Quantitative estimation of the viability of Toxoplasma gondii oocysts in soil.
Toxoplasma gondii oocysts spread in the environment are an important source of toxoplasmosis for humans and animal species. Although the life expectancy of oocysts has been studied through the infectivity of inoculated soil samples, the survival dynamics of oocysts in the environment are poorly documented. The aim of this study was to quantify oocyst viability in soil over time under two rain conditions. Oocysts were placed in 54 sentinel chambers containing soil and 18 sealed water tubes, all settled in two containers filled with soil. Containers were watered to simulate rain levels of arid and wet climates and kept at stable temperature for 21.5 months. At nine sampling dates during this period, we sampled six chambers and two water tubes. Three methods were used to measure oocyst viability: microscopic counting, quantitative PCR (qPCR), and mouse inoculation. In parallel, oocysts were kept refrigerated during the same period to analyze their detectability over time. Microscopic counting, qPCR, and mouse inoculation all showed decreasing values over time and highly significant differences between the decreases under dry and damp conditions. The proportion of oocysts surviving after 100 days was estimated to be 7.4% (95% confidence interval [95% CI] = 5.1, 10.8) under dry conditions and 43.7% (5% CI = 35.6, 53.5) under damp conditions. The detectability of oocysts by qPCR over time decreased by 0.5 cycle threshold per 100 days. Finally, a strong correlation between qPCR results and the dose infecting 50% of mice was found; thus, qPCR results may be used as an estimate of the infectivity of soil samples.


Wernicke's encephalopathy in a patient with unresectable gastric carcinoma and literature review.
Wernicke's encephalopathy (WE) is a disease classically associated with nutrition deficiency. It is characterized by typical symptoms like confusion, ataxia and ophthalmoparesis, and developes due to thiamine deficieny in alcoholic patients. Recently, it has been shown that WE could ocur in patients with gastric carcinoma without a history of alcohol use. In this paper, we have made some suggestions about early diagnosis, treatment and prevention of WE by discussing the development of WE in a patient with unresectable gastric carcinoma, who had been inpatient for a long time and given radiotherapy and chemotherapy.


Magnetic resonance imaging in young adults with cerebral infarction due to moyamoya.
The number, size, and location of cerebral infarctions, and blood flow in the middle cerebral artery as seen on proton magnetic resonance imaging were assessed in six white adults with angiographically documented moyamoya. Findings were correlated with clinical presentation, computed tomography, and angiography. Large hemispheric infarctions were found in five hemispheres, predominantly in watershed regions. Subcortical infarctions (n = 56) were found in all hemispheres. They were predominantly located in the centrum semiovale, in the distal beds of supply of the penetrating branches of the anterior and middle cerebral arteries. Infarction of the putamen was found in three hemispheres, caudate nucleus in four, globus pallidus in two, and anterior limb of the internal capsule in two. There were none in the posterior limb of the internal capsule, thalamus, brain stem, or cerebellum. Middle cerebral artery flow was visualized as a signal-void flow sign in only three hemispheres. Cerebral infarctions due to moyamoya are bilateral, multiple, often small, and asymptomatic, affecting predominantly the carotid circulation in watershed regions. Subcortical infarctions in the centrum semiovale and large hemispheric infarctions in hemodynamically compromised areas are the predominant findings.


Long-term outcome of fulminant myocarditis as compared with acute (nonfulminant) myocarditis.
Lymphocytic myocarditis causes left ventricular dysfunction that may be persistent or reversible. There are no clinical criteria that predict which patients will recover ventricular function and which cases will progress to dilated cardiomyopathy. We hypothesized that patients with fulminant myocarditis may have a better long-term prognosis than those with acute (nonfulminant) myocarditis. We identified 147 patients considered to have myocarditis according to the findings on endomyocardial biopsy and the Dallas histopathological criteria. Fulminant myocarditis was diagnosed on the basis of clinical features at presentation, including the presence of severe hemodynamic compromise, rapid onset of symptoms, and fever. Patients with acute myocarditis did not have these features. The incidence of the end point of this study, death or heart transplantation, was ascertained by contact with the patient or the patient's family or by a search of the National Death Index. The average period of follow-up was 5.6 years. A total of 15 patients met the criteria for fulminant myocarditis, and 132 met the criteria for acute myocarditis. Among the patients with fulminant myocarditis, 93 percent were alive without having received a heart transplant 11 years after biopsy (95 percent confidence interval, 59 to 99 percent), as compared with only 45 percent of those with acute myocarditis (95 percent confidence interval, 30 to 58 percent; P=0.05 by the log-rank test). Fulminant myocarditis was an independent predictor of survival after adjustments were made for age, histopathological findings, and hemodynamic variables. The rate of transplantation-free survival did not differ significantly between the patients considered to have borderline myocarditis and those considered to have active myocarditis according to the Dallas histopathological criteria. Fulminant myocarditis is a distinct clinical entity with an excellent long-term prognosis. Aggressive hemodynamic support is warranted for patients with this condition.


Lineage-specific regulation of epigenetic modifier genes in human liver and brain.
Despite an abundance of studies on chromatin states and dynamics, there is an astonishing dearth of information on the expression of genes responsible for regulating histone and DNA modifications. We used here a set of 156 defined epigenetic modifier genes (EMG) and profiled their expression pattern in cells of different lineages. As reference value, expression data from human embryonic stem cells (hESC) were used. Hepatocyte-like cells were generated from hESC, and their EMG expression was compared to primary human liver cells. In parallel, we generated postmitotic human neurons (Lu d6), and compared their relative EMG expression to human cortex (Ctx). Clustering analysis of all cell types showed that neuronal lineage samples grouped together (94 similarly regulated EMG), as did liver cells (61 similarly-regulated), while the two lineages were clearly distinct. The general classification was followed by detailed comparison of the major EMG groups; genes that were higher expressed in differentiated cells than in hESC included the acetyltransferase KAT2B and the methyltransferase SETD7. Neuro-specific EMGs were the histone deacetylases HDAC5 and HDAC7, and the arginine-methyltransferase PRMT8. Comparison of young (Lu d6) and more aged (Ctx) neuronal samples suggested a maturation-dependent switch in the expression of functionally homologous proteins. For instance, the ratio of the histone H3 K27 methyltransfereases, EZH1 to EZH2, was high in Ctx and low in Lu d6. The same was observed for the polycomb repressive complex 1 (PRC1) subunits CBX7 and CBX8. A large proportion of EMGs in differentiated cells was very differently expressed than in hESC, and absolute levels were significantly higher in neuronal samples than in hepatic cells. Thus, there seem to be distinct qualitative and quantitative differences in EMG expression between cell lineages.


Erythropoietin: a model system for studying oxygen-dependent gene regulation.
The physiological regulation of the red cell mass depends upon enhanced transcription of the erythropoietin (Epo) gene in response to hypoxia. Studies of Epo gene expression have been useful in investigating the mechanism by which cells and tissues sense hypoxia and respond with biologically appropriate alterations in gene expression. It is likely that oxygen sensing involves a heme protein in which cobalt and nickel can substitute for iron in the porphyrin ring. Indirect evidence suggests that the sensor is present in all cells and is a multi-subunit assembly containing an NAD(P)H oxidase capable of generating peroxide and reactive oxygen intermediates, which serve as signaling molecules. The up-regulation of Epo gene transcription by hypoxia is mediated by at least two known DNA-binding transcription factors, hypoxia-inducible factor 1 (HIF-1) and hepatic nuclear factor 4 (HNF-4), which bind to cognate response elements in a critical 3' enhancer approximately 50 bp in length. HIF-1 binding is induced by hypoxia as well as by cobalt. The activation of HIF-1 by hypoxia depends upon the selective protection of its alpha subunit from ubiquitin-dependent proteolysis by means of a mechanism that involves redox chemistry and perhaps phosphorylation. HNF-4 is an orphan nuclear receptor that is constitutively expressed in kidney and liver and which cooperates with HIF-1 to give maximal hypoxic induction. In hypoxic cells, p300 or a related family member forms a macromolecular assembly with HIF-1 and HNF-4, enabling transduction from the Epo 3' enhancer to the apparatus on the promoter responsible for the initiation of transcription.


Beyond the association. Toxoplasma gondii in schizophrenia, bipolar disorder, and addiction: systematic review and meta-analysis.
To perform a meta-analysis on studies reporting prevalence of Toxoplasma gondii (T. gondii) infection in any psychiatric disorder compared with healthy controls. Our secondary objective was to analyze factors possibly moderating heterogeneity. A systematic search was performed to identify studies into T. gondii infection for all major psychiatric disorders versus healthy controls. Methodological quality, publication bias, and possible moderators were assessed. A total of 2866 citations were retrieved and 50 studies finally included. Significant odds ratios (ORs) with IgG antibodies were found in schizophrenia (OR 1.81, P < 0.00001), bipolar disorder (OR 1.52, P = 0.02), obsessive-compulsive disorder (OR 3.4, P < 0.001), and addiction (OR 1.91, P < 0.00001), but not for major depression (OR 1.21, P = 0.28). Exploration of the association between T. gondii and schizophrenia yielded a significant effect of seropositivity before onset and serointensity, but not IgM antibodies or gender. The amplitude of the OR was influenced by region and general seroprevalence. Moderators together accounted for 56% of the observed variance in study effects. After controlling for publication bias, the adjusted OR (1.43) in schizophrenia remained significant. These findings suggest that T. gondii infection is associated with several psychiatric disorders and that in schizophrenia reactivation of latent T. gondii infection may occur.


Leisure-Time Physical Activity in adults with Cerebral Palsy.
Cerebral Palsy (CP) is becoming more prevalent in the adult population, but there is limited information available regarding their Leisure-Time Physical Activity (LTPA). To investigate the self-reported frequency and LTPA participation patterns in adults with CP, compared to the Canadian general population (CGP). This was a cross-sectional, follow-up-survey of a cohort of 145 persons with CP. The primary outcome was the level of participation in LTPA. Questions were also posed about the motivations and self-reported barriers to LTPA participation. The survey results were compared to CGP estimates from the Canadian Community Health Survey (CCHS). Fifty-four participants completed the survey, and 90% reported participation in at least one LTPA per week. On average, they reported participating in LTPA 7.3 ± 5.7 times/week. They also reported participating in an average of 4.1 ± 2.4 different types of LTPA. Walking, home-exercise, and swimming were the most frequently reported as a primary LTPA in the CP sample. These finding were comparable to those from the CGP. However, adults with CP were more likely to participate in home-exercise than the CGP (p < 0.05). More than 40% reported that the purpose of their LTPA was fitness or body maintenance and 56% indicated an interest in starting new activities. Various barriers were also reported. Adults with CP frequently participated in LTPA. However, the majority of them are not achieving recommended daily physical activity levels. Also their LTPA habitually focuses on rehabilitative exercises and the diversity of LTPA is limited by several barriers.


