Development and homeostasis of "resident" myeloid cells: the case of the microglia.
Microglia, macrophages of the central nervous system, play an important role in brain homeostasis. Their origin has been unclear. Recent fate-mapping experiments have established that microglia mostly originate from Myb-independent, FLT3-independent, but PU.1-dependent precursors that express the CSF1-receptor at E8.5 of embryonic development. These precursors are presumably located in the yolk sac (YS) at this time before invading the embryo between E9.5 and E10.5 and colonizing the fetal liver. Indeed, the E14.5 fetal liver contains a large population of Myb-independent YS-derived myeloid cells. This myeloid lineage is distinct from hematopoietic stem cells (HSCs), which require the transcription factor Myb for their development and maintenance. This "yolky" beginning and the independence from conventional HSCs are not unique to microglia. Indeed, several other populations of F4/80-positive macrophages develop also from YS Myb-independent precursors, such as Kupffer cells in the liver, Langerhans cells in the epidermis, and macrophages in the spleen, kidney, pancreas, and lung. Importantly, microglia and the other Myb-independent macrophages persist, at least in part, in adult mice and likely self-renew within their respective tissues of residence, independently of bone marrow HSCs. This suggests the existence of tissue resident macrophage "stem cells" within tissues such as the brain, and opens a new era for the molecular and cellular understanding of myeloid cells responses during acute and chronic inflammation.


Performance Against WELCOA's Worksite Health Promotion Benchmarks Across Years Among Selected US Organizations.
The purpose of this study was to quantify the performance of organizations' worksite health promotion (WHP) activities against the benchmarking criteria included in the Well Workplace Checklist (WWC). The Wellness Council of America (WELCOA) developed a tool to assess WHP with its 100-item WWC, which represents WELCOA's 7 performance benchmarks. Workplaces. This study includes a convenience sample of organizations who completed the checklist from 2008 to 2015. The sample size was 4643 entries from US organizations. The WWC includes demographic questions, general questions about WHP programs, and scales to measure the performance against the WELCOA 7 benchmarks. Descriptive analyses of WWC items were completed separately for each year of the study period. The majority of the organizations represented each year were multisite, multishift, medium- to large-sized companies mostly in the services industry. Despite yearly changes in participating organizations, results across the WELCOA 7 benchmark scores were consistent year to year. Across all years, benchmarks that organizations performed the lowest were senior-level support, data collection, and programming; wellness teams and supportive environments were the highest scoring benchmarks. In an era marked with economic swings and health-care reform, it appears that organizations are staying consistent in their performance across these benchmarks. The WWC could be useful for organizations, practitioners, and researchers in assessing the quality of WHP programs.


Maternal dietary patterns during early pregnancy and the odds of childhood germ cell tumors: A Children's Oncology Group study.
Maternal diet during pregnancy may be associated with cancer in offspring. Intake of individual foods, as well as dietary patterns, can be used when examining these relations. Here, the authors examined associations between maternal dietary intake patterns and pediatric germ cell tumors (GCTs) using principal components analysis and logistic regression. Mothers of 222 GCT cases aged less than 15 years who were diagnosed at a Children's Oncology Group institution between 1993 and 2001 and those of 336 frequency-matched controls completed a self-administered food frequency questionnaire of diet during early pregnancy. Four dietary patterns were identified: "Western," "fruits and vegetables," "protein," and "healthful." With adjustment for birth weight, parity, and vitamin use, the fruits and vegetables pattern was significantly associated with a lower odds for GCTs (odds ratio (OR) = 0.83, 95% confidence interval (CI): 0.69, 0.99; 2 sided). Upon stratification, the fruits and vegetables pattern was significantly associated with a lower odds in males (OR = 0.66, 95% CI: 0.47, 0.92) but not females (OR = 0.91, 95% CI: 0.72, 1.14). A quantitative assessment of assumed nondifferential reporting error indicated no notable deviations from unadjusted odds ratio estimates. Results of this exploratory analysis suggest that maternal prenatal dietary patterns could be considered in future studies of GCTs in offspring.


