an in-depth review of the in vitro and in vivo cardiac reprograming technology used in mouse and human cells to obtain iCMs and iCPCs, and discusses what challenges still lie ahead and what hurdles are to be overcome before results from this field can be transferred to the clinical settings.


Concurrent strength and endurance training: from molecules to man.
Strength and endurance training produce widely diversified adaptations, with little overlap between them. Strength training typically results in increases in muscle mass and muscle strength. In contrast, endurance training induces increases in maximal oxygen uptake and metabolic adaptations that lead to an increased exercise capacity. In many sports, a combination of strength and endurance training is required to improve performance, but in some situations when strength and endurance training are performed simultaneously, a potential interference in strength development takes place, making such a combination seemingly incompatible. The phenomenon of concurrent training, or simultaneously training for strength and endurance, was first described in the scientific literature in 1980 by Robert C. Hickson, and although work that followed provided evidence for and against it, the interference effect seems to hold true in specific situations. At the molecular level, there seems to be an explanation for the interference of strength development during concurrent training; it is now clear that different forms of exercise induce antagonistic intracellular signaling mechanisms that, in turn, could have a negative impact on the muscle's adaptive response to this particular form of training. That is, activation of AMPK by endurance exercise may inhibit signaling to the protein-synthesis machinery by inhibiting the activity of mTOR and its downstream targets. The purpose of this review is to briefly describe the problem of concurrent strength and endurance training and to examine new data highlighting potential molecular mechanisms that may help explain the inhibition of strength development when strength and endurance training are performed simultaneously.


Real-time optical and electronic sensing with a β-amino enone linked, triazine-containing 2D covalent organic framework.
Fully-aromatic, two-dimensional covalent organic frameworks (2D COFs) are hailed as candidates for electronic and optical devices, yet to-date few applications emerged that make genuine use of their rational, predictive design principles and permanent pore structure. Here, we present a 2D COF made up of chemoresistant β-amino enone bridges and Lewis-basic triazine moieties that exhibits a dramatic real-time response in the visible spectrum and an increase in bulk conductivity by two orders of magnitude to a chemical trigger - corrosive HCl vapours. The optical and electronic response is fully reversible using a chemical switch (NH3 vapours) or physical triggers (temperature or vacuum). These findings demonstrate a useful application of fully-aromatic 2D COFs as real-time responsive chemosensors and switches.


The promiscuous MLL gene links chromosomal translocations to cellular differentiation and tumour tropism.
MLL is a promiscuous gene involved in a diversity of chromosomal fusions in haematological malignancies, usually resulting from chromosomal translocations. MLL-associated chromosomal rearrangements usually occur in tumours of specific haematological lineages, suggesting a crucial role for the MLL fusion partner in determining disease phenotype (or tumour tropism). The MLL gene is homologous to Drosophila trithorax, and is likewise involved in embryo pattern formation. Common themes linking several of the MLL partners include a possible involvement in embryo patterning via Hox gene regulation and chromatin remodelling. These findings reinforce the link between developmental regulation and chromosomal translocations, and indicate the role of chromosomal translocation in activating genes capable of determining tumour phenotype in leukaemias and sarcomas.


Urbanicity and autism spectrum disorders.
The etiology of autism spectrum disorders (ASD) is for the majority of cases unknown and more studies of risk factors are needed. Geographic variation in ASD occurrence has been observed, and urban residence has been suggested to serve as a proxy for etiologic and identification factors in ASD. We examined the association between urbanicity level and ASD at birth and during childhood. The study used a Danish register-based cohort of more than 800,000 children of which nearly 4,000 children were diagnosed with ASD. We found a dose-response association with greater level of urbanicity and risk of ASD. This association was found for residence at birth as well as residence during childhood. Further, we found an increased risk of ASD in children who moved to a higher level of urbanicity after birth. Also, earlier age of ASD diagnosis in urban areas was observed. While we could not directly examine the specific reasons behind these associations, our results demonstrating particularly strong associations between ASD diagnosis and post-birth migration suggest the influence of identification-related factors such as access to services might have a substantive role on the ASD differentials we observed.


Studies on the survival of simultaneous canine renal and segmental pancreatic allografts.
Prolonged survival of the vascularized free-draining intraperitoneal pancreatic segmental allografts (FDPS) has been observed previously in immunosuppressed beagle littermates matched for low mixed lymphocyte culture (MLC) reactivity. When rejection (hyperglycemia) did occur, it was abrupt, unpredictable, and irreversible. This contrasts with renal allograft rejection in which elevations of serum creatinine are reversible with increased immunosuppression. In the present experiments, low MLC-reactive littermate pairs underwent simultaneous transplantation of kidney and FDPS allografts from the same donor. Increases in serum creatinine from 0.5 mg/dl to 1.5 mg/dl (renal rejection) occurred 4 to 5 days after transplantation (mean = 20.5 +/- 4.1) and preceded the onset of hyperglycemia by 6 to 22 days (mean = 1.06 +/- 4.6) in nonimmunosuppressed animals. At the onset of kidney rejection but before hyperglycemia developed, renal allograft biopsies revealed generalized mononuclear infiltration, while FDPS biopsies showed diffuse interstitial infiltration, but islets of Langerhans appeared to be spared. Treatment intervention with azathioprine and corticosteroids at the time of creatinine elevation prevented the onset of hyperglycemia from 46 to greater than 260 days in four of nine animals. Biopsies after 2 weeks of therapy showed resolution of the lymphoid infiltrates in the kidney and limitation of infiltrates to perivascular areas in the FDPS allografts. Immunological monitoring of peripheral blood lymphocyte function demonstrated the development of positive in vitro cell-mediated lymphocytoxicity shortly before the onset of hyperglycemia but only after creatinine elevation was well established and biopsies revealed evidence of rejection in both the renal and FDPS allografts.


Comparison of Novel Sandfly Control Interventions: A Pilot Study in Bangladesh.
In this pilot comparative study, we investigated and compared the effects of existing vector control tools on sandfly densities and mortality to inform and support the National Kala-azar Elimination Program (NKEP). The interventions included insecticidal wall painting (IWP), reduced-coverage insecticidal durable wall lining (DWL), insecticide-impregnated bednets (ITN), and indoor residual spraying with deltamethrin (IRS). Sakhua union with seven villages was the study area, which was the most highly endemic visceral leishmaniasis union in Trishal upazila, Bangladesh. Each cluster containing the different interventions included approximately 50 households. Study methods included random selection of clusters, collection of sandfly by CDC light trap and manual aspirator to determine sandfly density, and sandfly mortality determined by WHO cone bioassay test. Trained field research assistants interviewed household heads using structured questionnaires for sociodemographic information, as well as safety and acceptability of the interventions. Descriptive and analytical statistical methods measured interventions' effect and its duration on sandfly density reduction and mortality. We measured the relative efficacy of IWP on sandfly control against DWL, ITN, and IRS by the difference-in-difference regression model. We found that existing interventions were effective and safe for sandfly control with different duration of effect and acceptability. The relative efficacy of IWP for sandfly reduction varied by -59% to -91%, -75% to -81%, and -30% to -104% compared with DWL, ITN, and IRS, respectively, at different time points during the 12-month follow-up. These study results will guide the NKEP for selection of sandfly control tool(s) in its subsequent consolidation and maintenance phases.


Application of RFID technology-upper extremity rehabilitation training.
[Purpose] Upper extremity rehabilitation after an injury is very important. This study proposes radio frequency identification (RFID) technology to improve and enhance the effectiveness of the upper extremity rehabilitation. [Subjects and Methods] People use their upper extremities to conduct daily activities. When recovering from injuries, many patients neglect the importance of rehabilitation, which results in degraded function. This study recorded the training process using the traditional rehabilitation hand gliding cart with a RFID reader, RFID tags in the panel, and a servo host computer. [Results] Clinical evidence, time taken to achieve a full score, counts of missing the specified spots, and Brunnstrom stage of aided recovery, the proximal part of the upper extremity show that the RFID-based upper extremity training significantly and reduce negative impacts of the disability in daily life and activities. [Conclusion] This study combined a hand-gliding cart with an RFID reader, and when patients moved the cart, the movement could be observed via the activated RFID tags. The training data was collected and quantified for a better understanding of the recovery status of the patients. Each of the participating patients made progress as expected.