Dose-response association between moderate to vigorous physical activity and incident morbidity and mortality for individuals with a different cardiovascular health status: A cohort study among 142,493 adults from the Netherlands.
Moderate to vigorous physical activity (MVPA) is strongly associated with risk reductions of noncommunicable diseases and mortality. Cardiovascular health status may influence the benefits of MVPA. We compare the association between MVPA and incident major adverse cardiovascular events (MACE) and mortality between healthy individuals, individuals with elevated levels of cardiovascular risk factors (CVRF), and cardiovascular disease (CVD). A cohort study was performed in the 3 northern provinces of the Netherlands, in which data were collected between 2006 and 2018, with a median follow-up of 6.8 years (Q25 5.7; Q75 7.9). A total of 142,493 participants of the Lifelines Cohort Study were stratified at baseline as (1) healthy; (2) CVRF; or (3) CVD. Individuals were categorized into "inactive" and 4 quartiles of least (Q1) to most (Q4) active based on self-reported MVPA volumes. Primary outcome was a composite of incident MACE and all-cause mortality during follow-up. Cox regression was used to estimate hazard ratios (HRs), 95% confidence intervals (CIs) and P values. The main analyses were stratified on baseline health status and adjusted for age, sex, income, education, alcohol consumption, smoking, protein, fat and carbohydrate intake, kidney function, arrhythmias, hypothyroid, lung disease, osteoarthritis, and rheumatoid arthritis. The event rates were 2.2% in healthy individuals (n = 2,485 of n = 112,018), 7.9% in those with CVRF (n = 2,214 of n = 27,982) and 40.9% in those with CVD (n = 1,019 of n = 2,493). No linear association between MVPA and all-cause mortality or MACE was found for healthy individuals (P = 0.36) and individuals with CVRF (P = 0.86), but a linear association was demonstrated for individuals with CVD (P = 0.04). Adjusted HRs in healthy individuals were 0.81 (95% CI 0.64 to 1.02, P = 0.07), 0.71 (95% CI 0.56 to 0.89, P = 0.004), 0.72 (95% CI 0.57 to 0.91, P = 0.006), and 0.76 (95% CI 0.60 to 0.96, P = 0.02) for MVPA Q1 to Q4, respectively, compared to inactive individuals. In individuals with CVRF, HRs were 0.69 (95% CI 0.57 to 0.82, P < 0.001), 0.66 (95% CI 0.55 to 0.80, P < 0.001), 0.64 (95% CI 0.53 to 0.77, P < 0.001), and 0.69 (95% CI 0.57 to 0.84, P < 0.001) for MVPA Q1 to Q4, respectively, compared to inactive individuals. Finally, HRs for MVPA Q1 to Q4 compared to inactive individuals were 0.80 (95% CI 0.62 to 1.03, P = 0.09), 0.82 (95% CI 0.63 to 1.06, P = 0.13), 0.74 (95% CI 0.57 to 0.95, P = 0.02), and 0.70 (95% CI 0.53 to 0.93, P = 0.01) in CVD patients. Leisure MVPA was associated with the most health benefits, nonleisure MVPA with little health benefits, and occupational MVPA with no health benefits. Study limitations include its observational nature, self-report data about MVPA, and potentially residual confounding despite extensive adjustment for lifestyle risk factors and health-related factors. MVPA is beneficial for reducing adverse outcomes, but the shape of the association depends on cardiovascular health status. A curvilinear association was found in healthy and CVRF individuals with a steep risk reduction at low to moderate MVPA volumes and benefits plateauing at high(er) MVPA volumes. CVD patients demonstrated a linear association, suggesting a constant reduction of risk with higher volumes of MVPA. Therefore, individuals with CVDs should be encouraged that "more is better" regarding MVPA. These findings may help to optimize exercise prescription to gain maximal benefits of a physically active lifestyle.


Projected health effects of realistic dietary changes to address freshwater constraints in India: a modelling study.
The availability of freshwater for irrigation in the Indian agricultural sector is expected to decline over the coming decades. This might have implications for food production in India, with subsequent effects on diets and health. We identify realistic and healthy dietary changes that could enhance the resilience of the Indian food system to future decreases in water availability. In this modelling study, we optimised typical dietary patterns in an Indian population sample to meet projected decreases in the availability of water per person for irrigation (blue water footprint) due to population growth (to 2025 and 2050). The optimised diets met nutritional guidelines and minimised deviation from existing patterns. Resulting changes in life-years lost due to coronary heart disease, stroke, diabetes, and cancers were modelled using life tables, and changes in greenhouse gas emissions associated with the production of diets were estimated. The primary outcomes of the model were changes in life-years per 100 000 total population over 40 years (to 2050). The optimised diets had up to 30% lower blue water footprints and generally contained lower amounts of wheat, dairy, and poultry, and increased amounts of legumes. In the 2050 scenario, adoption of these diets would on average result in 6800 life-years gained per 100 000 total population (95% CI 1600-13 100) over 40 years. The dietary changes were accompanied by reductions in greenhouse gas emissions. The magnitude of the health and environmental effects varied between dietary patterns. Modest changes in diets could help to address projected reductions in the availability of freshwater for irrigation in India. These dietary changes could also simultaneously reduce diet-related greenhouse gas emissions and improve diet-related health outcomes. Wellcome Trust.


Three cousins with chronic foot ulcers from late-onset hereditary sensory and autonomic neuropathies type 2 (HSAN2).
The hereditary sensory and autonomic neuropathies (HSAN) are a group of rare disorders characterized by prominent sensory and autonomic neuropathy without motor involvement. We report three male cousins with chronic foot ulcers, all were affected with late-onset HSAN type 2 (HSAN2). In view of the history of consanguinity and male sex, X-linked recessive transmission was likely in our patients. According to the authors' knowledge this is the first report of HSAN2 from Iran.


Effects of electromagnetic fields on the reproductive success of American kestrels.
Reduced reproductive success of birds nesting near power lines has been documented but never directly attributed to electromagnetic fields (EMFs). Laboratory studies have identified EMF effects on embryonic development, but reproductive success of wild birds is dependent on additional factors, including fertility, egg size, hatching, and fledging success. We tested whether EMFs affect reproductive success of birds. Captive American kestrels (Falco sparverius) were bred for one season per year for 2 yr under either controlled or EMF conditions. EMF exposure was equivalent to that experienced by wild reproducing kestrels and was weakly associated with reduced egg laying in 1 yr only. In both years fertility was higher, but hatching success was lower in EMF pairs than control pairs. Fledging success was higher in EMF pairs than control pairs in 1995 only. Egg composition and embryonic development were examined in 1 yr only, but hatchlings were measured in both years. EMF eggs were larger, with more yolk, albumen, and water, but had thinner egg shells than control eggs. Late-term EMF embryos were larger and longer than control embryos, although hatchlings were similar in body mass and size. EMF exposure affected reproductive success of kestrels, increasing fertility, egg size, embryonic development, and fledging success but reducing hatching success.


How do chemokine/chemokine receptor activations affect tumorigenesis?
Cells that display chemokine receptors are capable of responding to a gradient of chemokine with a motility response that can translate into a chemotactic response. This continuous response to the chemokine sometimes requires that the chemokine receptor be internalized and recycled back to the membrane. We have shown that ligand activation of the CXC chemokine receptor, CXCR2, results in movement of the receptor into clathrin coated pits, followed by movement into the early endosome, the sorting endosome, then on to the recycling endosome prior to trafficking back into the plasma membrane compartment. Prolonged exposure to saturating concentrations of the ligand results in movement of a large percentage of the receptor into the late endosome and on to the lysosome for degradation. Mutation of the receptor in a manner which impairs receptor internalization by altering the binding of adaptor proteins AP-2 or beta arrestin to CXCR2, results in a marked reduction in the chemotactic response. Chemokine receptors also activate multiple intracellular signals that lead to the activation of the transcription factor, nuclear factor kappa beta (NF-kappaB). Transformation is often associated with a constitutive activation of NF-kappaB, leading to endogenous expression of chemokines and their receptors. This creates an autocrine loop with NF-kappaB in the activated state, and altered cxpression of factors that promote tumour angiogenesis and escape from apoptosis. We have shown that the constitutive activation of NF-kappaB in human melanoma tumours is accompanied by constitutive activation of the NF-kappaB inducing kinase (NIK) as well as the constitutive activation of AKT. As these factors that modulate the expression of anti-apoptotic factors work together, the tumour cells exhibit enhanced survival and growth. This never ending cycle of activation of NF-kappaB, leading to enhanced production of chemokines, enhanced activation of AKT and NF-kappaB, and enhanced transcription of inhibitors of apoptosis and chemokines, is one that has been used to foster the growth of the tumour to the disadvantage of the host. Thus we propose that blocking CXCR2 and/or NF-kappaB offers potential therapeutic promise for a number of chronic inflammatory conditions and cancers, including malignant melanoma.


Caldimonas manganoxidans gen. nov., sp. nov., a poly(3-hydroxybutyrate)-degrading, manganese-oxidizing thermophile.
A poly(3-hydroxybutyrate) (PHB)-degrading, gram-negative, aerobic bacterium, strain HS(T), was isolated from a hot spring and chemotaxonomically and phylogenetically characterized. The oxidase-positive, weakly catalase-positive, non-pigmented cells (0.6 x 2.6 microm) exhibited a single polar flagellum and accumulated PHB granules. Strain HS(T) was capable of manganese oxidation. Highest growth rate was attained at 50 degrees C. The optimum pH for growth was 7-8. The major respiratory quinone was ubiquinone-8 and major cellular fatty acids were C16:0, C16:1 and C18:1. The G+C content of the DNA was 66.2 mol%. Comparative 16S rDNA analysis indicated that strain HS(T) is related to the Rubrivivax subgroup and the family Comamonadaceae. The nearest phylogenetic relatives were Ideonella dechloratans (92.1% similarity), Leptothrix discophora (93.6%), Roseateles depolymerans (92.4%) and Rubrivivax gelatinosus (92.2%). On the basis of its phylogenetic and phenotypic properties, it is proposed that this isolate be designated Caldimonas manganoxidans gen. nov., sp. nov.; the type strain is HS(T) (= JCM 10698T = IFO 16448T = ATCC BAA-369T).