Tranexamic acid to reduce head injury death in people with traumatic brain injury: the CRASH-3 international RCT.
Tranexamic acid safely reduces mortality in traumatic extracranial bleeding. Intracranial bleeding is common after traumatic brain injury and can cause brain herniation and death. We assessed the effects of tranexamic acid in traumatic brain injury patients. To assess the effects of tranexamic acid on death, disability and vascular occlusive events in traumatic brain injury patients. We also assessed cost-effectiveness. Randomised trial and economic evaluation. Patients were assigned by selecting a numbered treatment pack from a box containing eight packs that were identical apart from the pack number. Patients, caregivers and those assessing outcomes were masked to allocation. All analyses were by intention to treat. We assessed the cost-effectiveness of tranexamic acid versus no treatment from a UK NHS perspective using the trial results and a Markov model. 175 hospitals in 29 countries. Adults with traumatic brain injury within 3 hours of injury with a Glasgow Coma Scale score of ≤ 12 or any intracranial bleeding on computerised tomography scan, and no major extracranial bleeding, were eligible. Tranexamic acid (loading dose 1 g over 10 minutes then infusion of 1 g over 8 hours) or matching placebo. Head injury death in hospital within 28 days of injury in patients treated within 3 hours of injury. Secondary outcomes were early head injury deaths, all-cause and cause-specific mortality, disability, vascular occlusive events, seizures, complications and adverse events. Among patients treated within 3 hours of injury (n = 9127), the risk of head injury death was 18.5% in the tranexamic acid group versus 19.8% in the placebo group (855/4613 vs. 892/4514; risk ratio 0.94, 95% confidence interval 0.86 to 1.02). In a prespecified analysis excluding patients with a Glasgow Coma Scale score of 3 or bilateral unreactive pupils at baseline, the results were 12.5% in the tranexamic acid group versus 14.0% in the placebo group (485/3880 vs. 525/3757; risk ratio 0.89, 95% confidence interval 0.80 to 1.00). There was a reduction in the risk of head injury death with tranexamic acid in those with mild to moderate head injury (166/2846 vs. 207/2769; risk ratio 0.78, 95% confidence interval 0.64 to 0.95), but in those with severe head injury (689/1739 vs. 685/1710; risk ratio 0.99, 95% confidence interval 0.91 to 1.07) there was no apparent reduction (p-value for heterogeneity = 0.030). Early treatment was more effective in mild and moderate head injury (p = 0.005), but there was no obvious impact of time to treatment in cases of severe head injury (p = 0.73). The risk of disability, vascular occlusive events and seizures was similar in both groups. Tranexamic acid is highly cost-effective for mild and moderate traumatic brain injury (base case of £4288 per quality-adjusted life-year gained). Early tranexamic acid treatment reduces head injury deaths. Treatment is cost-effective for patients with mild or moderate traumatic brain injury, or those with both pupils reactive. Further trials should examine early tranexamic acid treatment in mild head injury. Research on alternative routes of administration is needed. Time to treatment may have been underestimated. Current Controlled Trials ISRCTN15088122, ClinicalTrials.gov NCT01402882, EudraCT 2011-003669-14, Pan African Clinical Trial Registry PACTR20121000441277. The project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 26. See the NIHR Journals Library website for further project information. In addition, funding was provided by JP Moulton Charitable Trust, Joint Global Health Trials (Medical Research Council, Department for International Development and the Wellcome Trust). This project was funded by the NIHR Global Health Trials programme.


Modeling of arylamide helix mimetics in the p53 peptide binding site of hDM2 suggests parallel and anti-parallel conformations are both stable.
The design of novel α-helix mimetic inhibitors of protein-protein interactions is of interest to pharmaceuticals and chemical genetics researchers as these inhibitors provide a chemical scaffold presenting side chains in the same geometry as an α-helix. This conformational arrangement allows the design of high affinity inhibitors mimicking known peptide sequences binding specific protein substrates. We show that GAFF and AutoDock potentials do not properly capture the conformational preferences of α-helix mimetics based on arylamide oligomers and identify alternate parameters matching solution NMR data and suitable for molecular dynamics simulation of arylamide compounds. Results from both docking and molecular dynamics simulations are consistent with the arylamides binding in the p53 peptide binding pocket. Simulations of arylamides in the p53 binding pocket of hDM2 are consistent with binding, exhibiting similar structural dynamics in the pocket as simulations of known hDM2 binders Nutlin-2 and a benzodiazepinedione compound. Arylamide conformations converge towards the same region of the binding pocket on the 20 ns time scale, and most, though not all dihedrals in the binding pocket are well sampled on this timescale. We show that there are two putative classes of binding modes for arylamide compounds supported equally by the modeling evidence. In the first, the arylamide compound lies parallel to the observed p53 helix. In the second class, not previously identified or proposed, the arylamide compound lies anti-parallel to the p53 helix.


Induction and maintenance of bi-functional (IFN-γ + IL-2+ and IL-2+ TNF-α+) T cell responses by DNA prime MVA boosted subtype C prophylactic vaccine tested in a Phase I trial in India.
Effective vaccine design relies on accurate knowledge of protection against a pathogen, so as to be able to induce relevant and effective protective responses against it. An ideal Human Immunodeficiency virus (HIV) vaccine should induce humoral as well as cellular immune responses to prevent initial infection of host cells or limit early events of viral dissemination. A Phase I HIV-1 prophylactic vaccine trial sponsored by the International AIDS Vaccine Initiative (IAVI) was conducted in India in 2009.The trial tested a HIV-1 subtype C vaccine in a prime-boost regimen, comprising of a DNA prime (ADVAX) and Modified Vaccine Ankara (MVA) (TBC-M4) boost. The trial reported that the vaccine regimen was safe, well tolerated, and resulted in enhancement of HIV-specific immune responses. However, preliminary immunological studies were limited to vaccine-induced IFN-γ responses against the Env and Gag peptides. The present study is a retrospective study to characterize in detail the nature of the vaccine-induced cell mediated immune responses among volunteers, using Peripheral Blood Mononuclear Cells (PBMC) that were archived during the trial. ELISpot was used to measure IFN-γ responses and polyfunctional T cells were analyzed by intracellular multicolor flow cytometry. It was observed that DNA priming and MVA boosting induced Env and Gag specific bi-functional and multi-functional CD4+ and CD8+ T cells expressing IFN-γ, TNF-α and IL-2. The heterologous prime-boost regimen appeared to be slightly superior to the homologous prime-boost regimen in inducing favorable cell mediated immune responses. These results suggest that an in-depth analysis of vaccine-induced cellular immune response can aid in the identification of correlates of an effective immunogenic response, and inform future design of HIV vaccines.