Aromatase deficiency confers paradoxical postischemic cardioprotection.
The conventional view is that estrogen confers female cardioprotection. Estrogen synthesis depends on androgen availability, with aromatase regulating conversion of testosterone to estradiol. Extragonadal aromatase expression mediates estrogen production in some tissues, but a role for local steroid conversion has not yet been demonstrated in the heart. This study's goal was to investigate how aromatase deficiency influences myocardial function and ischemic resilience. RT-PCR analysis of C57Bl/6 mouse hearts confirmed cardiac-specific aromatase expression in adult females. Functional performance of isolated hearts from female aromatase knockout (ArKO) and aromatase wild-type mice were compared. Left ventricular developed pressures were similar in aerobic perfusion, but the maximal rate of rise of ventricular pressure was modestly reduced in ArKO hearts (3725 ± 144 vs. 4272 ± 154 mm Hg/sec, P < 0.05). After 25 min of ischemia, the recovery of left ventricular developed pressure was substantially improved in ArKO (percentage of basal at 60 min of reperfusion, 62 ± 8 vs. 30 ± 6%; P < 0.05). Hypercontracture was attenuated (end diastolic pressure, 25 ± 5 vs. 51 ± 1 mm Hg; P < 0.05), and lactate dehydrogenase content of coronary effluent was reduced throughout reperfusion in ArKO hearts. This was associated with a hyperphosphorylation of phospholamban and a reduction in phosphorylated Akt. Immediately after reperfusion, ArKO hearts exhibited increased incidence of ventricular premature beats (194 ± 70 vs. 46 ± 6, P < 0.05). These observations indicate more robust functional recovery, reduced cellular injury, and modified cardiomyocyte Ca(2+) handling in aromatase-deficient hearts. Our findings indicate that androgen-to-estrogen conversion may be of pathophysiologic importance to the heart and challenge the notion that estrogen deficiency is deleterious. These studies suggest the possibility that aromatase suppression may offer inotropic benefit in the acute ischemia/reperfusion setting with appropriate arrhythmia management.


Radiosensitization effect of luteolin on human gastric cancer SGC-7901 cells.
The radiosensitizing effects of luteolin were studied in the gastric cancer cell line SGC-7901. SGC-7901 cells were treated with luteolin or/and irradiation, and radiosensitizing effects were assessed by colony-forming assay with cells and nude mice. In order to study the underlying mechanism, the levels of apoptosis-related proteins, the activities of caspase-3 and -9, and the production of PGE2 were measured. The results showed that luteolin could enhance irradiation-induced colonogenic inhibition and the activities of Caspase-3 and -9. The remarkable down-regulation of Bcl-2 and release of cytochrome C were also observed. In addition, significantly reduced production of PGE(2) was observed in luteolin plus radiation treatment by ELISA, as well as decreased expression levels of VEGF and HIF-1 alpha. Finally, luteolin significantly enhances the radioresponse of human tumors transplanted into nude mice. Our results indicate that luteolin may be a promising radiosensitizer for use in the treatment of gastric cancer.


Duloxetine: a review of its use in the treatment of generalized anxiety disorder.
Duloxetine (Cymbalta(R)) is a potent serotonin and noradrenaline (norepinephrine) reuptake inhibitor (SNRI) in the CNS. It is indicated for the treatment of generalized anxiety disorder (GAD) as well as other indications. In patients with GAD of at least moderate severity, oral duloxetine 60-120 mg once daily was effective with regard to improvement from baseline in assessments of anxiety and functional impairment, and numerous other clinical endpoints. Longer-term duloxetine 60-120 mg once daily also demonstrated efficacy in preventing or delaying relapse in responders among patients with GAD. In addition, duloxetine was generally well tolerated, with most adverse events being of mild to moderate severity in patients with GAD in short- and longer-term trials. Additional comparative and pharmacoeconomic studies are required to position duloxetine among other selective serotonin reuptake inhibitors and SNRIs. However, available clinical data, and current treatment guidelines, indicate that duloxetine is an effective first-line treatment option for the management of GAD. Duloxetine is a potent and selective inhibitor of serotonin and noradrenaline transporters, and a weak inhibitor of dopamine transporters. It has a low affinity for neuronal receptors, such as alpha(1)- and alpha(2)-adrenergic, dopamine D(2), histamine H(1), muscarinic, opioid and serotonin receptors, as well as ion channel binding sites and other neurotransmitter transporters, such as choline and GABA transporters. It does not inhibit monoamine oxidase types A or B. The pharmacokinetics of duloxetine in healthy volunteers were dose proportional over the range of 40-120 mg once daily. Steady state was typically reached by day 3 of administration. Duloxetine may be administered without regard to food or time of day. Duloxetine is highly protein bound and is widely distributed throughout tissues. It is rapidly and extensively metabolized in the liver by cytochrome P450 (CYP) 1A2 and 2D6, and its numerous metabolites, which are inactive, are mainly excreted in the urine. The mean elimination half-life of duloxetine is approximately 12 hours. Duloxetine is a substrate for CYP1A2 and CYP2D6 and a moderate inhibitor of CYP2D6. Concomitant use of duloxetine and potent CYP1A2 inhibitors should be avoided and duloxetine should be used with caution in patients receiving drugs that are extensively metabolized by CYP2D6, particularly those with a narrow therapeutic index. Duloxetine was effective in the short-term treatment of patients with primary GAD of at least moderate severity. In four randomized, double-blind, placebo-controlled, multicentre, phase III trials, duloxetine 60-120 mg once daily for 9 or 10 weeks was significantly more effective than placebo with regard to the primary endpoint of mean change in Hamilton Anxiety Rating Scale (HAM-A) total score from baseline to study endpoint. In addition, all other endpoints were generally improved from baseline to a greater extent with duloxetine 60-120 mg once daily than with placebo. Duloxetine also improved patient role functioning (assessed using Sheehan Disability Scale global impairment functioning scores), health-related quality of life and patient well-being compared with placebo. Duloxetine was effective in patients with GAD who were aged >/=65 years. Pooled results of data from the two short-term efficacy trials that also included an active comparator arm showed that the mean change in HAM-A scores with duloxetine relative to placebo were of the same magnitude as those with venlafaxine extended release versus placebo. Duloxetine 60-120 mg once daily was also more effective than placebo in preventing or delaying relapse in responders to duloxetine in a longer-term study. In this study, patients with GAD received duloxetine during a 26-week, open-label, acute treatment phase and responders were then randomized to continue on duloxetine or receive placebo during a 26-week, double-blind, continuation phase. Time to relapse was significantly longer in duloxetine recipients than in placebo recipients. In addition, significantly fewer duloxetine recipients than placebo recipients relapsed during the double-blind phase of the trial and more duloxetine recipients achieved remission. Short- (9-10 weeks) and longer-term (52 weeks) treatment with duloxetine 60-120 mg once daily was generally well tolerated in patients with GAD, with the majority of adverse events being of mild to moderate severity. Nausea, dry mouth, headache, constipation, dizziness and fatigue were among the most common treatment-emergent adverse events. The adverse event profile of duloxetine did not differ with dose or treatment duration. Significantly more patients receiving short-term duloxetine than placebo discontinued treatment because of an adverse event, with nausea being the only event that resulted in significantly more treatment discontinuations in duloxetine recipients than in placebo recipients. Serious adverse events were uncommon with both short- and longer-term duloxetine treatment. Two episodes of attempted suicide and one episode of completed suicide occurred in duloxetine recipients during the 24-week open-label phase of a longer-term trial. No deaths or suicides were reported in any of the short-term trials. Discontinuation-emergent adverse events, most commonly nausea and dizziness, occurred in up to one-third of duloxetine recipients in the short-term trials.


The Patterson syndrome, leprechaunism, and pseudoleprechaunism.
A bizarre syndrome has hitherto masqueraded as leprechaunism, and although it is a quite different disorder it has been used as the prototype of leprechaunism in some birth defects atlases. It is proposed that this condition is designated the Patterson syndrome and details of a second case are reported. The features of this connective tissue and neuroendocrine disorder include bronzed hyperpigmentation, cutis laxa of the hands and feet, bodily disproportion, severe mental retardation, and major bony deformities. Radiographs revealed a unique and gross generalised skeletal dysplasia, unlikely to be confused with any other disorder. This endocrine abnormality comprised hyperadrenocorticism, cushingoid features, and diabetes mellitus in the first case, and premature adrenarche in the second case. The pathogenesis and aetiology of the Patterson syndrome are unknown, although quantitative and qualitative abnormalities of mucopolysaccharide excretion were found in the second case.


Clinical use of lactate monitoring in critically ill patients.
Increased blood lactate levels (hyperlactataemia) are common in critically ill patients. Although frequently used to diagnose inadequate tissue oxygenation, other processes not related to tissue oxygenation may increase lactate levels. Especially in critically ill patients, increased glycolysis may be an important cause of hyperlactataemia. Nevertheless, the presence of increased lactate levels has important implications for the morbidity and mortality of the hyperlactataemic patients. Although the term lactic acidosis is frequently used, a significant relationship between lactate and pH only exists at higher lactate levels. The term lactate associated acidosis is therefore more appropriate. Two recent studies have underscored the importance of monitoring lactate levels and adjust treatment to the change in lactate levels in early resuscitation. As lactate levels can be measured rapidly at the bedside from various sources, structured lactate measurements should be incorporated in resuscitation protocols.


Effect of diet-induced weight loss on total body bone mass.
1. Total body areal bone mineral density was measured by dual-energy X-ray absorptiometry in eight women before and 10 weeks after a very-low-calorie diet [405 kcal (1701 kJ)/day]. 2. The mean weight loss of 15.6 kg was accompanied by a statistically significant reduction in total body bone mineral density from 1.205 +/- 0.056 to 1.175 +/- 0.058 g/cm2 (mean +/- SD, P less than 0.005). 3. After cessation of the diet, weight gradually increased and by 10 months was similar to baseline values. Total body bone mineral density also increased after stopping the diet and mean values obtained 10 months after the diet did not differ significantly from initial values. Throughout the study total body bone mineral density values in all subjects were well within the range reported for normal subjects. 4. These data indicate that diet-induced weight loss is associated with rapid bone loss, subsequent weight gain being accompanied by increases in bone mass. Further studies are required to establish the clinical significance of these findings and, in particular, the skeletal distribution of bone loss.