Resuscitation with Lyophilized Plasma Is Safe and Improves Neurological Recovery in a Long-Term Survival Model of Swine Subjected to Traumatic Brain Injury, Hemorrhagic Shock, and Polytrauma.
We have shown previously that fresh frozen plasma (FFP) and lyophilized plasma (LP) decrease brain lesion size and improve neurological recovery in a swine model of traumatic brain injury (TBI) and hemorrhagic shock (HS). In this study, we examine whether these findings can be validated in a clinically relevant model of severe TBI, HS, and polytrauma. Female Yorkshire swine were subjected to TBI (controlled cortical impact), hemorrhage (40% volume), grade III liver and splenic injuries, rib fracture, and rectus abdominis crush. The animals were maintained in a state of shock (mean arterial pressure 30-35 mm Hg) for 2 h, and then randomized to resuscitation with normal saline (NS), FFP, or LP (n = 5 swine/group). Animals were recovered and monitored for 30 d, during which time neurological recovery was assessed. Brain lesion sizes were measured via magnetic resonance imaging (MRI) on post-injury days (PID) three and 10. Animals were euthanized on PID 30. The severity of shock and response to resuscitation was similar in all groups. When compared with NS-treated animals, plasma-treated animals (FFP and LP) had significantly lower neurologic severity scores (PID 1-7) and a faster return to baseline neurological function. There was no significant difference in brain lesion sizes between groups. LP treatment was well tolerated and similar to FFP. In this clinically relevant large animal model of severe TBI, HS, and polytrauma, we have shown that plasma-based resuscitation strategies are safe and result in neurocognitive recovery that is faster than recovery after NS-based resuscitation.


Saccadic Eye Movements and Attentional Control in Alzheimer's Disease.
Several studies have demonstrated saccadic eye movement (SEM) abnormalities in Alzheimer's disease (AD) when patients performed prosaccade (PS) and antisaccade (AS) tasks. Some studies have also showed that SEM abnormalities were correlated with dementia rating tests such as the Mini Mental State Evaluation (MMSE). Therefore, it has been suggested that SEMs could provide useful information for diagnosis. However, little is known about predictive saccades (PreS)-saccades triggered before or very quickly after stimuli appearance-and their relationships with cognition in AD. Here, we aimed to examine the relationships between our usual dementia screening tests and SEM parameters in PS, AS, and also PreS task. We compared SEMs in 20 patients suffering from AD and in 35 healthy older adults (OA) in PS, AS, and PreS task. All participants also completed a neuropsychological evaluation. We showed that AD patients had higher latency and latency variability regardless the tasks, and also higher AS cost, in comparison with OA. Moreover, AD patients made more uncorrected AS and took more time-to-correct incorrect AS. In PreS task, AD patients showed higher gain and gain variability than OA when they made anticipated saccades. Close relationships were found between the majority of SEM variables in PS, AS, and PreS tasks and dementia screening tests, especially the MMSE and episodic memory measures. Our findings, in agreement with previous studies, demonstrated that AD affects several SEM parameters. SEM abnormalities may reflect selective and executive-attention impairments in AD.


An audit of the students' corner of Journal of the Pakistan Medical Association.
To analyze the pattern of the first author's institutional affiliation and the distribution of different article types published in the students' corner of the Journal of Pakistan Medical Association. This cross-sectional study was carried out in July 2005 and analyzed the students' corner (whenever present) of the Journal of Pakistan Medical Association from January 1998 to June 2005. For the 90 issues of the journal in the stipulated period, 96 articles were published in the students' corner. Original studies 46 (47.9%) were the most commonly published article category followed by personal opinion/review category (43.8%) and case-reports 8 (8.3%). The number of personal opinion/review articles has been steadily decreasing. Students from Aga Khan University contributed 74 (77.1%) articles followed by students from Ziauddin Medical University 10 (10.4%). Almost 95% of the authors were from private medical colleges. Sindh was the location of the first authors institution in 90 (93.8%) cases. A major chunk of all articles published in the students' corner of the Journal of Pakistan Medical Association originates from two private medical colleges in Sindh. Efforts must be made to increase student participation across the country. This may be done by asking students to begin scientific writing by submitting personal opinion articles. Further research is needed to assess the status of student research in terms of published output in Pakistan.


Understanding type 2 diabetes mellitus screening practices among primary care physicians: a qualitative chart-stimulated recall study.
Early diagnosis and treatment of prediabetes and type 2 diabetes mellitus (T2DM) can prevent future health problems, yet many individuals with these conditions are undiagnosed. This could be due, in part, to primary care physicians' (PCP) screening practices, about which little is known. The objectives of this study were to identify factors that influence PCPs' decisions to screen patients for T2DM and to characterize their interpretation and communication of screening test results to patients. We conducted semi-structured chart-stimulated recall interviews with 20 University of Michigan Health System (UMHS) primary care physicians. PCPs were asked about their recent decisions to screen or not screen 134 purposively sampled non-diabetic patients who met American Diabetes Association criteria for screening for T2DM. Interviews were audio-recorded, transcribed, and analyzed using qualitative directed content analysis. Data on patient demographic characteristics and comorbidities were abstracted from the electronic health record. The most common reasons PCPs gave for not screening 63 patients for T2DM were knowledge of a previously normal screening test (49%) and a visit for reasons other than a health maintenance examination (48%). The most common reasons PCPs gave for screening 71 patients for T2DM were knowledge of a previously abnormal screening test (49%), and patients' weight (42%) and age (38%). PCPs correctly interpreted 89% of screening test results and communicated 95% of test results to patients. Among 24 patients found to have prediabetes, PCPs usually (58%) recommended weight loss and increased physical activity but never recommended participation in a Diabetes Prevention Program or use of metformin. Previous screening test results, visit types, and patients' weight and age influenced PCPs' decisions to screen for T2DM. When patients were screened, test results were generally correctly interpreted and consistently communicated. Recommendations to patients with prediabetes could better reflect evidence-based strategies to prevent T2DM.


Underwater digital holography for studies of marine plankton.
Conventional and digital holographies are proving to be increasingly important for studies of marine zooplankton and other underwater biological applications. This paper reports on the use of a subsea digital holographic camera (eHoloCam) for the analysis and identification of marine organisms and other subsea particles. Unlike recording on a photographic film, a digital hologram (e-hologram) is recorded on an electronic sensor and reconstructed numerically in a computer by simulating the propagation of the optical field in space. By comparison with other imaging techniques, an e-hologram has several advantages such as three-dimensional spatial reconstruction, non-intrusive and non-destructive interrogation of the recording sampling volume and the ability to record holographic videos. The basis of much work in optics lies in Maxwell's electromagnetic theory and holography is no exception: we report here on two of the numerical reconstruction algorithms we have used to reconstruct holograms obtained using eHoloCam and how their starting point lies in Maxwell's equations. Derivation of the angular spectrum algorithm for plane waves is provided as an exact method for the in-line numerical reconstruction of digital holograms. The Fresnel numerical reconstruction algorithm is derived from the angular spectrum method. In-line holograms are numerically processed before and after reconstruction to remove periodic noise from captured images and to increase image contrast. The ability of the Fresnel integration reconstruction algorithm to extend the reconstructed volume beyond the recording sensor dimensions is also shown with a 50% extension of the reconstruction area. Finally, we present some images obtained from recent deployments of eHoloCam in the North Sea and Faeroes Channel.


Inputs to combination-sensitive neurons in the medial geniculate body of the mustached bat: the missing fundamental.
This study examined projections to combination-sensitive neurons in the medial geniculate body of the mustached bat. These specialized neurons respond to the combination of two temporally and spectrally distinct components of the bat's sonar pulse and echo, encoding target information. Combination-sensitive neurons respond to the bat's sonar fundamental, between 24-31 kHz, in conjunction with a higher harmonic signal. They are thought to be formed in the medial geniculate body (MGB) by convergent input from inferior colliculus representations of 24-31 kHz and higher frequencies. This study used anterograde and retrograde tract-tracing methods in conjunction with physiological recording to test this MGB convergence hypothesis. In anterograde tracing experiments, multiple deposits of two different tracers were placed in the central nucleus of the inferior colliculus (ICC), one tracer in the 24-31 kHz region and another in an ICC representation responding to a higher sonar harmonic. We found only limited overlap in the MGB labeling patterns of the two tracers, and little in many areas where combination-sensitive neurons are common. In retrograde tracing experiments, a single deposit of tracer was placed at a combination-sensitive recording site in the MGB. With the deposit mostly limited to combination-sensitive MGB areas, labeling in 24-31 kHz representations of the ICC was absent or minor. These results suggest that many combination-sensitive neurons in the MGB do not receive 24-31 kHz ICC input. The strongest inputs to combination-sensitive MGB regions originate in high-frequency representations of the ICC and combination-sensitive regions of auditory cortex. Additional projections arrive from the thalamic reticular nucleus, external nucleus of the inferior colliculus, and pericollicular tegmentum. Each projection may contribute to the 24-31 kHz sensitivity of combination-sensitive neurons in the medial geniculate body.


Noninvasive ventilation and weaning in patients with chronic hypercapnic respiratory failure: a randomized multicenter trial.
The use of noninvasive ventilation (NIV) as an early weaning/extubation technique from mechanical ventilation remains controversial. To investigate NIV effectiveness as an early weaning/extubation technique in difficult-to-wean patients with chronic hypercapnic respiratory failure (CHRF). In 13 intensive care units, 208 patients with CHRF intubated for acute respiratory failure (ARF) who failed a first spontaneous breathing trial were randomly assigned to three groups: conventional invasive weaning group (n = 69), extubation followed by standard oxygen therapy (n = 70), or NIV (n = 69). NIV was permitted as rescue therapy for both non-NIV groups if postextubation ARF occurred. Primary endpoint was reintubation within 7 days after extubation. Secondary endpoints were: occurrence of postextubation ARF or death within 7 days after extubation, use of rescue postextubation NIV, weaning time, and patient outcomes. Reintubation rates were 30, 37, and 32% for invasive weaning, oxygen-therapy, and NIV groups, respectively (P = 0.654). Weaning failure rates, including postextubation ARF, were 54, 71, and 33%, respectively (P < 0.001). Rescue NIV success rates for invasive and oxygen-therapy groups were 45 and 58%, respectively (P = 0.386). By design, intubation duration was 1.5 days longer for the invasive group than in the two others. Apart from a longer weaning time in NIV than in invasive group (2.5 vs. 1.5 d; P = 0.033), no significant outcome difference was observed between groups. No difference was found in the reintubation rate between the three weaning strategies. NIV decreases the intubation duration and may improve the weaning results in difficult-to-wean patients with CHRF by reducing the risk of postextubation ARF. The benefit of rescue NIV in these patients deserves confirmation.