Easy and efficient bonding of biomolecules to an oxide surface of silicon.
A new method is described to attach biological molecules to the surface of silicon. Semiconductors such as Si modified with surface-bound capture molecules have enormous potential for use in biosensors for which an ideal detection platform should be inexpensive, recognize targets rapidly with high sensitivity and specificity, and possess superior stability. In this process, a self-assembled film of an organophosphonic acid is bonded to the native or synthesized oxide-coated Si surface as a film of the correspondingphosphonate. The phosphonate film is functionalized to enable covalently coupling biological molecules, ranging in size from small peptides to large multi-subunit proteins, to the Si surface. Surface modification and biomolecule coupling procedures are easily accomplished: all reactions can proceed in air, and most take place under ambient conditions. The biomolecule-modified surfaces are stable under physiological conditions, are selective for adhesion of specific cells types, and are reusable.


Nm23-H1 expression of metastatic tumors in the lymph nodes is a prognostic indicator of oral squamous cell carcinoma.
We recently reported that low Nm23-H1 expression of primary oral squamous cell carcinoma (OSCC) was correlated with the occurrence of lymphatic metastasis. However, little is known about whether Nm23-H1 level of metastatic tumors in the cervical lymph nodes is reduced in comparison with primary oral cancers and its significance for patients' prognosis. By immunohistochemistry, we analyzed the Nm23-H1 expression in 52 pairs of OSCC specimens from primary oral cancers and their metastatic lymph nodes. Western blot analysis further confirmed the immunohistochemical interpretation. To verify the effects of Nm23-H1 on cell migration and invasion, we established several stable clones derived from a human OSCC cell line (SAS) by knockdown and overexpression. Wound-healing closure, transwell migration and invasion assays were performed to determine cell motility, migratory and invasive activities. Western blot analysis was carried out to evaluate cyclin A expression of OSCC cells with the altered Nm23-H1 levels following knockdown and overexpression. By immunohistochemistry, Nm23-H1 expression of metastatic lymph nodes was significantly lower than that of their primary oral cancers, supporting a role of Nm23-H1 in metastasis suppression. Negative Nm23-H1 interpretation of OSCC specimens, in either primary oral cancers or metastatic lymph nodes, indicated a poor survival outcome of patients. On the basis of in vitro studies of Nm23-H1 knockdown and overexpression, we demonstrated an inverse correlation between Nm23-H1 expression and the invasiveness of OSCC cells. Moreover, we observed the concomitant reduction in Nm23-H1 and cyclin A levels of metastatic tumors in both results of in vitro OSCC cells and ex vivo tumor specimens.


Functional organization of crayfish abdominal ganglia: II. Sensory afferents and extensor motor neurons.
Abdominal ganglia of crayfish contain identifiable neuropils, commissures, longitudinal tracts, and vertical tracts. To determine the functional significance of this ganglionic framework, we backfilled the following types of neurons with cobalt chloride: sensory hair afferents, slow and fast extensor motor neurons, the segmental stretch receptor neurons, and their inhibitory accessory cells. After the cobalt ions were precipitated and intensified, we studied the central projections of the filled neurons within the ganglionic structures. All of the axons of these neurons exit or enter each of the first five abdominal ganglia through the second pair of nerves. Our description of the central projections of the hair afferents is the first in the literature. These afferents innervate the large ventral horseshoe neuropil (HN) in the core of each ganglion. This neuropil is homologous to the insect ventral association centers, which also process sensory information. Furthermore, we discovered that some of the crayfish afferents innervate glomeruli within the HN. The slow and fast extensor motor neurons, the stretch receptor neurons, and the accessory cells branch mostly in the dorsal part of the ganglion. We reinterpret previous identifications of the extensor neurons that were based largely on soma position. Together with our previous descriptions of the flexor motor neurons, these results allow us to relate both rapid tail-flips and slower postural movements to the structure of the segmental ganglia.


Feasibility of a randomized single-blind crossover trial to assess the effects of the second-generation slow-release dopamine agonists pramipexole and ropinirole on cued recall memory in idiopathic mild or moderate Parkinson's disease without cognitive impairment.
The aim was to assess the feasibility of a single-centre, single-blind, randomized, crossover design to explore the effects of two slow-release dopamine agonists, ropinirole and pramipexole, on cued recall in Parkinson's disease. As the design required a switch from the prescribed agonist (pramipexole-to-ropinirole, or ropinirole-to-pramipexole), the primary objectives were to (a) examine the efficacy of processes and procedures used to manage symptoms during the washout period and (b) to use cued recall estimates to inform a power calculation for a definitive trial. Secondary objectives were to assess consent and missing data rates, acceptability of clinical support for the OFF sessions, experience of the OFF sessions and of agonist switching, barriers-to-participation for patients and informal caregivers. Patients were randomized in a 1:1 ratio to two treatment arms and stabilized on each agonist for 6 weeks. The arms differed only in the sequence in which the agonists were administered. Cued recall was assessed ON medication and, following a washout period resulting in 93.75% agonist elimination, OFF medication. A total of 220 patients were screened: 145 were excluded and 75 invitations to participate were sent to eligible patients. Fifty-three patients declined, 22 consented and 16 completed the study. There were no serious adverse events, and rates of non-serious adverse events were equivalent between the agonists. Using the largest standard deviation (SD) of the ON-OFF difference cued recall score (inflated by ~25% to give a conservative estimate of the SD in a definitive trial) and assuming an effect of at least 10% of the observed range of OFF medication cued recall scores for either agonist to be clinically important, a main trial requires a sample size of just under 150 patients. The consent and missing data rates were 29 and 27% respectively. The washout period and the preparation for the OFF sessions were acceptable, and the sessions were manageable. The experience of switching was also manageable. Barriers to participation included concerns about disease stability, side effects, research process, carer workload and accessibility of the information sheet. This study presented challenges to recruitment both in design and execution, and while it was a major aim of the study to assess this, evaluation of these challenges provided the opportunity to explore how they could be overcome for future studies. EudraCT 2012-000801-64.