Is MRI better than CT for detecting a vascular component to dementia? A systematic review and meta-analysis.
Identification of causes of dementia soon after symptom onset is important, because appropriate treatment of some causes of dementia can slow or halt its progression or enable symptomatic treatment where appropriate. The accuracy of MRI and CT, and whether MRI is superior to CT, in detecting a vascular component to dementia in autopsy confirmed and clinical cohorts of patients with VaD, combined AD and VaD ("mixed dementia"), and AD remain unclear. We conducted a systematic review and meta-analysis to investigate this question. We searched eight databases and screened reference lists to identify studies addressing the review question. We assessed study quality using QUADAS. We estimated summary diagnostic accuracy according to imaging finding, and ratios of diagnostic odds ratios (RDORs) for MRI versus CT and high versus low risk of bias. We included 7 autopsy and 31 non-autopsy studies. There was little evidence that selective patient enrolment and risk of incorporation bias impacted on diagnostic accuracy (p = 0.12 to 0.95). The most widely reported imaging finding was white matter hyperintensities. For CT (11 studies) summary sensitivity and specificity were 71% (95% CI 53%-85%) and 55% (44%-66%). Corresponding figures for MRI (6 studies) were 95% (87%-98%) and 26% (12%-50%). General infarcts was the most specific imaging finding on MRI (96%; 95% CI 94%-97%) and CT (96%; 93%-98%). However, sensitivity was low for both MRI (53%; 36%-70%) and CT (52%; 22% to 80%). No imaging finding had consistently high sensitivity. Based on non-autopsy studies, MRI was more accurate than CT for six of seven imaging findings, but confidence intervals were wide. There is insufficient evidence to suggest that MRI is superior to CT with respect to identifying cerebrovascular changes in autopsy-confirmed and clinical cohorts of VaD, AD, and 'mixed dementia'.


Microcontact printing with aminosilanes: creating biomolecule micro- and nanoarrays for multiplexed microfluidic bioassays.
Microfluidic systems integrated with protein and DNA micro- and nanoarrays have been the most sought-after technologies to satisfy the growing demand for high-throughput disease diagnostics. As the sensitivity of these systems relies on the bio-functionalities of the patterned recognition biomolecules, the primary concern has been to develop simple technologies that enable biomolecule immobilization within microfluidic devices whilst preserving bio-functionalities. To address this concern, we introduce a two-step patterning approach to create micro- and nanoarrays of biomolecules within microfluidic devices. First, we introduce a simple aqueous based microcontact printing (μCP) method to pattern arrays of (3-aminopropyl)triethoxysilane (APTES) on glass substrates, with feature sizes ranging from a few hundred microns down to 200 nm (for the first time). Next, these substrates are integrated with microfluidic channels to then covalently couple DNA aptamers and antibodies with the micro- and nanopatterned APTES. As these biomolecules are covalently tethered to the device substrates, the resulting bonds enable them to withstand the high shear stresses originating from the flow in these devices. We further demonstrated the flexibility of this technique, by immobilizing multiple proteins onto these APTES-patterned substrates using liquid-dispensing robots to create multiple microarrays. Next, to validate the functionalities of these microfluidic biomolecule microarrays, we perform (i) aptamer-based sandwich immunoassays to detect human interleukin 6 (IL6); and (ii) antibody-based sandwich immunoassays to detect human c-reactive protein (hCRP) with the limit of detection at 5 nM, a level below the range required for clinical screening. Lastly, the shelf-life potential of these ready-to-use microfluidic microarray devices is validated by effectively functionalizing the patterns with biomolecules up to 3 months post-printing. In summary, with a single printing step, this aminosilane patterning technique enables the creation of functional microfluidic micro- and nano-biomolecule arrays, laying the foundation for high-throughput multiplexed bioassays.


Modularity of the wrist in extant hominines.
Wrist shape varies greatly across primates and previous studies indicate that the numerous morphological differences among them are related to a complex mixture of phylogeny and function. However, little is known about whether the variation in these various anatomical differences is linked and to what extent the wrist bones vary independently. Here, we used 3D geometric morphometrics on a sample of extant hominines (Homo sapiens, Pan troglodytes, Gorilla gorilla, and Gorilla beringei), to find the model that best describes the covariation patterns among four of the eight carpals (i.e., capitate, lunate, scaphoid, and trapezium). For this purpose, 15 modular hypotheses were tested using the Covariance Ratio. Results indicate that there is a covariation structure common to all hominines, which corresponds to stronger covariation within each carpal as compared to the covariation between carpals. However, the results also indicate that that there is a degree of codependence in the variation of some carpals, which is unique in humans, chimpanzees, and gorillas, respectively. In humans there is evidence of associated shape changes between the lunate and capitate, and between the scaphoid and trapezium. This covariation between lunate and capitate is also apparent in gorillas, while chimpanzees display the greatest disassociation among carpals, showing low covariation values in all pairwise comparisons. Our analyses indicate that carpals have an important level of variational independence which might suggest a high degree of independent evolvability in the wrists of hominines, and that although weak, the structure of associated changes of these four carpals varies across genera. To our knowledge this is the first report on the patterns of modularity between these four wrist bones in the Homininae and future studies might attempt to investigate whether the anatomical shape associations among carpals are functionally related to locomotion and manipulation.


Prevalence and trajectories of depressive symptoms among mothers of children with newly diagnosed epilepsy: A longitudinal 10-year study.
Parental depression significantly impacts children's health and well-being. This study aimed to (1) estimate the prevalence of depressive symptoms, at six time points, among mothers over the first 10 years after their child was diagnosed with epilepsy; (2) identify trajectories of maternal depressive symptoms over time; and (3) identify baseline factors associated with each trajectory. Data came from the Health-Related Quality of Life in Children with Epilepsy Study (HERQULES), a Canada-wide prospective cohort study. Data on child, parent, and family characteristics were collected at the time of diagnosis, and follow-ups at 0.5, 1, 2, 8, and 10 years. Maternal depressive symptoms were measured using the Center for Epidemiological Studies Depression Scale. Trajectories of depressive symptoms were evaluated using latent class growth modeling, and multinomial logistic regression was used to identify baseline factors associated with each trajectory. A total of 356 mothers participated in the study, of whom 57% scored in the at-risk range for major depression disorder (period-prevalence). Four unique trajectories were identified as follows: "Low-Stable" (29% of mothers), "Intermediate-Stable" (46%), "High-Stable" (20%), and "High-Decreasing" (5%). Positive family environment was consistently associated with a better trajectory of depressive symptoms over time; other significant factors included type of seizures, child cognitive comorbidity, maternal age, and maternal education. A substantial proportion of mothers of children with epilepsy are at risk for depression, and this risk is stable over the long term. Family environment at the time of diagnosis has long-term and persistent effects and may be an ideal target for interventions.


Malodour in denture wearers: an ill-defined problem.
Denture plaque has not been studied to the same extent as dental plaque, and although there are many similarities in microbial composition, there are some significant differences. Denture-induced stomatitis is associated with poor denture hygiene, a more acidogenic plaque and the presence of Candida albicans. Obligate Gram-negative anaerobic micro-organisms, although present in denture plaque, have rarely been specifically investigated. Opportunist pathogens including coliforms and staphylococci have been isolated from dentures. Teeth adjacent to partial dentures are more susceptible to caries and periodontal diseases, perhaps due to an increased plaque buildup at the prosthesis/tooth interface. Little work has been published on malodour associated with dentures. The inert material provides a substratum for the plaque biofilm, which encompasses a range of odour-producing species. The microbiology of the tongue in denture wearers has not been specifically studied. Thus the nature, origin and extent of malodour in denture wearers is ill-defined, but many species capable of producing malodorous compounds are present. The wide age and health range presented by denture wearers further confounds investigation. There is a need for further work in the area, both for cosmetic- and health-associated reasons in the increasing elderly population.


Ab initio molecular dynamics study of dissociation of water under an electric field.
The behavior of liquid water under an electric field is a crucial phenomenon in science and engineering. However, its detailed description at a microscopic level is difficult to achieve experimentally. Here we report on the first ab initio molecular-dynamics study on water under an electric field. We observe that the hydrogen-bond length and the molecular orientation are significantly modified at low-to-moderate field intensities. Fields beyond a threshold of about 0.35 V/Å are able to dissociate molecules and sustain an ionic current via a series of correlated proton jumps. Upon applying even more intense fields (∼1.0 V/Å), a 15%-20% fraction of molecules are instantaneously dissociated and the resulting ionic flow yields a conductance of about 7.8 Ω-1 cm-1, in good agreement with experimental values. This result paves the way to quantum-accurate microscopic studies of the effect of electric fields on aqueous solutions and, thus, to massive applications of ab initio molecular dynamics in neurobiology, electrochemistry, and hydrogen economy.