Multipole surface solitons in thermal media.
We address the existence and properties of multipole solitons localized at a thermally insulating interface between uniform or layered thermal media and a linear dielectric. We find that in the case of uniform media, only surface multipoles with less than three poles can be stable. In contrast, we reveal that periodic alternation of the thermo-optic coefficient in layered thermal media makes possible the stabilization of higher-order multipoles.


Recognizing and Reducing the Risk of Opioid Misuse in Orthopaedic Practice.
Orthopaedic surgeons often treat patients with chronic musculoskeletal pain. This musculoskeletal pain is increasingly being treated with opioid medications, contributing to the growing opioid epidemic in the United States. Opioid use and abuse before orthopaedic surgery are associated with worse clinical outcomes. This article reviews the risk factors for opioid use, misuse, and other behaviors in chronic pain patients, discusses the screening tools for opioid misuse in chronic pain patients, and provides recommendations for the orthopaedic surgeon's role in managing these complicated patients.


Bacterial community dynamics and activity in relation to dissolved organic matter availability during sea-ice formation in a mesocosm experiment.
The structure of sea-ice bacterial communities is frequently different from that in seawater. Bacterial entrainment in sea ice has been studied with traditional microbiological, bacterial abundance, and bacterial production methods. However, the dynamics of the changes in bacterial communities during the transition from open water to frozen sea ice is largely unknown. Given previous evidence that the nutritional status of the parent water may affect bacterial communities during ice formation, bacterial succession was studied in under ice water and sea ice in two series of mesocosms: the first containing seawater from the North Sea and the second containing seawater enriched with algal-derived dissolved organic matter (DOM). The composition and dynamics of bacterial communities were investigated with terminal restriction fragment length polymorphism (T-RFLP), and cloning alongside bacterial production (thymidine and leucine uptake) and abundance measurements (measured by flow cytometry). Enriched and active sea-ice bacterial communities developed in ice formed in both unenriched and DOM-enriched seawater (0-6 days). γ-Proteobacteria dominated in the DOM-enriched samples, indicative of their capability for opportunistic growth in sea ice. The bacterial communities in the unenriched waters and ice consisted of the classes Flavobacteria, α- and γ-Proteobacteria, which are frequently found in natural sea ice in polar regions. Furthermore, the results indicate that seawater bacterial communities are able to adapt rapidly to sudden environmental changes when facing considerable physicochemical stress such as the changes in temperature, salinity, nutrient status, and organic matter supply during ice formation.


Recency and frequency of HIV testing among men who have sex with men in Germany and socio-demographic factors associated with testing behaviour.
Testing for presence of HIV infection is a pre-requisite to qualify for antiretroviral treatment. A considerable proportion of German men who have sex with men (MSM) infected with HIV have a CD4 cell count below 350 cells/μl at time of diagnosis and are thus defined as "late presenters". Late presentation increases the risk of adverse disease outcomes. In addition, knowledge and assessment of HIV status is often used for decisions about condom use and anal intercourse with steady and non-steady partners. Incorrect assumptions may result in high risk for HIV transmission. Between 11/2013 and 01/2014 MSM were recruited to an online survey predominantly by personalized invitation messages from MSM social networking and dating websites. Respondents were asked about demographic characteristics, HIV testing history, reasons for testing decisions, and sexual behaviours. We describe reasons for not testing and analyse factors associated with not or infrequent testing using univariable and multivariable multinomial regression. Questions on HIV testing history were answered by 15,297 respondents. An HIV test within the last 12 months was reported by 38%, a test more than 12 months ago by 27% and 35% had never been tested for HIV. Compared to recently tested, respondents who had never tested were more likely to be younger than 25 years (adjusted relative risk ratio (aRRR) 2.90, 95% CI 2.11-3.99), living in a settlement with less than 100,000 inhabitants (aRRR 1.47, 95% CI 1.18-1.83), being less open about their sexual orientation to their co-workers/classmates, and particularly to their primary care provider (aRRR 4.54, 95% CI 4.02-5.11). Untested and less frequently tested respondents reported less sex partners and a lower proportion reported unprotected anal intercourse (UAI) with a non-steady partner (24% compared to 38% among those recently tested). MSM who were younger, who did not live in large cities, and who were not out about their sexual orientation tested less frequently for HIV. Apart from strengthening protection from sexual orientation-related discrimination and empowering MSM who conceal their orientation, more opportunities to test anonymously and without revealing one's sexual orientation should be provided.


Unmet Need for Family Planning and Experience of Unintended Pregnancy Among Female Sex Workers in Urban Cameroon: Results From a National Cross-Sectional Study.
Female sex workers (FSWs) in Cameroon commonly have unmet need for contraception posing a high risk of unintended pregnancy. Unintended pregnancy leads to a range of outcomes, and due to legal restrictions, FSWs often seek unsafe abortions. Aside from the high burden of HIV, little is known about the broader sexual and reproductive health of FSWs in Cameroon. From December 2015 to October 2016, we recruited FSWs aged ≥18 years through respondent-driven sampling across 5 Cameroonian cities. Cross-sectional data were collected through a behavioral questionnaire. Modified-robust Poisson regression was used to approximate adjusted prevalence ratios (aPR) for TOP and current use of effective nonbarrier contraception. Among 2,255 FSWs (median age 28 years), 57.6% reported history of unintended pregnancy and 40.0% reported prior TOP. In multivariable analysis, TOP history was associated with current nonbarrier contraceptive use (aPR=1.23, 95% confidence interval [CI]=1.07, 1.42); ever using emergency contraception (aPR=1.34, 95% CI=1.17, 1.55); >60 clients in the past month (aPR=1.29, 95% CI= 1.07, 1.54) compared to ≤30; inconsistent condom use with clients (aPR=1.17, 95% CI=1.00, 1.37); ever experiencing physical violence (aPR=1.24, 95% CI=1.09, 1.42); and older age. Most (76.5%) women used male condoms for contraception, but only 33.2% reported consistent condom use with all partners. Overall, 26.4% of women reported currently using a nonbarrier contraceptive method, and 6.2% reported using a long-acting method. Previous TOP (aPR=1.41, 95%CI=1.16, 1.72) and ever using emergency contraception (aPR=2.70, 95% CI=2.23, 3.26) were associated with higher nonbarrier contraceptive use. Recent receipt of HIV information (aPR=0.72, 95% CI=0.59, 0.89) and membership in an FSW community-based organization (aPR=0.73, 95% CI=0.57, 0.92) were associated with lower use nonbarrier contraceptive use. Experience of unintended pregnancies and TOP is common among FSWs in Cameroon. Given the low use of nonbarrier contraceptive methods and inconsistent condom use, FSWs are at risk of repeat unintended pregnancies. Improved integration of client-centered, voluntary family planning within community-led HIV services may better support the sexual and reproductive health and human rights of FSWs consistent with the United Nations Declaration of Human Rights.


Evaluation of urinary antigen ELISA for diagnosing Legionella pneumophila serogroup 1 infection.
The enzyme linked immunosorbent assay (ELISA) described was developed to detect a soluble antigen in the urine of patients with Legionnaires' disease caused by Legionella pneumophila serogroup 1 (L.pn 1). The assay was evaluated and showed good specificity (100%) and intra-assay reproducibility. Antigen was detected in the urine of 93 (77%) of 120 patients, overall, and in 86% of patients from whom a specimen obtained within seven days of onset of illness was available. On all but one occasion the first urine sample taken from a patient for whom a positive ELISA result was obtained, was itself positive. In one case antigen was not detected at four days but was present on the fifth day after onset of symptoms. In two patients urinary antigen was detectable as early as two days after onset of symptoms. In another the antigen persisted for at least 60 days. More than half the patients, however, had stopped producing detectable antigen within 14 days of onset of symptoms. It is therefore important that where Legionnaires' disease is suspected urine is collected as early as possible in the course of the disease.


Patterns of asthma medication use: early asthma therapy initiation and asthma outcomes at age 8.
Wheeze has many underlying pathophysiologies in childhood, but is the main reason for anti-asthma drugs prescription. This study was conducted to describe asthma medication use patterns among children in their first eight years of life. Longitudinal medication use data from 777 children participating in the PIAMA study were used. Medication patterns were described for four groups that started therapy before the third birthday, when the peak in prescriptions occurred in our cohort; short-acting β-agonists (SABA), inhaled corticosteroids (ICS), SABA + ICS or none of these. One third (n = 255) of the children received a first SABA or ICS prescription before age 8. Only three children (1.2%) used medication continuously during follow-up. Of the children who started SABA, 53.8% discontinued within 1-2 years. Of the children who started ICS before age 3, 42.1% discontinued within 1-2 years and 31.6% received additional SABA. 41.5% of the children who started SABA + ICS used this short-term (≤1 -2 years) and 21.5% long-term (≥ 3 years). Fifteen percent of children who did not start asthma therapy in their first 3 years of life did receive prescriptions between age 3 and 8. Children prescribed SABA + ICS before age 3 had the highest prevalence of hyper responsiveness at age 8, and similar prevalence of atopy as the other groups. Asthma medication is prescribed frequently in the first 8 years of life, particularly before age 3, and only few children use it continuously. ICS and SABA prescription occurs especially in those who were more likely to develop signs of asthma at age 8.


Differentiating prenatal exposure to methamphetamine and alcohol versus alcohol and not methamphetamine using tensor-based brain morphometry and discriminant analysis.
Here we investigate the effects of prenatal exposure to methamphetamine (MA) on local brain volume using magnetic resonance imaging. Because many who use MA during pregnancy also use alcohol, a known teratogen, we examined whether local brain volumes differed among 61 children (ages 5-15 years), 21 with prenatal MA exposure, 18 with concomitant prenatal alcohol exposure (the MAA group), 13 with heavy prenatal alcohol but not MA exposure (ALC group), and 27 unexposed controls. Volume reductions were observed in both exposure groups relative to controls in striatal and thalamic regions bilaterally and in right prefrontal and left occipitoparietal cortices. Striatal volume reductions were more severe in the MAA group than in the ALC group, and, within the MAA group, a negative correlation between full-scale intelligence quotient (FSIQ) scores and caudate volume was observed. Limbic structures, including the anterior and posterior cingulate, the inferior frontal gyrus (IFG), and ventral and lateral temporal lobes bilaterally, were increased in volume in both exposure groups. Furthermore, cingulate and right IFG volume increases were more pronounced in the MAA than ALC group. Discriminant function analyses using local volume measurements and FSIQ were used to predict group membership, yielding factor scores that correctly classified 72% of participants in jackknife analyses. These findings suggest that striatal and limbic structures, known to be sites of neurotoxicity in adult MA abusers, may be more vulnerable to prenatal MA exposure than alcohol exposure and that more severe striatal damage is associated with more severe cognitive deficit.