Mathematical model of real-time PCR kinetics.
Several real-time PCR (rtPCR) quantification techniques are currently used to determine the expression levels of individual genes from rtPCR data in the form of fluorescence intensities. In most of these quantification techniques, it is assumed that the efficiency of rtPCR is constant. Our analysis of rtPCR data shows, however, that even during the exponential phase of rtPCR, the efficiency of the reaction is not constant, but is instead a function of cycle number. In order to understand better the mechanisms belying this behavior, we have developed a mathematical model of the annealing and extension phases of the PCR process. Using the model, we can simulate the PCR process over a series of reaction cycles. The model thus allows us to predict the efficiency of rtPCR at any cycle number, given a set of initial conditions and parameter values, which can mostly be estimated from biophysical data. The model predicts a precipitous decrease in cycle efficiency when the product concentration reaches a sufficient level for template-template re-annealing to compete with primer-template annealing; this behavior is consistent with available experimental data. The quantitative understanding of rtPCR provided by this model can allow us to develop more accurate methods to quantify gene expression levels from rtPCR data.


Self-Consistent Scheme for Spike-Train Power Spectra in Heterogeneous Sparse Networks.
Recurrent networks of spiking neurons can be in an asynchronous state characterized by low or absent cross-correlations and spike statistics which resemble those of cortical neurons. Although spatial correlations are negligible in this state, neurons can show pronounced temporal correlations in their spike trains that can be quantified by the autocorrelation function or the spike-train power spectrum. Depending on cellular and network parameters, correlations display diverse patterns (ranging from simple refractory-period effects and stochastic oscillations to slow fluctuations) and it is generally not well-understood how these dependencies come about. Previous work has explored how the single-cell correlations in a homogeneous network (excitatory and inhibitory integrate-and-fire neurons with nearly balanced mean recurrent input) can be determined numerically from an iterative single-neuron simulation. Such a scheme is based on the fact that every neuron is driven by the network noise (i.e., the input currents from all its presynaptic partners) but also contributes to the network noise, leading to a self-consistency condition for the input and output spectra. Here we first extend this scheme to homogeneous networks with strong recurrent inhibition and a synaptic filter, in which instabilities of the previous scheme are avoided by an averaging procedure. We then extend the scheme to heterogeneous networks in which (i) different neural subpopulations (e.g., excitatory and inhibitory neurons) have different cellular or connectivity parameters; (ii) the number and strength of the input connections are random (Erdős-Rényi topology) and thus different among neurons. In all heterogeneous cases, neurons are lumped in different classes each of which is represented by a single neuron in the iterative scheme; in addition, we make a Gaussian approximation of the input current to the neuron. These approximations seem to be justified over a broad range of parameters as indicated by comparison with simulation results of large recurrent networks. Our method can help to elucidate how network heterogeneity shapes the asynchronous state in recurrent neural networks.


Indirect protection of adults from rotavirus by pediatric rotavirus vaccination.
Pediatric vaccination has resulted in declines in disease in unvaccinated individuals through decreasing pathogen circulation in the community. About 2 years after implementation of pediatric rotavirus vaccination in the United States, dramatic declines in rotavirus disease were observed in both vaccinated and unvaccinated children. Whether this protection extends to adults is unknown. The prevalence of rotavirus, as determined by Rotaclone enzyme immunoassay, in adults who had stools submitted for bacterial stool culture (BSC) between February to May to Northwestern Memorial Hospital, Chicago, was compared between the prepediatric impact era (2006-2007) and the pediatric impact era (2008-2010). Isolates were genotyped and clinical characteristics of those with rotavirus were compared. Of the 5788 BSC sent, 4725 met inclusion criteria and 3530 of these (74.7%) were saved for rotavirus testing. The prevalence of rotavirus among adults who had stool sent for BSC declined from 4.35% in 2006-2007 to 2.24% in 2008-2010 (a relative decline of 48.4%; P = .0007). The decline in the prevalence of rotavirus was of similar significant magnitude in both outpatients and inpatients. Marked year-to-year variability was observed in circulating rotavirus genotypes, with strain G2P[4] accounting for 24%; G1P[8], 22%; G3P[8], 11%; and G12P[6], 10% overall. About 30% of adults from whom rotavirus was isolated were immunocompromised and this remained constant. Pediatric rotavirus vaccination correlated with a relative decline of almost 50% in rotavirus identified from adult BSC during the peak rotavirus season, suggesting that pediatric rotavirus vaccination protects adults from rotavirus.


Robust estimation of quantitative perfusion from multi-phase pseudo-continuous arterial spin labeling.
Multi-phase PCASL has been proposed as a means to achieve accurate perfusion quantification that is robust to imperfect shim in the labeling plane. However, there exists a bias in the estimation process that is a function of noise in the data. In this work, this bias is characterized and then addressed in animal and human data. The proposed algorithm to overcome bias uses the initial biased voxel-wise estimate of phase tracking error to cluster regions with different off-resonance phase shifts, from which a high-SNR estimate of regional phase offset is derived. Simulations were used to predict the bias expected at typical SNR. Multi-phase PCASL in 3 rat strains (n = 21) at 9.4 T was considered, along with 20 human subjects previously imaged using ASL at 3 T. The algorithm was extended to include estimation of arterial blood flow velocity. Based on simulations, a perfusion estimation bias of 6-8% was expected using 8-phase data at typical SNR. This bias was eliminated when a high-precision estimate of phase error was available. In the preclinical data, the bias-corrected measure of perfusion (107 ± 14 mL/100g/min) was lower than the standard analysis (116 ± 14 mL/100g/min), corresponding to a mean observed bias across strains of 8.0%. In the human data, bias correction resulted in a 15% decrease in the estimate of perfusion. Using a retrospective algorithmic approach, it was possible to exploit common information found in multiple voxels within a whole region of the brain, offering superior SNR and thus overcoming the bias in perfusion quantification from multi-phase PCASL.