Comparison between magnetic resonance imaging, computed tomography, and arthrography to identify artificially induced cartilage defects of the equine carpal joints.
While articular cartilage changes are considered to be one of the initial events in the pathological cascade leading to osteoarthritis, these changes remain difficult to detect using conventional diagnostic imaging modalities such as plain radiography. The aim of this prospective, experimental, methods comparison study was to compare the sensitivity of magnetic resonance imaging (MRI), magnetic resonance arthrography, computed tomography (CT), and CT arthrography in the detection of artificially induced articular cartilage defects in the equine carpal joints. Defects were created in the antebrachiocarpal and middle carpal joint using curettage by a board-certified equine surgeon. Normal articular cartilage thickness varied from a maximum of 1.22 mm at the level of the distal aspect of the radius to a minimum of 0.17 mm in the proximal articular surface of the third carpal bone. Regarding cartilaginous defect measurements the remaining cartilaginous bed range from a maximum of 0.776 mm in the partial thickness defects, and 0 mm (defect reaches the subchondral bone) when total thickness defect were made. Computed tomography and magnetic resonance imaging were performed followed by CT arthrography and magnetic resonance arthrography after antebrachiocarpal and middle carpal intraarticular contrast administration. All images were reviewed by two board-certified veterinary radiologists, both of whom were blinded to the location, presence of, and thickness of the cartilage defects. A total number of 72 lesions in nine limbs were created. Mean sensitivity for localizing cartilage defects varied between imaging modalities with CT arthrography showing the best sensitivity (69.9%), followed by magnetic resonance arthrography (53.5%), MRI (33.3%), and CT (18.1%) respectively. The addition of contrast arthrography in both magnetic resonance and CT improved the rate of cartilage lesion detection although no statistical significance was found. Computed tomographic arthrography displayed the best sensitivity for detecting articular cartilage defects in the equine antebrachiocarpal and middle-carpal joints, compared to magnetic resonance arthrography, MRI, and CT.


E7090, a Novel Selective Inhibitor of Fibroblast Growth Factor Receptors, Displays Potent Antitumor Activity and Prolongs Survival in Preclinical Models.
The FGFR signaling pathway has a crucial role in proliferation, survival, and migration of cancer cells, tumor angiogenesis, and drug resistance. FGFR genetic abnormalities, such as gene fusion, mutation, and amplification, have been implicated in several types of cancer. Therefore, FGFRs are considered potential targets for cancer therapy. E7090 is an orally available and selective inhibitor of the tyrosine kinase activities of FGFR1, -2, and -3. In kinetic analyses of the interaction between E7090 and FGFR1 tyrosine kinase, E7090 associated more rapidly with FGFR1 than did the type II FGFR1 inhibitor ponatinib, and E7090 dissociated more slowly from FGFR1, with a relatively longer residence time, than did the type I FGFR1 inhibitor AZD4547, suggesting that its kinetics are more similar to the type V inhibitors, such as lenvatinib. E7090 showed selective antiproliferative activity against cancer cell lines harboring FGFR genetic abnormalities and decreased tumor size in a mouse xenograft model using cell lines with dysregulated FGFR Furthermore, E7090 administration significantly prolonged the survival of mice with metastasized tumors in the lung. Our results suggest that E7090 is a promising candidate as a therapeutic agent for the treatment of tumors harboring FGFR genetic abnormalities. It is currently being investigated in a phase I clinical trial. Mol Cancer Ther; 15(11); 2630-9. ©2016 AACR.


The source of haemorrhage in traumatic basal subarachnoid haemorrhage.
Traumatic basal subarachnoid haemorrhage (TBSH) following trauma to the head, face or neck is well-established as a cause of death; however it remains a heavily disputed topic as the site of vascular injury is difficult to identify. Whilst many regions within the vasculature of the head and neck have been proposed as more susceptible to rupture, the vertebral artery remains the focal point of many investigations. We present a retrospective case review of TBSH in our forensic centre at Forensic and Scientific Services in Brisbane, Australia, from 2003 to 2011. Thirteen cases of TBSH were found, one case excluded due to vasculopathy. All decedents were male, the majority of which were involved in an altercation receiving blows to the head, face, or neck and were unconscious at the scene. All victims were under the influence of alcohol, drugs, or a combination thereof. External examination revealed injuries to the head, face, and neck in all cases. Various combinations of further examination techniques were used during the post-mortem examination including brain and/or cervical spine retention, CT imaging, and angiography. Vascular injury was identified in eight of the twelve cases, all of which occurred intracranially, with seven involving the vertebral artery. Histology was most reliable in identifying the rupture site and angiography failed to reveal a rupture site. The added benefits of histology over angiography are the ability to identify the microscopic architecture of the tear and to diagnose vasculopathy that may have rendered the individual more susceptible to TBSH.


Validating the Draw-A-Man Test as a personal neglect test.
The purpose of this study was to determine the reliability and validity of a Draw-A-Man Test in measuring personal neglect in patients with right brain stroke. Draw-A-Man Test was administered to 51 persons with right cerebrovascular accident (CVA) and 110 age-matched persons without brain insult. A categorical classification was developed based on the man drawn in the test. Participants who showed homogeneous bilateral representation of body parts were considered to not have personal neglect, whereas those who showed unilateral body parts were considered to have personal neglect. The completed tests were used to blindly categorize the persons with and without personal neglect according to the above definition by two raters for calculating interrater reliability. The Klein-Bell ADL (Activities of Daily Living) Scale was also administered to the participants with right CVA to validate the Draw-A-Man Test. This dichotomy--bilateral representation versus unilateral representation--showed a high percentage of agreement between two raters. Rater A classified all 110 "normal" participants as being without personal neglect and classified 13 of the 51 participants with stroke as having personal neglect. Participants demonstrating personal neglect showed significantly poorer ADL performance than did those without personal neglect. ADL performance was also found to be significantly related to somatosensation, motor status of the impaired limbs, and muscle strength of the sound limbs. However, even after controlling the effect of these variables by partial correlation, personal neglect was still highly related to ADL performance. The Draw-A-Man Test is a reliable and valid tool for discriminating clients with personal neglect from those without.


Management of the contaminated anterior cruciate ligament graft.
This systematic review explores management strategies for intraoperative anterior cruciate ligament (ACL) graft contamination. Two databases (Medline and EMBASE) were screened for studies involving ACL graft contamination published between 1946 and April 2013. We included studies evaluating the management of a contaminated graft and excluded small case-series studies. We conducted a full-text review of eligible studies, and the references were searched for additional eligible studies. Inclusion and exclusion criteria were applied to the searched studies. Our search yielded 6 laboratory investigations with a total of 495 graft samples used. These samples were contaminated and cleansed by various methods. The most successful sterilization protocols used chlorhexidine or mechanical agitation with a polymyxin B-bacitracin solution to achieve sterility in 100% of their respective experimental graft tissues. A chlorhexidine soak and plain bacitracin soak were also effective, at 97.5% and 97%, respectively. Povidone-iodine and an antibiotic soak of polymyxin-bacitracin were the least effective, with sterility rates of 48% and 57%, respectively. The results of this review suggest that the optimal agent for sterilizing a dropped graft is chlorhexidine. A protocol of mechanical agitation and serial dilution with a polymyxin B-bacitracin solution was also highly effective; however, the sample size was too small to realistically recommend its use. Bacitracin alone was also found to be an effective sterilization agent, as was a combined solution of neomycin and polymyxin B. Pooled results showed that normal saline solution, povidone-iodine, and a polymyxin B-bacitracin solution all yielded suboptimal sterilization. The available evidence, however, is laboratory based and may not accurately reflect clinical conditions; moreover, there is a lack of biomechanical studies evaluating sterilized grafts. As a result, the findings should be interpreted with caution. Level IV, systematic review of basic science studies.


Role of cannabis in inflammatory bowel diseases.
For many centuries, cannabis (marijuana) has been used for both recreational and medicinal purposes. Currently, there are about 192 million cannabis users worldwide, constituting approximately 3.9% of the global population. Cannabis comprises more than 70 aromatic hydrocarbon compounds known as cannabinoids. Endogenous circulating cannabinoids, or endocannabinoids, such as anandamide and 2-arachidonoyl-glycerol, their metabolizing enzymes (fatty acid amide hydrolase and monoacylglycerol lipase) and 2 G-protein coupled cannabinoid receptors, CB1 and CB2, together represent the endocannabinoid system and are present throughout the human body. In the gastrointestinal (GI) tract, the activated endocannabinoid system reduces gut motility, intestinal secretion and epithelial permeability, and induces inflammatory leukocyte recruitment and immune modulation through the cannabinoid receptors present in the enteric nervous and immune systems. Because of the effects of cannabinoids on the GI tract, attempts have been made to investigate their medicinal properties, particularly for GI disorders such as pancreatitis, hepatitis, and inflammatory bowel diseases (IBD). The effects of cannabis on IBD have been elucidated in several small observational and placebo-controlled studies, but with varied results. The small sample size and short follow-up duration in these studies make it difficult to show the clear benefits of cannabis in IBD. However, cannabis is now being considered as a potential drug for inflammatory GI conditions, particularly IBD, because of its spreading legalization in the United States and other countries and the growing trend in its use. More high-quality controlled studies are warranted to elucidate the mechanism and benefits of cannabis use as a possible option in IBD management.