Gastric polyps: relationship of size and histology to cancer risk.
Management of gastric polyps based on polyp size (< or > 2 cm), and histology obtained from forceps biopsy sampling is controversial. To illuminate this subject, the 4-yr experience with endoscopic management of gastric epithelial polyps at a university hospital and a Veterans Administration medical center was reviewed with histopathologic correlation. A computer data-base was used to recall the endoscopic diagnosis of "gastric polyp." Endoscopy reports, video, and still photography were reviewed for data on polyp appearance, size, location, and management. These data had been entered prospectively as required by the Computer-Based Management System. Histopathology was reviewed by a second, blinded, pathologist. Gastric polyps of epithelial origin, at least 0.5 cm in diameter, and not associated with polyposis syndromes, were included. Thirty-five gastric polyps in 23 patients met inclusion criteria. Snare polypectomy was ultimately performed on 26, and complete resection with forceps biopsy alone on 9. On histopathology 31 polyps were hyperplastic and 4 were adenomas. Six hyperplastic polyps contained focal dysplasia. Among these, carcinoma in situ was identified in three, all <2.0 cm. Furthermore, forceps biopsy in two of these did not reveal the dysplastic components. One adenomatous polyp also contained carcinoma, also <2.0 cm. These data emphasize that management based on polyp size or histology obtained from forceps biopsy sampling may be faulty. We recommend that gastric polyps >0.5 cm be removed in toto.


Hepatic Sirt1 deficiency in mice impairs mTorc2/Akt signaling and results in hyperglycemia, oxidative damage, and insulin resistance.
Insulin resistance is a major risk factor for type 2 diabetes mellitus. The protein encoded by the sirtuin 1 (Sirt1) gene, which is a mouse homolog of yeast Sir2, is implicated in the regulation of glucose metabolism and insulin sensitivity; however, the underlying mechanism remains elusive. Here, using mice with a liver-specific null mutation of Sirt1, we have identified a signaling pathway involving Sirt1, Rictor (a component of mTOR complex 2 [mTorc2]), Akt, and Foxo1 that regulates gluconeogenesis. We found that Sirt1 positively regulates transcription of the gene encoding Rictor, triggering a cascade of phosphorylation of Akt at S473 and Foxo1 at S253 and resulting in decreased transcription of the gluconeogenic genes glucose-6-phosphatase (G6pase) and phosphoenolpyruvate carboxykinase (Pepck). Liver-specific Sirt1 deficiency caused hepatic glucose overproduction, chronic hyperglycemia, and increased ROS production. This oxidative stress disrupted mTorc2 and impaired mTorc2/Akt signaling in other insulin-sensitive organs, leading to insulin resistance that could be largely reversed with antioxidant treatment. These data delineate a pathway through which Sirt1 maintains insulin sensitivity and suggest that treatment with antioxidants might provide protection against progressive insulin resistance in older human populations.


Pulse bundles and passive harmonic mode-locked pulses in Tm-doped fiber laser based on nonlinear polarization rotation.
We demonstrate the nanosecond-level pulses in Tm-doped fiber laser generated by passively harmonic mode-locking. Nonlinear polarization rotation performed by two polarization controllers (PCs) is employed to induce the self-starting harmonic mode-locking. The fundamental repetition rate of the laser is 448.8 kHz, decided by the length of the cavity. Bundles of pulses with up to 17 uniform subpulses are generated due to the split of pulse when the pump power increases and the PCs are adjusted. Continuous harmonic mode-locked pulse trains are obtained with 1st to 6th and even more than 15th order when the positions of the PCs are properly fixed and the pump power is scaled up. The widths of all the uniform individual pulses are mostly 3-5 ns, and pulse with width of 304 ns at fundamental repetition rate can also be generated by adjusting the PCs. Hysteresis phenomenon of the passively harmonic mode-locked pulses' repetition frequency versus pump power is observed. The rather wide 3dB spectral bandwidth of the pulse train (25 nm) indicates that they may resemble noise-like pulses.


Long term cultivation of Plasmodium falciparum in Aotus trivirgatus erythrocytes.
The erythrocytes of the Colombian owl monkey Aotus trivirgatus griseimembra can be used for the long-term in vitro cultivation of Plasmodium falciparum employing a modified Trager -Jensen method. Cultures are grown in HEPES-buffered RPMI-1640 using a 4% suspension of monkey erythrocytes and 10% pooled heat-inactivated human AB serum, with initial parasitemias in a range between 0.2 and 0.5%. Adaptation of new strains from human erythrocytes cultures can be performed by simply subculturing from human to owl monkey erythrocytes in a stepwise manner. When 5% human AB serum is included in cultures to support growth, as much as 5% monkey serum can be added in order to investigate serum effects, such as antibody activity against P. falciparum. The Aotus trivirgatus continuous culture system has provided a stable, consistent source of infected erythrocytes for in vitro experimentation, and the techniques developed have been used to further refine and support the animal experiments in progress.


Do red herrings swim in circles? Controlling for the endogeneity of time to death.
Studies on the effect of ageing on health care expenditure (HCE) have revealed the importance of controlling for time-to-death (TTD). These studies, however, are subject to possible endogeneity if HCE influences the remaining life expectancy. This paper introduces a 10-year observation period on monthly HCE, socioeconomic characteristics and survivor status to first predict TTD and then use the predicted values as an instrument in the regression for HCE. While exogeneity of TTD has to be rejected, core results concerning the role of TTD rather than age as a determinant of HCE (the 'red herring' hypothesis) are confirmed.


Faster clean catch urine collection (Quick-Wee method) from infants: randomised controlled trial.
Objective To determine if a simple stimulation method increases the rate of infant voiding for clean catch urine within five minutes.Design Randomised controlled trial.Setting Emergency department of a tertiary paediatric hospital, Australia.Participants 354 infants (aged 1-12 months) requiring urine sample collection as determined by the treating clinician. 10 infants were subsequently excluded.Interventions Infants were randomised to either gentle suprapubic cutaneous stimulation (n=174) using gauze soaked in cold fluid (the Quick-Wee method) or standard clean catch urine with no additional stimulation (n=170), for five minutes.Main outcome measures The primary outcome was voiding of urine within five minutes. Secondary outcomes were successful collection of a urine sample, contamination rate, and parental and clinician satisfaction with the method.Results The Quick-Wee method resulted in a significantly higher rate of voiding within five minutes compared with standard clean catch urine (31% v 12%, P<0.001), difference in proportions 19% favouring Quick-Wee (95% confidence interval for difference 11% to 28%). Quick-Wee had a higher rate of successful urine sample collection (30% v 9%, P<0.001) and greater parental and clinician satisfaction (median 2 v 3 on a 5 point Likert scale, P<0.001). The difference in contamination between Quick-Wee and standard clean catch urine was not significant (27% v 45%, P=0.29). The number needed to treat was 4.7 (95% confidence interval 3.4 to 7.7) to successfully collect one additional urine sample within five minutes using Quick-Wee compared with standard clean catch urine.Conclusions Quick-Wee is a simple cutaneous stimulation method that significantly increases the five minute voiding and success rate of clean catch urine collection.Trial registration Australian New Zealand Clinical Trials Registry ACTRN12615000754549.


Polymodal sensory function of the Caenorhabditis elegans OCR-2 channel arises from distinct intrinsic determinants within the protein and is selectively conserved in mammalian TRPV proteins.
Caenorhabditis elegans OCR-2 (OSM-9 and capsaicin receptor-related) is a TRPV (vanilloid subfamily of transient receptor potential channel) protein that regulates serotonin (5-HT) biosynthesis in chemosensory neurons and also mediates olfactory and osmotic sensation. Here, we identify the molecular basis for the polymodal function of OCR-2 in its native cellular environment. We show that OCR-2 function in 5-HT production and osmotic sensing is governed by its N-terminal region upstream of the ankyrin repeats domain, but the diacetyl sensitivity is mediated by independent mechanisms. The ocr-2(yz5) mutation results in a glycine-to-glutamate substitution (G36E) within the N-terminal region. The G36E substitution causes dramatic downregulation of 5-HT synthesis in the ADF neurons, eliminates osmosensation mediated by the ASH neurons, but does not affect the response to the odorant diacetyl mediated by the AWA neurons. Conversely, wild-type sequence of the N-terminal segment confers osmotic sensitivity and upregulation of 5-HT production to a normally insensitive C. elegans homolog, OCR-4, but this chimeric channel does not respond to diacetyl stimuli. Furthermore, expression of either the mouse or human TRPV2 gene under the ocr-2 promoter can substantially restore 5-HT biosynthesis in ocr-2-null mutants but cannot improve the deficits in osmotic or olfactory sensation, suggesting that TRPV2 can substitute for the role of OCR-2 only in serotonergic neurons. Thus, different sensory functions of OCR-2 arise from separable intrinsic determinants, and specific functional properties of TRPV channel proteins may be selectively conserved across phyla.


Vpr Enhances Tumor Necrosis Factor Production by HIV-1-Infected T Cells.
The HIV-1 accessory protein Vpr displays different activities potentially impacting viral replication, including the arrest of the cell cycle in the G2 phase and the stimulation of apoptosis and DNA damage response pathways. Vpr also modulates cytokine production by infected cells, but this property remains partly characterized. Here, we investigated the effect of Vpr on the production of the proinflammatory cytokine tumor necrosis factor (TNF). We report that Vpr significantly increases TNF secretion by infected lymphocytes. De novo production of Vpr is required for this effect. Vpr mutants known to be defective for G2 cell cycle arrest induce lower levels of TNF secretion, suggesting a link between these two functions. Silencing experiments and the use of chemical inhibitors further implicated the cellular proteins DDB1 and TAK1 in this activity of Vpr. TNF secreted by HIV-1-infected cells triggers NF-κB activity in bystander cells and allows viral reactivation in a model of latently infected cells. Thus, the stimulation of the proinflammatory pathway by Vpr may impact HIV-1 replication in vivo. The role of the HIV-1 accessory protein Vpr remains only partially characterized. This protein is important for viral pathogenesis in infected individuals but is dispensable for viral replication in most cell culture systems. Some of the functions described for Vpr remain controversial. In particular, it remains unclear whether Vpr promotes or instead prevents proinflammatory and antiviral immune responses. In this report, we show that Vpr promotes the release of TNF, a proinflammatory cytokine associated with rapid disease progression. Using Vpr mutants or inhibiting selected cellular genes, we show that the cellular proteins DDB1 and TAK1 are involved in the release of TNF by HIV-infected cells. This report provides novel insights into how Vpr manipulates TNF production and helps clarify the role of Vpr in innate immune responses and inflammation.