A simplified predictive index for the detection of women at risk for postnatal depression.
Many women who suffer from postnatal depression are never diagnosed or treated. The objective of this study was to develop an index for use in maternity settings that identifies women who may be at risk for postnatal depression. Women (n = 1762) attending the "booking-in" clinic were screened for antenatal risk factors for postnatal depression. On the third postnatal day eligible women were screened for postnatal risk factors. The Edinburgh Postnatal Depression Scale was mailed to participants 16 weeks after the birth. A predictive index was developed, based on the mean Edinburgh Postnatal Depression Scale scores for each risk factor. The sensitivity, specificity, positive predictive value, and negative predictive value were used to assess the diagnostic value of the index. Seven hundred and twenty-three (50.1%) of the eligible women completed all phases of the study. Of this group, 93 (12.2%) women scored higher than 12 on the Edinburgh Postnatal Depression Scale. At a cutoff of 6, the index had positive predictive value of 39.8 percent for postnatal depression, a threefold improvement over the base rate. The Brisbane Postnatal Depression Index provides a clinically useful method for identifying women at risk for developing postnatal depression. It has applications for early intervention or to identify high-risk groups for research purposes.


The long arm of childhood: the influence of early-life social conditions on men's mortality.
Increasingly, social scientists are turning to childhood to gain a better understanding of the fundamental social causes of adult mortality. However, evidence of the link between childhood and the mortality of adults is fragmentary, and the intervening mechanisms remain unclear. Drawing on the National Longitudinal Survey of Older Men, our analysis shows that men's mortality is associated with an array of childhood conditions, including socioeconomic status, family living arrangements, mother's work status, rural residence, and parents' nativity. With the exception of parental nativity, socioeconomic-achievement processes in adulthood and lifestyle factors mediated these associations. Education, family income, household wealth, and occupation mediated the influence of socioeconomic status in childhood. Adult lifestyle factors, particularly body mass, mediated the effects of family living arrangements in childhood, mother's work status, and rural residence. Our findings bring into sharp focus the idea that economic and educational policies that are targeted at children's well-being are implicitly health policies with effects that reach far into the adult life course.


Localization of human herpesvirus type 8 in human sperms by in situ PCR.
Defining the mechanism of infection with human herpesvirus-8 (HHV-8) or Kaposi's sarcoma associated herpesvirus (KSHV) is an important clinical issue. HHV-8 has been linked to Kaposi's sarcoma (KS) development in HIV-1-infected individuals, and KS develops in 40% of those infected with both viruses. A series of epidemiological data suggest that sexual transmission is one of the routes of transmission for HHV-8. In our studies, we sought to assess the cellular reservoirs of HHV-8 DNA in the semen of HIV-1-infected men and the potential role of HHV-8 infected spermatozoa in horizontal transmission. A nested polymerase chain reaction (PCR), in situ PCR (ISPCR) and a sodium iodide (NaI) DNA isolation technique that extracts both nuclear and episomal DNA were utilized to amplify specific genes in vitro and within intact cells to evaluate the types of seminal cells infected with HHV-8 in HIV-1-infected and uninfected men. HHV-8 was present in the spermatozoa and mononuclear cells of the semen in 64 of 73 (88%) HIV-1 infected individuals. Both the sperms as well as the mononuclear cells of the semen specimens of HIV-1 infected men were found to be infected with HHV-8. Multiplex ISPCR revealed that a significantly higher percentage of semen cells were infected with HHV-8 than HIV-1 (p>0.001). Rare (less than one in a 100,000) sperm cells were co-infected with both viruses. A co-culture of HHV-8 infected sperm with uninfected 293 or Sup-T1 cell lines resulted in an abortive infection of these cells with HHV-8. DNA isolation by NaI yielded 73% of the positive sperm, whereas the standard phenol/chloroform method resulted in significantly lower positives (45%) from the same specimens. Design and methods: Our data strongly suggest a potential sexual/horizontal route of transmission of HHV-8, via the HHV-8 infected sperm and other semen cells, where a large percentage of HIV-1 infected men's sperm and other semen cells are infected with HHV-8. Co-culture studies have further supported the observations that HHV-8 in the sperm cells is infectious and capable of transmission of the virus to uninfected cells.


A realist synthesis of effective continuing professional development (CPD): A case study of healthcare practitioners' CPD.
Continuing professional development (CPD) in healthcare is fundamental for making sure frontline staff practice safely and effectively. This requires practitioners to update knowledge and skills regularly to match the changing complexity of healthcare needs. The drive towards using limited resources effectively for service improvements and the need for a flexible workforce necessitate a review of ad hoc approaches to CPD. To develop strategies for achieving effective CPD in healthcare. A case study design drawing on principles of realist synthesis was used during two phases of the study to identify and test what works and in what circumstances. One National Health Service Trust in South East England. CPD stakeholders including professional regulatory bodies (n = 8), commissioners of healthcare (n = 15), facilitators of clinical skills development (n = 34), NHS staff in clinical leadership positions (n = 38), NHS staff undertaking skills development post graduate programs (n = 31), service user advocates (n = 8) and an international expert reference group (ERG) (n = 10). Data sources included a review of scholarly and grey literature, an online survey and a consensus workshop. Thematic and content analyses were used during data processing. The findings present four interdependent transformation theories comprising transforming individual practice, skills for the changing healthcare contexts, knowledge translation and workplace cultures to optimize learning, development and healthcare performance. The transformation theories contextualize CPD drivers and identify conditions conducive for effective CPD. Practitioner driven CPD in healthcare is effective within supportive organizations, facilitated workplace learning and effective workplace cultures. Organizations and teams with shared values and purpose enable active generation of knowledge from practice and the use of different types of knowledge for service improvements.