Dabigatran reduces endothelial permeability through inhibition of thrombin-induced cytoskeleton reorganization.
Dabigatran etexilate (DE), a new oral anti-coagulant, is a direct thrombin inhibitor. Clinical trials showed the favorable benefit-to-risk profile of DE compared to warfarin for the prevention of ischemic stroke in patients with atrial fibrillation. Remarkably, patients treated with dabigatran showed reduced rates of intracerebral hemorrhage compared to warfarin. As the breakdown of endothelial barrier integrity is associated with hemorrhagic events and as thrombin increases endothelial permeability, we hypothesized that dabigatran preserves the endothelial barrier by inhibiting thrombin-induced permeability. We assessed leakage of fluorescein isothiocyanate (FITC)-dextran through the endothelial monolayer and measured trans-endothelial electrical resistance of the endothelial monolayer after treatment of thrombin or thrombin pre-incubated with dabigatran. Thrombin increased the permeability of endothelial cells. Dabigatran effectively blocked the ability of thrombin to increase permeability. Dabigatran inhibited the formation of actin stress fibers induced by thrombin and inhibited consequent destabilization of junctional protein complexes and intercellular gap formation. The interaction of thrombin with protease activated receptor-1 activates the Rho A guanosine triphosphate (GTP)ase-myosin light chain (MLC) phosphorylation signaling axis, leading to actin cytoskeleton changes. This signaling pathway was effectively inhibited by dabigatran in endothelial cells. Consistently, the number of phosphorylated MLC-positive cells was significantly decreased in ischemic tissue of rat brains. These results indicate dabigatran blocks the ability of thrombin to induce vascular permeability and the resulting underlying signaling cascade in endothelial cells. Our findings provide evidence that dabigatran may confer a lower risk of intracerebral hemorrhage by preserving endothelial barrier integrity.


Acute sleep loss results in tissue-specific alterations in genome-wide DNA methylation state and metabolic fuel utilization in humans.
Curtailed sleep promotes weight gain and loss of lean mass in humans, although the underlying molecular mechanisms are poorly understood. We investigated the genomic and physiological impact of acute sleep loss in peripheral tissues by obtaining adipose tissue and skeletal muscle after one night of sleep loss and after one full night of sleep. We find that acute sleep loss alters genome-wide DNA methylation in adipose tissue, and unbiased transcriptome-, protein-, and metabolite-level analyses also reveal highly tissue-specific changes that are partially reflected by altered metabolite levels in blood. We observe transcriptomic signatures of inflammation in both tissues following acute sleep loss, but changes involving the circadian clock are evident only in skeletal muscle, and we uncover molecular signatures suggestive of muscle breakdown that contrast with an anabolic adipose tissue signature. Our findings provide insight into how disruption of sleep and circadian rhythms may promote weight gain and sarcopenia.


Fitness attenuates the prevalence of increased coronary artery calcium in individuals with metabolic syndrome.
Background The association between cardiorespiratory fitness, physical activity and coronary artery calcium (CAC) is unclear, and whether higher levels of fitness attenuate CAC prevalence in subjects with metabolic syndrome is not fully elucidated. The present study aims to: a) investigate the independent association of fitness on the prevalence of CAC, after adjustment for moderate-to-vigorous physical activity and sedentary time, and b) study the possible attenuation of increased CAC by higher fitness, in participants with metabolic syndrome. Design Cross-sectional. Methods In total 678 participants (52% women), 50-65 years old, from the SCAPIS pilot study were included. Fitness (VO2max) was estimated by submaximal cycle ergometer test and moderate-to-vigorous physical activity and sedentary time were assessed using hip-worn accelerometers. CAC score (CACS) was quantified using the Agatston score. Results The odds of having a significant CACS (≥100) was half in participants with moderate/high fitness compared with their low fitness counterparts. Further consideration of moderate-to-vigorous physical activity, sedentary time and number of components of the metabolic syndrome did only slightly alter the effect size. Those with metabolic syndrome had 47% higher odds for significant CAC compared with those without metabolic syndrome. However, moderate/high fitness seems to partially attenuate this risk, as further joint analysis indicated an increased odds for having significant CAC only in the unfit metabolic syndrome participants. Conclusions Being fit is associated with a reduced risk of having significant CAC in individuals with metabolic syndrome. While still very much underutilized, fitness should be taken into consideration in everyday clinical risk prediction in addition to the traditional risk factors of the metabolic syndrome.


A novel rat robot controlled by electrical stimulation of the nigrostriatal pathway.
Artificial manipulation of animal movement could offer interesting advantages and potential applications using the animal's inherited superior sensation and mobility. Although several behavior control models have been introduced, they generally epitomize virtual reward-based training models. In this model, rats are trained multiple times so they can recall the relationship between cues and rewards. It is well known that activation of one side of the nigrostriatal pathway (NSP) in the rat induces immediate turning toward the contralateral side. However, this NSP stimulation-induced directional movement has not been used for the purpose of animal-robot navigation. In this study, the authors aimed to electrically stimulate the NSP of conscious rats to build a command-prompt rat robot. Repetitive NSP stimulation at 1-second intervals was applied via implanted electrodes to induce immediate contraversive turning movements in 7 rats in open field tests in the absence of any sensory cues or rewards. The rats were manipulated to navigate from the start arm to a target zone in either the left or right arm of a T-maze. A leftward trial was followed by a rightward trial, and each rat completed a total of 10 trials. In the control group, 7 rats were tested in the same way without NSP stimulation. The time taken to navigate the maze was compared between experimental and control groups. All rats in the experimental group successfully reached the target area for all 70 trials in a short period of time with a short interstimulus interval (< 0.7 seconds), but only 41% of rats in the control group reached the target area and required a longer period of time to do so. The experimental group made correct directional turning movements at the intersection zone of the T-maze, taking significantly less time than the control group. No significant difference in navigation duration for the forward movements on the start and goal arms was observed between the two groups. However, the experimental group showed quick and accurate movement at the intersection zone, which made the difference in the success rate and elapsed time of tasks. The results of this study clearly indicate that a rat-robot model based on NSP stimulation can be a practical alternative to previously reported models controlled by virtual sensory cues and rewards.


The effects of the social relations of production on productivity and workers' safety: an ignored set of relationships.
This paper considers the interrelationships between the social relations of production, workers' safety, and the productivity of labor. The argument is that the social relations of production directly influence the intensity of labor (one facet of labor productivity), which in turn influences the rate of industrial accidents (one aspect of workers' safety). These relationships are illustrated with data from a carefully controlled comparison between two Chrysler plants in Europe in 1976 (Poissy in France and Ryton in England). The data are from internal company sources and are considered very reliable. The data show that Poissy had a higher labor productivity than Ryton, although both made the same car. This is partly accounted for by differences in the intensity of labor at the two plants. The evidence strongly suggests that a key reason for this difference lies in the contrasting nature of the social relations of production at the two plants. Ryton workers were better organized and more militant on the shop floor than were Poissy workers. Finally, it was found that the accident rate was about sixty times higher at Poissy than at Ryton, which provides strong support for the interrelationships proposed.


Delayed breast cellulitis: an evolving complication of breast conservation.
Delayed breast cellulitis (DBC) is characterized by the late onset of breast erythema, edema, tenderness, and warmth. This retrospective study analyzes the risk factors and clinical course of DBC. From 1985 through 2004, 580 sequential women with 601 stage T0-2N0-1 breast cancers underwent breast conserving therapy. Cases of DBC were identified according to accepted clinical criteria: diffuse breast erythema, edema, tenderness, and warmth occurring >3 months after definitive surgery and >3 weeks after radiotherapy. Potential risk factors analyzed included patient comorbidity, operative technique, acute complications, and details of adjunctive therapy. Response to treatment and long-term outcome were analyzed to characterize the natural course of this syndrome. Of the 601 cases, 16%, 52%, and 32% were Stage 0, I, and II, respectively. The overall incidence of DBC was 8% (50/601). Obesity, ecchymoses, T stage, the presence and aspiration of a breast hematoma/seroma, removal of >5 axillary lymph nodes, and arm lymphedema were significantly associated with DBC. The median time to onset of DBC from the date of definitive surgery was 226 days. Ninety-two percent of DBC patients were empirically treated with antibiotics. Fourteen percent required more invasive intervention. Twenty-two percent had recurrent episodes of DBC. Ultimately, 2 patients (4%) underwent mastectomy for intractable breast pain related to DBC. Although multifactorial, we believe DBC is primarily related to a bacterial infection in the setting of impaired lymphatic drainage and may appear months after completion of radiotherapy. Invasive testing before a trial of antibiotics is generally not recommended.