Neurodevelopmental Animal Models Reveal the Convergent Role of Neurotransmitter Systems, Inflammation, and Oxidative Stress as Biomarkers of Schizophrenia: Implications for Novel Drug Development.
Schizophrenia is a life altering disease with a complex etiology and pathophysiology, and although antipsychotics are valuable in treating the disorder, certain symptoms and/or sufferers remain resistant to treatment. Our poor understanding of the underlying neuropathological mechanisms of schizophrenia hinders the discovery and development of improved pharmacological treatment, so that filling these gaps is of utmost importance for an improved outcome. A vast amount of clinical data has strongly implicated the role of inflammation and oxidative insults in the pathophysiology of schizophrenia. Preclinical studies using animal models are fundamental in our understanding of disease development and pathology as well as the discovery and development of novel treatment options. In particular, social isolation rearing (SIR) and pre- or postnatal inflammation (PPNI) have shown great promise in mimicking the biobehavioral manifestations of schizophrenia. Furthermore, the "dual-hit" hypothesis of schizophrenia states that a first adverse event such as genetic predisposition or a prenatal insult renders an individual susceptible to develop the disease, while a second insult (e.g., postnatal inflammation, environmental adversity, or drug abuse) may be necessary to precipitate the full-blown syndrome. Animal models that emphasize the "dual-hit" hypothesis therefore provide valuable insight into understanding disease progression. In this Review, we will discuss SIR, PPNI, as well as possible "dual-hit" animal models within the context of the redox-immune-inflammatory hypothesis of schizophrenia, correlating such changes with the recognized monoamine and behavioral alterations of schizophrenia. Finally, based on these models, we will review new therapeutic options, especially those targeting immune-inflammatory and redox pathways.


Identification of epidural neoplasm. Radiography and bone scintigraphy in the symptomatic and asymptomatic spine.
Early identification and treatment of epidural neoplasm, before the development of significant neurologic deficits, provides the best opportunity for a favorable outcome. Among the many patients with symptoms, signs, or scintigraphic or radiographic findings suggesting possible epidural disease, a small proportion will have the lesion. The selection of patients for definitive imaging of the epidural space should be based on a determination of the risk of this complication. In this study, the medical records, plain spinal radiographs, bone scintigraphs and myelograms of 43 patients were analyzed retrospectively to assess the risk of epidural disease associated with specific clinical, radiographic, and scintigraphic findings. Cervical, thoracic, and lumbosacral spinal segments were evaluated independently. Symptomatic segments (SS) (N = 41), defined by focal pain or neurologic dysfunction, were distinguished from asymptomatic segments (AS). At SS, epidural disease was found at 86% and 8% of abnormal and normal spinal radiographs, respectively (P less than 0.001), and at 69% and 0% of abnormal and normal scintigrams, respectively (P less than 0.001), whereas at AS epidural disease occurred in 43% and 3% of abnormal and normal spinal radiographs, respectively (P less than 0.001), and 14% and 7% of abnormal and normal scintigrams, respectively (P = NS). Vertebral collapse was highly predictive of an epidural lesion. Epidural disease occurred in 12% of SS and 0% of AS with an abnormal scintigram and normal radiograph, 86% of SS and 45% of AS with abnormalities on both scintigram and radiograph, and at two AS when both were normal. Decision analysis applied to these data yielded a specific conditional probability of epidural disease for each combination of clinical, scintigraphic, and radiographic findings. These data provide a basis for the selection of patients for additional evaluation of the epidural space before neurologic deficits develop.


Structure of the rare archaeal biosphere and seasonal dynamics of active ecotypes in surface coastal waters.
Marine Archaea are important players among microbial plankton and significantly contribute to biogeochemical cycles, but details regarding their community structure and long-term seasonal activity and dynamics remain largely unexplored. In this study, we monitored the interannual archaeal community composition of abundant and rare biospheres in northwestern Mediterranean Sea surface waters by pyrosequencing 16S rDNA and rRNA. A detailed analysis of the rare biosphere structure showed that the rare archaeal community was composed of three distinct fractions. One contained the rare Archaea that became abundant at different times within the same ecosystem; these cells were typically not dormant, and we hypothesize that they represent a local seed bank that is specific and essential for ecosystem functioning through cycling seasonal environmental conditions. The second fraction contained cells that were uncommon in public databases and not active, consisting of aliens to the studied ecosystem and representing a nonlocal seed bank of potential colonizers. The third fraction contained Archaea that were always rare but actively growing; their affiliation and seasonal dynamics were similar to the abundant microbes and could not be considered a seed bank. We also showed that the major archaeal groups, Thaumarchaeota marine group I and Euryarchaeota group II.B in winter and Euryarchaeota group II.A in summer, contained different ecotypes with varying activities. Our findings suggest that archaeal diversity could be associated with distinct metabolisms or life strategies, and that the rare archaeal biosphere is composed of a complex assortment of organisms with distinct histories that affect their potential for growth.


Structure-function analysis of the C3 binding region of Staphylococcus aureus immune subversion protein Sbi.
Among the recently discovered Staphylococcus aureus immune evasion proteins, Sbi is unique in its ability to interact with components of both the adaptive and innate immune systems of the host. Sbi domains I and II (Sbi-I and Sbi-II) bind IgG. Sbi domain IV (residues 198-266) binds the central complement protein C3. When linked to Sbi-III, Sbi-IV induces a futile consumption of complement via alternative pathway activation, whereas isolated Sbi-IV specifically inhibits the alternative pathway without complement consumption. Here we have determined the three-dimensional structure of Sbi-IV by NMR spectroscopy, showing that Sbi-IV adopts a three-helix bundle fold similar to those of the S. aureus complement inhibitors Efb-C, Ehp, and SCIN. The (1)H-(15)N HSQC spectrum of Sbi-III indicates that this domain, essential for futile complement consumption, is natively unfolded, at least when isolated from the rest of Sbi. Sbi-IV and Sbi-III-IV both bind C3dg with 1:1 stoichiometry and submicromolar affinity. Despite low overall sequence identity, Sbi possesses the same residues as Efb at two positions essential for Efb-C binding to C3d. Mutation to alanine of either of these residues, Arg-231 and Asn-238, abolishes both Sbi-IV binding to C3dg and Sbi-IV alternative pathway inhibition. The almost complete conservation of Sbi-III and Sbi-IV amino acid sequences across more than 30 strains isolated from human and animal hosts indicates that the unique mechanism of Sbi in complement system subversion is a feature of infections of both humans and economically important animals.


The effect of payment and incentives on motivation and focus of community health workers: five case studies from low- and middle-income countries.
Community health workers (CHWs) have been proposed as a means for bridging gaps in healthcare delivery in rural communities. Recent CHW programmes have been shown to improve child and neonatal health outcomes, and it is increasingly being suggested that paid CHWs become an integral part of health systems. Remuneration of CHWs can potentially effect their motivation and focus. Broadly, programmes follow a social, monetary or mixed market approach to remuneration. Conscious understanding of the differences, and of what each has to offer, is important in selecting the most appropriate approach according to the context. The objective of this review is to identify and examine different remuneration models of CHWs that have been utilized in large-scale sustained programmes to gain insight into the effect that remuneration has on the motivation and focus of CHWs. A MEDLINE search using Ovid SP was undertaken and data collected from secondary sources about CHW programmes in Iran, Ethiopia, India, Bangladesh and Nepal. Five main approaches were identified: part-time volunteer CHWs without regular financial incentives, volunteers that sell health-related merchandise, volunteers with financial incentives, paid full-time CHWs and a mixed model of paid and volunteer CHWs. Both volunteer and remunerated CHWs are potentially effective and can bring something to the health arena that the other may not. For example, well-trained, supervised volunteers and full-time CHWs who receive regular payment, or a combination of both, are more likely to engage the community in grass-roots health-related empowerment. Programmes that utilize minimal economic incentives to part-time CHWs tend to limit their focus, with financially incentivized activities becoming central. They can, however, improve outcomes in well-circumscribed areas. In order to maintain benefits from different approaches, there is a need to distinguish between CHWs that are trained and remunerated to be a part of an existing health system and those who, with little training, take on roles and are motivated by a range of contextual factors. Governments and planners can benefit from understanding the programme that can best be supported in their communities, thereby maximizing motivation and effectiveness.


Changes in anxiety-related behaviors and hypothalamic-pituitary-adrenal activity in mice lacking the 5-HT-3A receptor.
The serotonin-3 (5-HT-3A) receptor has been localized in limbic and brainstem structures that regulate anxiety-related behavior and hypothalamic-pituitary-adrenal (HPA) activity, but its role in regulating anxiety-related behaviors is equivocal, and evidence for its role in regulating HPA activity is limited. Therefore, we used 5-HT-3A receptor knockout (KO) mice to further study these issues. Behavior in the elevated plus maze, open field, light-dark box and after Pavlovian fear conditioning was examined in addition to HPA activity under basal and acute stress conditions. Compared to age-matched adult male wild-type (WT) controls, adult male KO mice exhibited increased distance traveled in the open arms of the elevated plus maze, consistent with decreased measures of anxiety. There were no differences between the two genotypes in exploratory behavior in the open field or light-dark test. KO mice displayed enhanced fear conditioning indexed by fear-induced freezing behavior. KO mice displayed lower adrenocorticotropin (ACTH) responses to restraint or lipopolysaccharide (LPS). In addition, lower vasopressin mRNA in the paraventricular nucleus of the hypothalamus (PVN) and higher corticotropin-releasing hormone (CRH) mRNA in the central amygdala were observed in KO compared to WT mice. Therefore, deletion of the 5-HT-3A receptor revealed an important role for this receptor in regulating HPA responses to acute stress and a potential interaction between the 5-HT-3A receptor and CRH in the amygdala. Together, these data suggest that the 5-HT-3A receptor does not have a unitary role in the regulation of anxiety- and fear-related behaviors but has a potentially substantial role in the regulation of HPA activity.