Just drop it and run: the effect of limb autotomy on running distance and locomotion energetics of field crickets (Gryllus bimaculatus).
This is the first study to examine the direct metabolic costs of autotomy, the voluntary shedding of an appendage as an escape mechanism, in invertebrates. We investigated the effects of limb autotomy upon endurance and metabolic cost of locomotion in the field cricket Gryllus bimaculatus. Compared with control (intact) crickets, animals that had autotomised a single hindlimb were slower, stopped more often, moved a shorter distance and expended more energy doing so. Both the cost of locomotion (COT) and minimal cost of locomotion (MCOT) were significantly higher for autotomised animals. We compare these data with locomotion energetics of 36 other invertebrate species, and discuss the results in terms of the biomechanics of walking in crickets.


Does predation maintain eyespot plasticity in Bicyclus anynana?
The butterfly Bicyclus anynana exhibits phenotypic plasticity involving the wet-season phenotype, which possesses marginal eyespots on the ventral surface of the wings, and the dry-season form, which lacks these eyespots. We examined the adaptive value of phenotypic plasticity of B. anynana in relation to the defence mechanisms of crypsis and deflection. We assessed the visibility differences between spotless and spotted butterflies against backgrounds of brown (dry season) or green (wet season) leaves. Spotless butterflies were highly cryptic and less predated by adult bird predators than were spotted ones when presented against brown leaf litter. However, the advantage of crypsis disappeared in the wet-season habitat as both forms were equally visible. In later experiments, naive birds presented with resting butterflies in the wet-season habitat tended to learn more rapidly to capture spotless butterflies, suggesting a slight selective advantage of possessing eyespots. Moreover, marginal eyespots increased significantly the escape probability of butterflies that were attacked by naive birds compared to those attacked by adult birds, although there were no differences in prey capture success within naive predators. Our results show that natural selection acts against eyespots in the dry season, favouring crypsis, whereas in the wet season it may favour eyespots as deflective patterns.


Breastfeeding and maternal and infant health outcomes in developed countries.
We reviewed the evidence on the effects of breastfeeding on short- and long-term infant and maternal health outcomes in developed countries. We searched MEDLINE(R), CINAHL, and the Cochrane Library in November of 2005. Supplemental searches on selected outcomes were searched through May of 2006. We also identified additional studies in bibliographies of selected reviews and by suggestions from technical experts. We included systematic reviews/meta-analyses, randomized and non-randomized comparative trials, prospective cohort, and case-control studies on the effects of breastfeeding and relevant outcomes published in the English language. Included studies must have a comparative arm of formula feeding or different durations of breastfeeding. Only studies conducted in developed countries were included in the updates of previous systematic reviews. The studies were graded for methodological quality. We screened over 9,000 abstracts. Forty-three primary studies on infant health outcomes, 43 primary studies on maternal health outcomes, and 29 systematic reviews or meta-analyses that covered approximately 400 individual studies were included in this review. We found that a history of breastfeeding was associated with a reduction in the risk of acute otitis media, non-specific gastroenteritis, severe lower respiratory tract infections, atopic dermatitis, asthma (young children), obesity, type 1 and 2 diabetes, childhood leukemia, sudden infant death syndrome (SIDS), and necrotizing enterocolitis. There was no relationship between breastfeeding in term infants and cognitive performance. The relationship between breastfeeding and cardiovascular diseases was unclear. Similarly, it was also unclear concerning the relationship between breastfeeding and infant mortality in developed countries. For maternal outcomes, a history of lactation was associated with a reduced risk of type 2 diabetes, breast, and ovarian cancer. Early cessation of breastfeeding or not breastfeeding was associated with an increased risk of maternal postpartum depression. There was no relationship between a history of lactation and the risk of osteoporosis. The effect of breastfeeding in mothers on return-to-pre-pregnancy weight was negligible, and the effect of breastfeeding on postpartum weight loss was unclear. A history of breastfeeding is associated with a reduced risk of many diseases in infants and mothers from developed countries. Because almost all the data in this review were gathered from observational studies, one should not infer causality based on these findings. Also, there is a wide range of quality of the body of evidence across different health outcomes. For future studies, clear subject selection criteria and definition of "exclusive breastfeeding," reliable collection of feeding data, controlling for important confounders including child-specific factors, and blinded assessment of the outcome measures will help. Sibling analysis provides a method to control for hereditary and household factors that are important in certain outcomes. In addition, cluster randomized controlled studies on the effectiveness of various breastfeeding promotion interventions will provide further opportunity to investigate any disparity in health outcomes as a result of the intervention.