Comparing the predictive value of the pelvic ring injury classification systems by Tile and by Young and Burgess.
Radiology-based classifications of pelvic ring injuries and their relevance for the prognosis of morbidity and mortality are disputed in the literature. The purpose of this study was to evaluate potential differences between the pelvic ring injury classification systems by Tile and by Young and Burgess with regard to their predictive value on mortality, transfusion/infusion requirement and concomitant injuries. Two-hundred-and-eighty-five consecutive patients with pelvic ring fractures were analyzed for mortality within 30 days after admission, number of blood units and total volume of fluid infused during the first 24h after trauma, the Abbreviated Injury Severity (AIS) scores for head, chest, spine, abdomen and extremities as a function of the Tile and the Young-Burgess classifications. There was no significant relationship between occurrence of death and fracture pattern but a significant relationship between fracture pattern and need for blood units/total fluid volume for Tile (p<.001/p<.001) and Young-Burgess (p<.001/p<.001). In both classifications, open book fractures were associated with more fluid requirement and more severe injuries of the abdomen, spine and extremities (p<.05). When divided into the larger subgroups "partially stable" and "unstable", unstable fractures were associated with a higher mortality rate in the Young-Burgess system (p=.036). In both classifications, patients with unstable fractures required significantly more blood transfusions (p<.001) and total fluid infusion (p<.001) and higher AIS scores. In this first direct comparison of both classifications, we found no clinical relevant differences with regard to their predictive value on mortality, transfusion/infusion requirement and concomitant injuries.


Secretory factors from OP9 stromal cells delay differentiation and increase the expansion potential of adult erythroid cells in vitro.
Development of in vitro culture systems for the generation of red blood cells is a goal of scientists globally with the aim of producing clinical grade products for transfusion. Although mature reticulocytes can be efficiently generated by such systems, the numbers produced fall short of that required for therapeutics, due to limited proliferative capacity of the erythroblasts. To overcome this hurdle, approaches are required to increase the expansion potential of such culture systems. The OP9 mouse stromal cell line is known to promote haematopoietic differentiation of pluripotent stem cells, however an effect of OP9 cells on erythropoiesis has not been explored. In this study, we show not only OP9 co-culture, but factors secreted by OP9 cells in isolation increase the proliferative potential of adult erythroid cells by delaying differentiation and hence maintaining self-renewing cells for an extended duration. The number of reticulocytes obtained was increased by approximately 3.5-fold, bringing it closer to that required for a therapeutic product. To identify the factors responsible, we analysed the OP9 cell secretome using comparative proteomics, identifying 18 candidate proteins. These data reveal the potential to increase erythroid cell numbers from in vitro culture systems without the need for genetic manipulation or co-culture.


Evidence of widespread metabolite abnormalities in Myalgic encephalomyelitis/chronic fatigue syndrome: assessment with whole-brain magnetic resonance spectroscopy.
Previous neuroimaging studies have detected markers of neuroinflammation in patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Magnetic Resonance Spectroscopy (MRS) is suitable for measuring brain metabolites linked to inflammation, but has only been applied to discrete regions of interest in ME/CFS. We extended the MRS analysis of ME/CFS by capturing multi-voxel information across the entire brain. Additionally, we tested whether MRS-derived brain temperature is elevated in ME/CFS patients. Fifteen women with ME/CFS and 15 age- and gender-matched healthy controls completed fatigue and mood symptom questionnaires and whole-brain echo-planar spectroscopic imaging (EPSI). Choline (CHO), myo-inositol (MI), lactate (LAC), and N-acetylaspartate (NAA) were quantified in 47 regions, expressed as ratios over creatine (CR), and compared between ME/CFS patients and controls using independent-samples t-tests. Brain temperature was similarly tested between groups. Significant between-group differences were detected in several regions, most notably elevated CHO/CR in the left anterior cingulate (p < 0.001). Metabolite ratios in seven regions were correlated with fatigue (p < 0.05). ME/CFS patients had increased temperature in the right insula, putamen, frontal cortex, thalamus, and the cerebellum (all p < 0.05), which was not attributable to increased body temperature or differences in cerebral perfusion. Brain temperature increases converged with elevated LAC/CR in the right insula, right thalamus, and cerebellum (all p < 0.05). We report metabolite and temperature abnormalities in ME/CFS patients in widely distributed regions. Our findings may indicate that ME/CFS involves neuroinflammation.


New investments in primary care in Australia.
There is a crisis in primary care health workforce shortages in Australia. Its government has attempted to fix this by role-substitution (replacing medical work with nursing instead). This was not completely successful. Obstacles included entrenched social roles (leading to doctors 'checking' their nurse role-substituted work) and structures (nurses subservient to doctors)--both exacerbated by primary care doctors' ageing demographic; doctors owning their own practices; doctors feeling themselves to have primary responsibility for the care delivered; and greater attraction towards independence that may have selected doctors into primary care in the first place.Yet there is much to be optimistic about this social experiment. It was conducted, if not ideally, at least in an environment that the Australian government has enriched with capacity for research and evaluation.


Negative effect of the 5'-untranslated leader sequence on Ac transposon promoter expression.
Transposable elements are used in heterologous plant hosts to clone genes by insertional mutagenesis. The Activator (Ac) transposable element has been cloned from maize, and introduced into a variety of plants. However, differences in regulation and transposition frequency have been observed between different host plants. The cause of this variability is still unknown. To better understand the activity of the Ac element, we analyzed the Ac promoter region and its 5'-untranslated leader sequence (5' UTL). Transient assays in tobacco NT1 suspension cells showed that the Ac promoter is a weak promoter and its activity was localized by deletion analyses. The data presented here indicate that the core of the Ac promoter is contained within 153 bp fragment upstream to transcription start sites. An important inhibitory effect (80%) due to the presence of the 5' UTL was found on the expression of LUC reporter gene. Here we demonstrate that the presence of the 5' UTL in the constructs reduces the expression driven by either strong or weak promoters.


Methanomicrobium antiquum sp. nov., a hydrogenotrophic methanogen isolated from deep sedimentary aquifers in a natural gas field.
A mesophilic, hydrogenotrophic methanogen, designated strain MobHT, was isolated from sediments derived from deep sedimentary, natural-gas-bearing aquifers in Japan. Strain MobHT utilized H2/CO2 or formate, but not ethanol, 1-propanol, 2-propanol, 2-butanol or cyclopentanol, for growth and methane production. In addition, acetate and tungsten were required for growth. Yeast extract stimulated the growth, but was not required. The cells were weakly motile with multiple flagella, presented as a curved-rod-shaped (0.8×2.0 µm) and occurred singly or in pairs. Strain MobHT grew at 15-40 °C (optimum 35 °C) and at pH 5.9-7.9 (optimum pH 7.0-7.5). The sodium chloride range for growth was 0-5.8 % (optimum 2 %). The G+C content of the genomic DNA was 37.6 mol%. In the phylogenetic tree based on the 16S rRNA gene sequences, strain MobHT clustered together with Methanomicrobium mobile (95.4 % in sequence similarity), and formed a distinct clade from Methanolacinia petrolearia SEBR 4847T (95.6 %) and Methanolacinia paynteri G-2000T (95.4 %). The two species of the genus Methanolacinia utilized 2-propanol, whereas strain MobHT and Methanomicrobium mobile, the sole species of the genus Methanomicrobium, do not. Based on phenotypic and phylogenetic features, we propose a novel species for the isolate with the name, Methanomicrobiumantiquum sp. nov. The type strain is MobHT (=DSM 21220T=NBRC 104160T).


Body size shifts and early warning signals precede the historic collapse of whale stocks.
Predicting population declines is a key challenge in the face of global environmental change. Abundance-based early warning signals have been shown to precede population collapses; however, such signals are sensitive to the low reliability of abundance estimates. Here, using historical data on whales harvested during the 20th century, we demonstrate that early warning signals can be present not only in the abundance data, but also in the more reliable body size data of wild populations. We show that during the period of commercial whaling, the mean body size of caught whales declined dramatically (by up to 4 m over a 70-year period), leading to early warning signals being detectable up to 40 years before the global collapse of whale stocks. Combining abundance and body size data can reduce the length of the time series required to predict collapse, and decrease the chances of false positive early warning signals.


A Prediction Model for Pediatric Radiographic Pneumonia.
Chest radiographs (CXRs) are frequently used in the diagnosis of community-acquired pneumonia (CAP). We sought to construct a predictive model for radiographic CAP based on clinical features to decrease CXR use. We performed a single-center prospective study of patients 3 months to 18 years of age with signs of lower respiratory infection who received a CXR for suspicion of CAP. We used penalized multivariable logistic regression to develop a full model and bootstrapped backward selection models to develop a parsimonious reduced model. We evaluated model performance at different thresholds of predicted risk. Radiographic CAP was identified in 253 (22.2%) of 1142 patients. In multivariable analysis, increasing age, prolonged fever duration, tachypnea, and focal decreased breath sounds were positively associated with CAP. Rhinorrhea and wheezing were negatively associated with CAP. The bootstrapped reduced model retained 3 variables: age, fever duration, and decreased breath sounds. The area under the receiver operating characteristic for the reduced model was 0.80 (95% confidence interval: 0.77-0.84). Of 229 children with a predicted risk of <4%, 13 (5.7%) had radiographic CAP (sensitivity of 94.9% at a 4% risk threshold). Conversely, of 229 children with a predicted risk of >39%, 140 (61.1%) had CAP (specificity of 90% at a 39% risk threshold). A predictive model including age, fever duration, and decreased breath sounds has excellent discrimination for radiographic CAP. After external validation, this model may facilitate decisions around CXR or antibiotic use in CAP.