Coding and decoding with adapting neurons: a population approach to the peri-stimulus time histogram.
The response of a neuron to a time-dependent stimulus, as measured in a Peri-Stimulus-Time-Histogram (PSTH), exhibits an intricate temporal structure that reflects potential temporal coding principles. Here we analyze the encoding and decoding of PSTHs for spiking neurons with arbitrary refractoriness and adaptation. As a modeling framework, we use the spike response model, also known as the generalized linear neuron model. Because of refractoriness, the effect of the most recent spike on the spiking probability a few milliseconds later is very strong. The influence of the last spike needs therefore to be described with high precision, while the rest of the neuronal spiking history merely introduces an average self-inhibition or adaptation that depends on the expected number of past spikes but not on the exact spike timings. Based on these insights, we derive a 'quasi-renewal equation' which is shown to yield an excellent description of the firing rate of adapting neurons. We explore the domain of validity of the quasi-renewal equation and compare it with other rate equations for populations of spiking neurons. The problem of decoding the stimulus from the population response (or PSTH) is addressed analogously. We find that for small levels of activity and weak adaptation, a simple accumulator of the past activity is sufficient to decode the original input, but when refractory effects become large decoding becomes a non-linear function of the past activity. The results presented here can be applied to the mean-field analysis of coupled neuron networks, but also to arbitrary point processes with negative self-interaction.


Alternative Isoform Analysis of Ttc8 Expression in the Rat Pineal Gland Using a Multi-Platform Sequencing Approach Reveals Neural Regulation.
Alternative isoform regulation (AIR) vastly increases transcriptome diversity and plays an important role in numerous biological processes and pathologies. However, the detection and analysis of isoform-level differential regulation is difficult, particularly in the face of complex and incompletely-annotated transcriptomes. Here we have used Illumina short-read/high-throughput RNA-Seq to identify 55 genes that exhibit neurally-regulated AIR in the pineal gland, and then used two other complementary experimental platforms to further study and characterize the Ttc8 gene, which is involved in Bardet-Biedl syndrome and non-syndromic retinitis pigmentosa. Use of the JunctionSeq analysis tool led to the detection of several novel exons and splice junctions in this gene, including two novel alternative transcription start sites which were found to display disproportionately strong neurally-regulated differential expression in several independent experiments. These high-throughput sequencing results were validated and augmented via targeted qPCR and long-read Pacific Biosciences SMRT sequencing. We confirmed the existence of numerous novel splice junctions and the selective upregulation of the two novel start sites. In addition, we identified more than 20 novel isoforms of the Ttc8 gene that are co-expressed in this tissue. By using information from multiple independent platforms we not only greatly reduce the risk of errors, biases, and artifacts influencing our results, we also are able to characterize the regulation and splicing of the Ttc8 gene more deeply and more precisely than would be possible via any single platform. The hybrid method outlined here represents a powerful strategy in the study of the transcriptome.


How Often Are Patient-Important Outcomes Represented in Neonatal Randomized Controlled Trials? An Analysis of Cochrane Neonatal Reviews.
Research findings based on patient-important outcomes (PIOs) provide more useful conclusions than those that are based on surrogate outcomes. It is unclear to what extent PIOs are represented in neonatal randomized controlled trials (RCTs). We determined the proportion of PIOs in neonatal RCTs included in Cochrane Neonatal reviews. We extracted up to 5 outcomes from each RCT included in Cochrane Neonatal reviews published until January 2018, with independent determination of PIOs among authors followed by a discussion leading to a consensus. We defined PIOs as outcomes that matter to patient care, such as clinical events or physiological or laboratory parameters that are widely used to guide management. Among 6,832 outcomes extracted from 1,874 RCTs included in 276 reviews, 5,349 (78.3%) were considered PIOs; 461 studies (24.5%) included 5 or more PIOs, 1,278 (68.2%) included 1-4 PIOs, while 135 (7.2%) had no PIO included. PIOs were observed more often among dichotomous than among continuous outcomes (94.9 vs. 61.5%; RR: 1.54; 95% CI: 1.50-1.58), and more among subjective than among objective outcomes (95.9 vs. 76.8%; RR: 1.25; 95% CI: 1.22-1.28). Newer studies were more likely to have a greater number of PIOs (adjusted OR: 1.033 [95% CI: 1.025-1.041] with each publication year). The large and increasing representation of PIOs over the years suggests an improving awareness by neonatal trialists of the need to incorporate important outcomes in order to justify the utilization of resources. Further research should explore the reasons for non-inclusion or non-reporting of PIOs in a small proportion of RCTs.


A Practical Solution for Dyspareunia in Breast Cancer Survivors: A Randomized Controlled Trial.
Dyspareunia is common in breast cancer survivors because of low estrogen. This study explored whether dyspareunia is introital pain, preventable with analgesic liquid. In a randomized, controlled, double-blind trial, estrogen-deficient breast cancer survivors with severe penetrative dyspareunia applied either saline or 4% aqueous lidocaine to the vulvar vestibule for 3 minutes before vaginal penetration. After a 1-month blinded trial of patient-assessed twice-per-week tampon insertion or intercourse, all patients received lidocaine for 2 months in an open-label trial. The primary outcome was patient-related assessment of penetration pain on a scale of zero to 10. Secondary outcomes were sexual distress (Female Sexual Distress Scale), sexual function (Sexual Function Questionnaire), and resumption of intercourse. Comparisons were made with the Mann-Whitney U and Wilcoxon signed rank test with significance set at P < .05. In all, 46 patients, screened to exclude those with pelvic muscle and organ pain, uniformly had clinical evidence of severe vulvovaginal atrophy, dyspareunia (median pain score, 8 of 10; interquartile range [IQR], 7 to 9), increased sexual distress scores (median, 30.5; IQR, 23 to 37; abnormal, > 11), and abnormal sexual function. Users of lidocaine reported less pain during intercourse in the blinded phase (median score of 1.0 compared with saline score of 5.3; P = .007). After open-label lidocaine use, 37 (90%) of 41 reported comfortable penetration. Sexual distress decreased (median score, 14; IQR, 3 to 20; P < .001), and sexual function improved in all but one domain. Of 20 prior abstainers from intercourse who completed the study, 17 (85%) had resumed comfortable penetrative intimacy. No partners reported penile numbness. Breast cancer survivors with menopausal dyspareunia can have comfortable intercourse after applying liquid lidocaine compresses to the vulvar vestibule before penetration.


Specificity, kinetics and longevity of antibody responses to avian influenza A(H7N9) virus infection in humans.
The long-term dynamics of antibody responses in patients with influenza A(H7N9) virus infection are not well understood. We conducted a longitudinal serological follow-up study in patients who were hospitalized with A(H7N9) virus infection, during 2013-2018. A(H7N9) virus-specific antibody responses were assessed by hemagglutination inhibition (HAI) and neutralization (NT) assays. A random intercept model was used to fit a curve to HAI antibody responses over time. HAI antibody responses were compared by clinical severity. Of 67 patients with A(H7N9) virus infection, HAI antibody titers reached 40 on average 11 days after illness onset and peaked at a titer of 290 after three months, and average titers of ≥80 and ≥40 were present until 11 months and 22 months respectively. HAI antibody responses were significantly higher in patients who experienced severe disease, including respiratory failure and acute respiratory distress syndrome, compared with patients who experienced less severe illness. Patients with A(H7N9) virus infection who survived severe disease mounted higher antibody responses that persisted for longer periods compared with those that experienced moderate disease. Studies of convalescent plasma treatment for A(H7N9) patients should consider collection of donor plasma from survivors of severe disease between 1 and 11 months after illness onset.


Primary health care nurses' management practices of common mental health conditions in KwaZulu-Natal, South Africa.
Psychiatric conditions contribute to 13%of the global burden of diseases and account for one third of years lost because of disability (YLD). Despite the high prevalence of mental health problems, primary health care (PHC) services remain ineffective in managing patients with mental health conditions. The aim of the study was to determine the practices of PHC nurses in the management of psychiatric patients in primary health care clinics in one of the rural districts in South Africa. A survey was conducted amongst nurses working in several PHC clinics in KwaZulu-Natal (KZN) in order to determine their practices in the management of psychiatric patients. Mixed methods were used to determine the PHC nurses practices in the management of psychiatric patients. The findings revealed that in five sites (83.3%) treatments are not reviewed every six months, there were no local protocols on the administration of psychiatric emergency drugs, and none of the study sites provided psychiatric patients with education on their medication and its possible side effects. Based on the results of this study it is evident that psychiatric patients at PHC clinics in the district where the study was conducted do not receive quality treatment according to institutional mental health guidelines.


Technical Failure of MR Elastography Examinations of the Liver: Experience from a Large Single-Center Study.
Purpose To assess the determinants of technical failure of magnetic resonance (MR) elastography of the liver in a large single-center study. Materials and Methods This retrospective study was approved by the institutional review board. Seven hundred eighty-one MR elastography examinations performed in 691 consecutive patients (mean age, 58 years; male patients, 434 [62.8%]) in a single center between June 2013 and August 2014 were retrospectively evaluated. MR elastography was performed at 3.0 T (n = 443) or 1.5 T (n = 338) by using a gradient-recalled-echo pulse sequence. MR elastography and anatomic image analysis were performed by two observers. Additional observers measured liver T2* and fat fraction. Technical failure was defined as no pixel value with a confidence index higher than 95% and/or no apparent shear waves imaged. Logistic regression analysis was performed to assess potential predictive factors of technical failure of MR elastography. Results The technical failure rate of MR elastography at 1.5 T was 3.5% (12 of 338), while it was higher, 15.3% (68 of 443), at 3.0 T. On the basis of univariate analysis, body mass index, liver iron deposition, massive ascites, use of 3.0 T, presence of cirrhosis, and alcoholic liver disease were all significantly associated with failure of MR elastography (P < .004); but on the basis of multivariable analysis, only body mass index, liver iron deposition, massive ascites, and use of 3.0 T were significantly associated with failure of MR elastography (P < .004). Conclusion The technical failure rate of MR elastography with a gradient-recalled-echo pulse sequence was low at 1.5 T but substantially higher at 3.0 T. Massive ascites, iron deposition, and high body mass index were additional independent factors associated with failure of MR elastography of the liver with a two-dimensional gradient-recalled-echo pulse sequence. © RSNA, 2017.