Demographic and psychosocial features of participants in bondage and discipline, "sadomasochism" or dominance and submission (BDSM): data from a national survey.
People with sexual interests in bondage and discipline, "sadomasochism" or dominance and submission (BDSM) have been seen by many professionals as damaged or dangerous. To examine sexual behavior correlates of involvement in BDSM and test the hypothesis that BDSM is practiced by people with a history of sexual coercion, sexual difficulties, and/or psychological problems. In Australia in 2001-2002, a representative sample of 19,307 respondents aged 16-59 years was interviewed by telephone. Weighted data analysis used univariate logistic regression. Self-reported demographic and psychosocial factors; sexual behavior and identity; sexual difficulties. In total, 1.8% of sexually active people (2.2% of men, 1.3% of women) said they had been involved in BDSM in the previous year. This was more common among gay/lesbian and bisexual people. People who had engaged in BDSM were more likely to have experienced oral sex and/or anal sex, to have had more than one partner in the past year, to have had sex with someone other than their regular partner, and to have: taken part in phone sex, visited an Internet sex site, viewed an X-rated (pornographic) film or video, used a sex toy, had group sex, or taken part in manual stimulation of the anus, fisting or rimming. However, they were no more likely to have been coerced into sexual activity, and were not significantly more likely to be unhappy or anxious-indeed, men who had engaged in BDSM scored significantly lower on a scale of psychological distress than other men. Engagement in BDSM was not significantly related to any sexual difficulties. Our findings support the idea that BDSM is simply a sexual interest or subculture attractive to a minority, and for most participants not a pathological symptom of past abuse or difficulty with "normal" sex.


Environmental change and the carbon balance of Amazonian forests.
Extreme climatic events and land-use change are known to influence strongly the current carbon cycle of Amazonia, and have the potential to cause significant global climate impacts. This review intends to evaluate the effects of both climate and anthropogenic perturbations on the carbon balance of the Brazilian Amazon and to understand how they interact with each other. By analysing the outputs of the Intergovernmental Panel for Climate Change (IPCC) Assessment Report 4 (AR4) model ensemble, we demonstrate that Amazonian temperatures and water stress are both likely to increase over the 21st Century. Curbing deforestation in the Brazilian Amazon by 62% in 2010 relative to the 1990s mean decreased the Brazilian Amazon's deforestation contribution to global land use carbon emissions from 17% in the 1990s and early 2000s to 9% by 2010. Carbon sources in Amazonia are likely to be dominated by climatic impacts allied with forest fires (48.3% relative contribution) during extreme droughts. The current net carbon sink (net biome productivity, NBP) of +0.16 (ranging from +0.11 to +0.21) Pg C year(-1) in the Brazilian Amazon, equivalent to 13.3% of global carbon emissions from land-use change for 2008, can be negated or reversed during drought years [NBP = -0.06 (-0.31 to +0.01) Pg C year(-1) ]. Therefore, reducing forest fires, in addition to reducing deforestation, would be an important measure for minimizing future emissions. Conversely, doubling the current area of secondary forests and avoiding additional removal of primary forests would help the Amazonian gross forest sink to offset approximately 42% of global land-use change emissions. We conclude that a few strategic environmental policy measures are likely to strengthen the Amazonian net carbon sink with global implications. Moreover, these actions could increase the resilience of the net carbon sink to future increases in drought frequency.


Decreeing organizational change: judicial supervision of public institutions.
In the last fifteen years or so, courts have issued a small but significant number of decrees requiring that governmental bodies reorganize themselves so that their behavior will comport with certain legal standards. Such decrees, addressed to school systems, prison and mental hospital officials, welfare administrators, and public housing authorities, insert trial courts in the ongoing business of public administration. In this article, Professor Horowitz traces the origins, characteristics, and consequences of organizational change decrees. He finds their roots in an unusually fluid and indeterminate system of procedural forms and legal rules, a system hospitable to the impact of changing ideas about the performance of bureaucracy and the role of courts. He explores the problematic character of organizational change litigation, underscoring the ways in which organizational behaviour is fraught with a variety of informal relationships beyond the contemplation of the courts. In Professor Horowitz 's judgment, efforts to augment the capacity of courts to cope more effectively with organizational change litigation may redound to the disadvantage of the judicial process by emphasizing the new managerial role of the courts at the expense of their traditional moral function. He concludes by suggesting that capricious budgetary ramifications, unintended consequences, and the impact of unconventional enforcement practices on the courts themselves be included among the elements of a full evaluation of organizational change litigation.


CRTH2 expression on T cells in asthma.
Mast cell-derived prostaglandin D2 (PGD2) is the major prostanoid found within the airway of asthmatics immediately following allergen challenge. PGD2 has been shown to have chemokinetic effects on eosinophils and T helper type 2 (Th2) cells in vitro. This occurs through the interaction of PGD2 with the G-protein-coupled chemokine receptor homologous molecule expressed on Th2 lymphocytes (CRTH2). The expression of CRTH2 has been shown to be highly selective for Th2 cells. Using flow cytometry we have studied the expression of CRTH2 on T cells in blood and bronchoalveolar lavage fluid in asthmatics and normal subjects. CRTH2 expression was confined to a small percentage of blood T cells in asthmatics (1.8%+/-0.2) and normal (1.6%+/-0.2) subjects. CRTH2 was enriched significantly on interleukin (IL)-4+/IL-13+ T cells compared to interferon (IFN)-gamma+ T cells (P<0.001). There was a small population of CRTH2+ T cells in the bronchoalveolar lavage (BAL) of asthmatics (2.3%+/-0.6) and normal subjects (0.3%+/-0.1), and there was a significant difference between the two groups (P<0.05). There were similar amounts of PGD2 in the BAL of asthma and normal subjects. Within paired blood-BAL samples from the same subject there was no increase in CRTH2+ T cells in the BAL compared to blood in asthmatics. Enrichment of CRTH2 on IL-4+ and IL-13+ T cells compared to IFN-gamma+ T cells was also seen in BAL from asthmatics (P<0.001). CRTH2 is expressed preferentially by IL-4+/IL-13+ T cells compared to IFN-gamma+ T cells. However, given their small numbers they are unlikely to have a significant involvement in the pathogenesis of asthma. CRTH2 antagonism may not diminish T cell accumulation in the asthmatic lung.