Medical Student Perception of Lifestyle Medicine and Willingness to Engage in Lifestyle Counseling: A Pilot Study of Allopathic and Osteopathic Medical Students.
Introduction. This study assessed medical students' perception of lifestyle medicine and readiness to engage in lifestyle counseling. Methods. All medical students in one allopathic and one osteopathic medical school received a survey involving items designed to measure their awareness and interest in lifestyle medicine, perception of physicians serving as lifestyle role models for patients, and intent to practice lifestyle counseling. Results. Two hundred and eight-nine subjects (145 allopathic and 144 osteopathic students) responded to the survey. A total of 24.1% of responding allopathic students had heard about lifestyle medicine compared with 53.9% of responding osteopathic students (P < .01). A total of 90.5% of allopathic students rated their current knowledge of lifestyle medicine as inadequate or poor compared with 78.7% of osteopathic students (P < .01). Ninety-two percent of all respondents wanted to learn more about lifestyle medicine, while 95.2% believed they would provide more effective counseling if they were trained sufficiently to serve as a healthy lifestyle role model for their patients. Conclusions. Both cohorts favored learning more about lifestyle medicine and believed physicians should provide lifestyle counseling to patients with chronic diseases. Given these findings, and the demonstrated benefits of lifestyle medicine-based health care, the authors suggest that training in lifestyle medicine be increased in undergraduate medical education.


Rapid Immunochromatographic Test for the Identification and Discrimination of Mycobacterium tuberculosis Complex Isolates from Non-tuberculous Mycobacteria.
A new rapid Immunochromatographic test (ICT) kit (SDBioline TB Ag MPT64RAPID(®)) developed by Standard Diagnostics, South Korea was evaluated for rapid differentiation of M. tuberculosis from non tuberculous mycobacteria (NTM). It detects MPT 64 antigen in M. tuberculosis isolates using mouse monoclonal MPT 64 antibody. The kit was assessed for routine identification of the Acid Fast Bacilli(AFB) isolated in our laboratory. Two hundred eight culture isolates of Mycobacteria were tested using ICT test kit for detection of MPT 64 antigen from liquid and solid culture. H37Rv strain was employed as the positive reference control. Any negative result was referred for confirmation by Gen Probe Accu Probe assay for MTB Complex (Gen-Probe, San Diego, Calif.). Speciation of NTM was performed using genotypic Mycobacterium CM assay (Hain's life sciences, Germany). Of the 208 culture positive isolates tested, 182 (87.5%) were found positive for Mycobacterium tuberculosis Complex and remaining 26 (12.5%) were considered as NTM. These results were further confirmed by Gen Probe Accu probe assay that served as the reference method for detection of MTBC. H37Rv reference strain was taken as a control for ICT test and molecular tests. The reference strain showed the presence of MPT64 antigen band in the ICT test. Similar bands were formed in all MTBC (182) isolates tested, proving 100 per cent sensitivity and no bands were detected in 48 (100%) NTM isolates tested, proving 100 per cent specificity of the ICT kit. Tuberculosis is a global pandemic. Rapid identification of Mycobacteria as MTB complex or non-tuberculous Mycobacteria from culture is important for treatment of infected cases and drug susceptibility testing of the culture isolate. MPT 64 TB antgen detection using SD Bioline Immunochromatographic test is a simple and cost effective method for differentiation of Mycobacterial cultures as MTB complex from non- tuberculous Mycobacteria.


Opportunistic pathogens and large microbial diversity detected in source-to-distribution drinking water of three remote communities in Northern Australia.
In the wet-dry tropics of Northern Australia, drinking water in remote communities is mostly sourced from bores accessing groundwater. Many aquifers contain naturally high levels of iron and some are shallow with surface water intrusion in the wet season. Therefore, environmental bacteria such as iron-cycling bacteria promoting biofilm formation in pipes or opportunistic pathogens can occur in these waters. An opportunistic pathogen endemic to northern Australia and Southeast Asia and emerging worldwide is Burkholderia pseudomallei. It causes the frequently fatal disease melioidosis in humans and animals. As we know very little about the microbial composition of drinking water in remote communities, this study aimed to provide a first snapshot of the microbiota and occurrence of opportunistic pathogens in bulk water and biofilms from the source and through the distribution system of three remote water supplies with varying iron levels. Using 16s-rRNA gene sequencing, we found that the geochemistry of the groundwater had a substantial impact on the untreated microbiota. Different iron-cycling bacteria reflected differences in redox status and nutrients. We cultured and sequenced B. pseudomallei from bores with elevated iron and from a multi-species biofilm which also contained iron-oxidizing Gallionella, nitrifying Nitrospira and amoebae. Gallionella are increasingly used in iron-removal filters in water supplies and more research is needed to examine these interactions. Similar to other opportunistic pathogens, B. pseudomallei occurred in water with low organic carbon levels and with low heterotrophic microbial growth. No B. pseudomallei were detected in treated water; however, abundant DNA of another opportunistic pathogen group, non-tuberculous mycobacteria was recovered from treated parts of one supply. Results from this study will inform future studies to ultimately improve management guidelines for water supplies in the wet-dry tropics.


Rituximab treatment for isolated IgG4-related hypophysitis in a teenage female.
IgG4-related hypophysitis is an important diagnostic consideration in patients with a pituitary mass or pituitary dysfunction and can initially present with headaches, visual field deficits and/or endocrine dysfunction. Isolated IgG4-related pituitary disease is rare, with most cases of IgG4-related disease involving additional organ systems. We report the case of a teenage female patient with isolated IgG4-related hypophysitis, diagnosed after initially presenting with headaches. Our patient had no presenting endocrinologic abnormalities. She was treated with surgical resection, prednisolone and rituximab with no further progression of disease and sustained normal endocrine function. This case, the youngest described patient with isolated IgG4-related hypophysitis and uniquely lacking endocrinologic abnormalities, adds to the limited reports of isolated pituitary disease. The use of rituximab for isolated pituitary disease has never been described. While IgG4-related hypophysitis has been increasingly recognized, substantial evidence concerning the appropriate treatment and follow-up of these patients is largely lacking. Learning points: IgG4-related hypophysitis most often occurs in the setting of additional organ involvement but can be an isolated finding. This diagnosis should therefore be considered in a patient presenting with pituitary abnormalities. Most patients with IgG4-related hypophysitis will have abnormal pituitary function, but normal functioning does not exclude this diagnosis. Corticosteroids have been the mainstay of therapy for IgG4-related disease, with other immunosuppressive regimens being reserved for refractory cases. Further research is needed to understand the effectiveness of corticosteroid-sparing regimens and whether there is utility in using these agents as first-line therapies.


MicroRNAs control neurobehavioral development and function in zebrafish.
microRNAs (miRNAs) have emerged as regulators of a broad spectrum of neurodevelopmental processes, including brain morphogenesis, neuronal differentiation, and survival. While the role of miRNAs in establishing and maintaining the developing nervous system is widely appreciated, the developmental neurobehavioral role of miRNAs has yet to be defined. Here we show that transient disruption of brain morphogenesis by ethanol exposure results in behavioral hyperactivity in larval zebrafish challenged with changes in lighting conditions. Aberrations in swimming activity persist in juveniles that were developmentally exposed to ethanol. During early neurogenesis, multiple gene expression profiling studies revealed widespread changes in mRNA and miRNA abundance in ethanol-exposed embryos. Consistent with a role for miRNAs in neurobehavioral development, target prediction analyses identified multiple miRNAs misexpressed in the ethanol-exposed cohorts that were also predicted to target inversely expressed transcripts known to influence brain morphogenesis. In vivo knockdown of miR-9/9* or miR-153c persistently phenocopied the effect of ethanol on larval and juvenile swimming behavior. Structural analyses performed on adults showed that repression of miR-153c during development impacts craniofacial skeletal development. Together, these data support an integral role for miRNAs in the establishment of vertebrate neurobehavioral and skeletal systems.


The diabetes drug liraglutide ameliorates aberrant insulin receptor localisation and signalling in parallel with decreasing both amyloid-β plaque and glial pathology in a mouse model of Alzheimer's disease.
Alzheimer's disease (AD) has been shown to involve desensitised insulin receptor (IR) signalling. Liraglutide, a novel glucagon-like peptide 1 (GLP-1) analogue that facilitates insulin signalling, is currently approved for use in type 2 diabetes mellitus. In the present study, we show that distinctive alterations in the localisation and distribution of the IR and increased levels of insulin receptor substrate (IRS)-1 phosphorylated at serine 616 (IRS-1 pS(616)), a key marker of insulin resistance, are associated with amyloid-β plaque pathology in the frontal cortex of a mouse model of AD, APPSWE/PS1dE9. Altered IR status in APPSWE/PS1dE9 is most evident in extracellular deposits with the appearance of dystrophic neurites, with significantly increased IRS-1 pS(616) levels detected within neurons and neurites. The IR and IRS-1 pS(616) changes occur in the vicinity of all plaques in the APPSWE/PS1dE9 brain, and a significant upregulation of astrocytes and microglia surround this pathology. We show that liraglutide treatment for 8 weeks at 25 nmol/kg body weight i.p. once daily in 7-month-old mice significantly decreases IR aberrations in conjunction with a concomitant decrease in amyloid plaque load and levels of IRS-1 pS(616). Liraglutide also induces a highly significant reduction in astrocytosis and microglial number associated with both plaques and IR pathology. The amelioration of IR aberrations and attenuation of IRS-1 pS(616) upregulation, plaque and glial activation in APPSWE/PS1dE9 mice treated with liraglutide support the investigation of the therapeutic potential of liraglutide and long-lasting GLP-1 agonists in patients with AD.