Eps15 homology domain 1-associated tubules contain phosphatidylinositol-4-phosphate and phosphatidylinositol-(4,5)-bisphosphate and are required for efficient recycling.
The C-terminal Eps15 homology domain (EHD) 1/receptor-mediated endocytosis-1 protein regulates recycling of proteins and lipids from the recycling compartment to the plasma membrane. Recent studies have provided insight into the mode by which EHD1-associated tubular membranes are generated and the mechanisms by which EHD1 functions. Despite these advances, the physiological function of these striking EHD1-associated tubular membranes remains unknown. Nuclear magnetic resonance spectroscopy demonstrated that the Eps15 homology (EH) domain of EHD1 binds to phosphoinositides, including phosphatidylinositol-4-phosphate. Herein, we identify phosphatidylinositol-4-phosphate as an essential component of EHD1-associated tubules in vivo. Indeed, an EHD1 EH domain mutant (K483E) that associates exclusively with punctate membranes displayed decreased binding to phosphatidylinositol-4-phosphate and other phosphoinositides. Moreover, we provide evidence that although the tubular membranes to which EHD1 associates may be stabilized and/or enhanced by EHD1 expression, these membranes are, at least in part, pre-existing structures. Finally, to underscore the function of EHD1-containing tubules in vivo, we used a small interfering RNA (siRNA)/rescue assay. On transfection, wild-type, tubule-associated, siRNA-resistant EHD1 rescued transferrin and beta1 integrin recycling defects observed in EHD1-depleted cells, whereas expression of the EHD1 K483E mutant did not. We propose that phosphatidylinositol-4-phosphate is an essential component of EHD1-associated tubules that also contain phosphatidylinositol-(4,5)-bisphosphate and that these structures are required for efficient recycling to the plasma membrane.


GLP-1 receptor activation indirectly reduces hepatic lipid accumulation but does not attenuate development of atherosclerosis in diabetic male ApoE(-/-) mice.
Glucagon-like peptide-1 receptor (GLP-1R) agonists reduce lipid accumulation in peripheral tissues, attenuating atherosclerosis and hepatic steatosis in preclinical studies. We examined whether GLP-1R activation decreases atherosclerosis progression in high-fat diet-fed male ApoE(-/-) mice after administration of streptozotocin and treatment with the long-acting GLP-1R agonist taspoglutide administered once monthly vs. metformin in the drinking water for 12 wk. Taspoglutide did not reduce plaque area or lipid content in the aortic arch or abdominal aorta, and no significant change in aortic macrophage accumulation was detected after taspoglutide or metformin. In contrast, hepatic triglyceride levels were significantly reduced in livers from taspoglutide-treated mice. Both peripheral and intracerebroventricular administration of exendin-4 rapidly decreased plasma triglyceride levels in fasted mice, and taspoglutide therapy in ApoE(-/-) mice modulated the expression of hepatic genes controlling fatty acid uptake and oxidation. We were unable to detect expression of the entire Glp1r coding sequence in macrophages isolated from ApoE(-/-), C57BL/6, and IL10(-/-) mice. Similarly, Glp1r mRNA transcripts were not detected in RNA from isolated murine hepatocytes. Using Western blotting and tissue extracts from Glp1r(+/+) and Glp1r(-/-) mice, and cells transfected with a tagged murine GLP-1R cDNA, we could not validate the sensitivity and specificity of three different GLP-1R antisera commonly used for the detection of GLP-1R protein. Taken together, these findings illustrate divergent actions of GLP-1R agonists on atherosclerosis progression and accumulation of ectopic lipid in ApoE(-/-) mice and highlight the importance of indirect GLP-1R actions for the control of hepatic lipid accumulation.


The Complex Emergency Database: a global repository of small-scale surveys on nutrition, health and mortality.
Evidence has become central for humanitarian decision making, as it is now commonly agreed that aid must be provided solely in proportion to the needs and on the basis of needs assessments. Still, reliable epidemiological data from conflict-affected communities are difficult to acquire in time for effective decisions, as existing health information systems progressively lose functionality with the onset of conflicts. In the last decade, health and nutrition humanitarian agencies have made substantial progress in collecting quality data using small-scale surveys. In 2002, a group of academics, non-governmental organizations, and UN agencies launched the Standardized Monitoring and Assessment of Relief and Transitions (SMART) methodology. Since then, field agencies have conducted thousands of surveys. Although the contribution of each survey by itself is limited by its small sample and the impossibility to extrapolate results to national level, their aggregation can provide a more stable view of both trends and distributions in a larger region. The Complex Emergency Database (CEDAT) was set up in order to make best use of the collective force of these surveys. Functioning as a central repository, it can provide valuable information on trends and patterns of mortality and nutrition indicators from conflict-affected communities. Given their high spatial resolution and their high frequency, CEDAT data can complement official statistics in between nationwide surveys. They also provide information of the displacement status of the measured population, pointing out vulnerabilities. CEDAT is hosted at the Centre for Research on the Epidemiology of Disasters, University of Louvain. It runs on voluntary agreements between the survey implementer and the CEDAT team. To date, it contains 3309 surveys from 51 countries, and is a unique repository of such data.


Altered glycolysis triggers impaired mitochondrial metabolism and mTORC1 activation in diabetic β-cells.
Chronic hyperglycaemia causes a dramatic decrease in mitochondrial metabolism and insulin content in pancreatic β-cells. This underlies the progressive decline in β-cell function in diabetes. However, the molecular mechanisms by which hyperglycaemia produces these effects remain unresolved. Using isolated islets and INS-1 cells, we show here that one or more glycolytic metabolites downstream of phosphofructokinase and upstream of GAPDH mediates the effects of chronic hyperglycemia. This metabolite stimulates marked upregulation of mTORC1 and concomitant downregulation of AMPK. Increased mTORC1 activity causes inhibition of pyruvate dehydrogenase which reduces pyruvate entry into the tricarboxylic acid cycle and partially accounts for the hyperglycaemia-induced reduction in oxidative phosphorylation and insulin secretion. In addition, hyperglycaemia (or diabetes) dramatically inhibits GAPDH activity, thereby impairing glucose metabolism. Our data also reveal that restricting glucose metabolism during hyperglycaemia prevents these changes and thus may be of therapeutic benefit. In summary, we have identified a pathway by which chronic hyperglycaemia reduces β-cell function.


No glucotoxicity after 53 hours of 6.0 mmol/l hyperglycaemia in normal man.
In vitro and in vivo studies have suggested that metabolic deterioration can be induced by hyperglycaemia per se. The effect of 53 h of 2.2 mg glucose.kg ideal body weight-1.min-1 was examined in four normal male subjects. This produced overnight hyperglycaemia of 6.0 mmol/l on the two nights of the study compared with 4.7 mmol/l on the control night (p less than 0.05). In response there was a sustained, two-fold increase in basal plasma insulin (p less than 0.005) and C-peptide (p less than 0.05) levels. After two days of hyperglycaemia an increased Beta-cell response was demonstrated in response to an additional glucose infusion stimulus (estimated Beta-cell function median of 84% on the control day to 100% after two days glucose infusion). Plasma insulin and C-peptide responses to a 10.0 mmol/l hyperglycaemic clamp increased over the two days of the study (insulin from median 48 mU/l to 73 mU/l and C-peptide from median 2.0 pmol/ml to 2.6 pmol/l). Glucose tolerance to the additional glucose infusion stimulus improved, suggesting that the increased insulin response during hyperglycaemia was enhancing peripheral glucose uptake. The calculated peripheral insulin sensitivity was unchanged during the hyperglycaemic clamp. Thus, in response to the two days of basal hyperglycaemia, both the basal and stimulated Beta-cell responses were enhanced and there was no evidence for 'glucose toxicity' to the Beta-cells.


Icatibant for Multiple Hereditary Angioedema Attacks across the Controlled and Open-Label Extension Phases of FAST-3.
In randomized, controlled, double-blind, multicenter phase 3 studies, one icatibant injection was efficacious and generally well tolerated in patients with a single hereditary angioedema (HAE) attack. Here, the efficacy and safety of icatibant for multiple HAE attacks was evaluated across the controlled and open-label extension phases of the For Angioedema Subcutaneous Treatment (FAST)-3 study (NCT00912093). In the controlled phase, adults with HAE type I or II were randomized (1:1) to receive a single subcutaneous injection of icatibant 30 mg or placebo within 6 h of an attack becoming mild (laryngeal) or moderate (cutaneous/abdominal). Open-label icatibant was administered for severe laryngeal symptoms. In the open-label extension phase, patients could receive up to three icatibant injections per attack. Efficacy and safety were analyzed for the first five icatibant-treated attacks at any location (prospective analysis) and laryngeal attacks (post hoc analysis) across both phases. Efficacy outcomes were based on patient-reported symptom severity (visual analog scale). In groups of patients with one to five icatibant-treated attacks at any location (n = 88), the median times to onset of symptom relief, onset of primary symptom relief and almost complete symptom relief were 1.9-2.1, 1.5-2.0 and 3.5-19.7 h, respectively. The same outcomes for laryngeal attacks (n = 25) were 1.0-2.0, 1.0-2.0 and 1.5-8.1 h, respectively. The most frequently reported adverse events were a worsening or recurrence of HAE attack, headache and nasopharyngitis. Two serious adverse events (arrhythmia and noncardiac chest pain) were considered to be related to icatibant. Icatibant was efficacious and generally well tolerated across multiple HAE attacks, including laryngeal attacks.


A clinical comparison of pain perception and extent of area anesthetized by Wand(®) and a traditional syringe.
In the contemporary dental practice, alleviation of pain is the most important factor to ameliorate patient's condition and to gain one's confidence towards the skills of the operator. Such confidence aids to the ultimate success of the treatment procedures. This study compares the pain response of a group of 10 subjects to the Wand(®) with the response to traditional syringe injections and also compares the extent of the area anesthetized. 10 subjects were selected for the study and 20 injections were given contralaterally to them, 10 with Wand(®), and rest with the traditional aspirating syringe. Each subject received 2 injections on the palate, Left side with Wand(®) (test) and Right side with Traditional syringe (control). All injections were given by the same investigator without the use of topical anesthetic spray/gel. Pain perception levels were recorded with a visual analogue scale. Also the extent of area anesthetized with a single palatal injection was assessed by probing. The results showed injections with the syringe were more painful than injections with the Wand(®) in 2 of 10 subjects. Also the extent of the area anesthetized by both the techniques was similar except in 2 patients. The Wand(®) results in less painful injections; however, mean ratings of pain for both the groups, were mostly below the annoying level of pain. Also, the areas covered by the anesthetic effect of both the injections were comparatively similar.