Quantifying fine particle emission events from time-resolved measurements: Method description and application to 18 California low-income apartments.
PM2.5 exposure is associated with significant health risk. Exposures in homes derive from both outdoor and indoor sources, with emissions occurring primarily in discrete events. Data on emission event magnitudes and schedules are needed to support simulation-based studies of exposures and mitigations. This study applied an identification and characterization algorithm to quantify time-resolved PM2.5 emission events from data collected during 224 days of monitoring in 18 California apartments with low-income residents. We identified and characterized 836 distinct events with median and mean values of 12 and 30 mg emitted mass, 16 and 23 minutes emission duration, 37 and 103 mg/h emission rates, and pseudo-first-order decay rates of 1.3 and 2.0/h. Mean event-averaged concentrations calculated using the determined event characteristics agreed to within 6% of measured values for 14 of the apartments. There were variations in event schedules and emitted mass across homes, with few events overnight and most emissions occurring during late afternoons and evenings. Event characteristics were similar during weekdays and weekends. Emitted mass was positively correlated with number of residents (Spearman coefficient, ρ=.10), bedrooms (ρ=.08), house volume (ρ=.29), and indoor-outdoor CO2 difference (ρ=.27). The event schedules can be used in probabilistic modeling of PM2.5 in low-income apartments.


Cerebellar long-term depression requires dephosphorylation of TARP in Purkinje cells.
Cerebellar long-term depression (LTD) at parallel fiber (PF)-Purkinje cell synapses is thought to play an essential role in certain forms of motor learning. Like hippocampal LTD, cerebellar LTD is mediated by the endocytosis of AMPA (α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate) receptors at postsynaptic sites. However, similar sets of kinases and phosphatases have opposite regulatory effects on hippocampal and cerebellar LTD, although the mechanisms responsible for this difference remain largely unclear. Activity-dependent dephosphorylation of stargazin (an AMPA receptor auxiliary protein) by calcineurin regulates hippocampal LTD, but whether and how stargazin is involved in cerebellar LTD is unknown. In this study, we showed that stargazin is highly phosphorylated at basal states and is dephosphorylated by the application of high KCl plus glutamate (K-glu) or of a metabotropic glutamate receptor agonist, (S)-3,5-dihydroxyphenylglycine (DHPG), both of which chemically induced LTD in cerebellar slices. This chemically induced dephosphorylation of stargazin was specifically blocked by a calcineurin inhibitor. Indeed, inclusion of the calcineurin auto-inhibitory peptide in the patch pipette solution completely inhibited the LTD induced by the conjunctive stimulation of PFs and Purkinje cells. Furthermore, in Purkinje cells expressing stargazin-9D, in which all nine serine residues are mutated to aspartate, neither conjunctive stimulus nor DHPG treatment induced LTD. Finally, immunohistochemical analyses revealed that neither K-glu nor DHPG induced the endocytosis of AMPA receptors in Purkinje cells expressing stargazin-9D. Together, these results indicate that hippocampal and cerebellar LTD share a common pathway, namely dephosphorylation of stargazin by calcineurin.


Leisure time activity as a determinant of survival: a 26-year follow-up of a Swedish cohort.
An individual's leisure time (pastime) engagements are in a way important for society. Irrespective of whether leisure time activities are causal determinants of health or health is a prerequisite for taking full part in society, the interaction is a challenge for Public Health. The first question is whether the sum of their influence results in coherence between enjoying good health and having leisure time activity. The aim of this study was to estimate their covariance.A random sample was drawn from the adult population of Stockholm County, Sweden. The residents were mailed a questionnaire regarding their social circumstances, their health complaints, the social repercussions of the complaints, and if they had any leisure time activity. Altogether, 7252 (about 93%) individuals responding to the questionnaire constituted our cohort. The individuals aged 18-65 y in November 1969 were followed up to the age of 65 y, or to 1996 as to mortality. The main outcome measure was mortality irrespective of cause of death. More than two-thirds of the respondents (71%) reported that they had some leisure time activity. Leisure time activity was a determinant of survival in the statistical sense. The risk ratio was 0.77 and its 95% confidence interval was 0.68-0.87 for those reporting leisure time activity when age, sex, baseline health and baseline alcohol consumption was discounted. The conclusion was that having leisure time activity, unspecified, covaried with health. Further studies should specify the pastime activities.


A qualitative study on trainees' and supervisors' perceptions of assessment for learning in postgraduate medical education.
Recent changes in postgraduate medical training curricula usually encompass a shift towards more formative assessment, or assessment for learning. However, though theoretically well suited to postgraduate training, evidence is emerging that engaging in formative assessment in daily clinical practice is complex. We aimed to explore trainees' and supervisors' perceptions of what factors determine active engagement in formative assessment. Focus group study with postgraduate trainees and supervisors in obstetrics and gynaecology. Three higher order themes emerged: individual perspectives on feedback, supportiveness of the learning environment and the credibility of feedback and/or feedback giver. Engaging in formative assessment with a genuine impact on learning is complex and quite a challenge to both trainees and supervisors. Individual perspectives on feedback, a supportive learning environment and credibility of feedback are all important in this process. Every one of these should be taken into account when the utility of formative assessment in postgraduate medical training is evaluated.


Selection of vaccine strains for serotype O foot-and-mouth disease viruses (2007-2012) circulating in Southeast Asia, East Asia and Far East.
Foot-and-mouth disease (FMD) is endemic in Southeast Asia (SEA) and East Asia with circulation of multiple serotypes and multiple genotypes within each serotype of the virus. Although countries like Japan and South Korea in the Far East were free of FMD, in 2010 FMD serotype O (O/Mya-98) outbreaks were recorded and since then South Korea has experienced several FMD outbreaks despite regular vaccination. In this study a total of 85 serotype O FMD viruses (FMDV) isolated from 2007 to 2012 from SEA, East Asia and Far East were characterized by virus neutralisation tests using antisera to four existing (O/HKN/6/83, O/IND/R2/75, O/SKR/2010 and O/PanAsia-2) and one putative (O/MYA/2009) vaccine strains, and by full capsid sequencing. Serological studies revealed broad cross-reactivity with the vaccine strains; O/PanAsia-2 exhibited a good match with 95.3%, O/HKN/6/83 with 91.8%, O/IND/R2/75 with 80%, and the putative strain O/MYA/2009 with 89.4% isolates employed in this study. Similarly O/PanAsia-2 and O/IND/R2/75 vaccines showed a good match with all eight viruses belonging to O-Ind-2001d sublineage whereas the vaccines of O/Mya-98 lineage, O/MYA/2009 and O/SKR/2010 exhibited the lowest match indicating their unsuitability to protect infections from O-Ind-2001d viruses. A Bayesian analysis of the capsid sequence data indicated these circulating viruses (n = 85) to be of either SEA or Middle East-South Asian (ME-SA) topotype. The ME-SA topotype viruses were mainly detected in Lao PDR, Vietnam, Myanmar and Thailand reflecting the trade links with the Indian subcontinent, and also within the SEA countries. Implications of these results in the context of FMD control in SEA and East Asian countries are discussed.


Prevalence of Schizophrenia Spectrum Disorders in Average-IQ Adults with Autism Spectrum Disorders: A Meta-analysis.
Since their separation as independent diagnostics, autism spectrum disorders (ASD) and schizophrenia spectrum disorders (SSD) have been conceptualized as mutually exclusive disorders. Similarities between both disorders can lead to misdiagnosis, especially when it comes to average-IQ adults who were not identified during childhood. The aim of this review was to examine the occurrence of SSD in average-IQ adults with ASD. Electronic and manual searches identified a total of 278 references, of which 10 were included in a meta-analysis. The pooled prevalence of SSD in the total ASD sample was close to 6%, pointing to a high co-occurrence of the two conditions. Further research is needed to determine the factors that predispose members of this population to the emergence of psychotic disorders.


The Molecular Basis of Human Brain Evolution.
Humans are a remarkable species, especially because of the remarkable properties of their brain. Since the split from the chimpanzee lineage, the human brain has increased three-fold in size and has acquired abilities for vocal learning, language and intense cooperation. To better understand the molecular basis of these changes is of great biological and biomedical interest. However, all the about 16 million fixed genetic changes that occurred during human evolution are fully correlated with all molecular, cellular, anatomical and behavioral changes that occurred during this time. Hence, as humans and chimpanzees cannot be crossed or genetically manipulated, no direct evidence for linking particular genetic and molecular changes to human brain evolution can be obtained. Here, I sketch a framework how indirect evidence can be obtained and review findings related to the molecular basis of human cognition, vocal learning and brain size. In particular, I discuss how a comprehensive comparative approach, leveraging cellular systems and genomic technologies, could inform the evolution of our brain in the future.