The effect of pesticide exposure on time to pregnancy.
The Ontario Farm Family Health Study provided data for examination of the effects of pesticide exposure on time to pregnancy. In this retrospective cohort study of farm couples in Ontario, Canada, the farm operator, husband, and wife completed questionnaires during 1991-1992. We asked about pesticides used on the farm and pesticide activities of the husband and wife for each month of trying to conceive. After exclusions, 2,012 planned pregnancies remained for analysis. We used an analog of the Cox proportional hazards model to calculate conditional fecundability ratios (conditional on pregnancy). There was no strong or consistent pattern of associations of pesticide exposure with time to pregnancy. During exposure intervals in which women participated in pesticide activities (during most of which the men also participated), however, 6 of 13 pesticide exposure categories were associated with a decrease in fecundability (conditional fecundability ratio range = 0.51-0.80). For exposure intervals in which only the men participated in pesticide activities or in which neither men nor women participated in pesticide activities but pesticides had been used on the farm, conditional fecundability ratios ranged from 0.75 to 1.50, with no apparent consistency among pesticide classes, chemical families, or active ingredients.


Examining characteristics, knowledge and regulatory practices of specialized drug shops in Sub-Saharan Africa: a systematic review of the literature.
Specialized drug shops such as pharmacies and drug shops are increasingly becoming important sources of treatment. However, knowledge on their regulatory performance is scarce. We set out to systematically review literature on the characteristics, knowledge and practices of specialized drug shops in Sub-Saharan Africa. We searched PubMed, EMBASE, WEB of Science, CAB Abstracts, PsycINFO and websites for organizations that support medicine policies and usage. We also conducted open searches using Google Scholar, and searched manually through references of retrieved articles. Our search included studies of all designs that described characteristics, knowledge and practices of specialized drug shops. Information was abstracted on authors, publication year, country and location, study design, sample size, outcomes investigated, and primary findings using a uniform checklist. Finally, we conducted a structured narrative synthesis of the main findings. We obtained 61 studies, mostly from Eastern Africa, majority of which were conducted between 2006 and 2011. Outcome measures were heterogeneous and included knowledge, characteristics, and dispensing and regulatory practices. Shop location and client demand were found to strongly influence dispensing practices. Whereas shops located in urban and affluent areas were more likely to provide correct treatments, those in rural areas provided credit facilities more readily. However, the latter also charged higher prices for medicines. A vast majority of shops simply sold whatever medicines clients requested, with little history taking and counseling. Most shops also stocked popular medicines at the expense of policy recommended treatments. Treatment policies were poorly communicated overall, which partly explained why staff had poor knowledge on key aspects of treatment such as medicine dosage and side effects. Overall, very little is known on the link between regulatory enforcement and practices of specialized drug shops. Evidence suggests that characteristics and practices of specialized drug shops differ across rural and urban locations, and that these providers are highly responsive to client demand. However, there is a dearth in knowledge on how regulatory enforcement influences their characteristics and practices, and what strategies can be employed to strengthen the governance of the retail pharmaceutical sector.


B cell depletion therapy for 19 patients with refractory systemic lupus erythematosus.
B cell dysregulation is involved in the development of childhood-onset systemic lupus erythematosus (SLE). The safety and efficacy of B cell depletion therapy is evaluated in the the largest series of children to be presented in the literature. 19 children (89% female) with SLE, aged 6-16 (median 14) years, treated with rituximab in a single centre were retrospectively reviewed. The British Isles Lupus Assessment Group (BILAG) index and biochemical, haematological and immunological parameters were evaluated before and after treatment, with the primary outcome assessed as normal results. Rituximab therapy was used for acute life- or organ-threatening symptoms or symptoms that had not responded to standard treatment. The range of symptoms included lupus nephritis, cerebral lupus and severe general symptoms. Rituximab 750 mg/m(2) was given intravenously twice, usually within a 2-week period. Patients were followed up for 6-38 (median 20) months. Rapid reduction of SLE disease activity was observed within the first month, represented by a reduction of BILAG scores (14 to 6, p<0.005) and an improvement in renal function (estimated glomerular filtration rate of 54 to 68 ml/min/1.73 m(2), p = 0.07), immunological (complement C3: 0.46 to 0.83 g/l, p = 0.02) and haematological (haemoglobin: 9.7 to 10.3 g/dl, p = 0.04) parameters. No serious side effects were observed, except for herpes zoster in five cases. In our cohort of children, rituximab was safe and effective when used in combination with standard immunosuppressive agents. Randomised controlled studies are needed to further evaluate the safety and efficacy of rituximab therapy.


Design and analysis of metal/multi-insulator/metal waveguide plasmonic Bragg grating.
A metal/multi-insulator/metal waveguide plasmonic Bragg grating with a large dynamic range of index modulation is investigated analytically and numerically. Theoretical formalism of the dispersion relation for the present and general one-dimensional gratings is developed for TMwaves in the vicinity of each stop band.Wide-band and narrow-band designs with their respective FWHM bandwidths of 173.4 nm and < 3.4 nm in the 1550 nm band using a grating length of <16.0 microm are numerically demonstrated. Time-average power vortexes near the silica-silicon interfaces are revealed in the stop band and are attributed to the contra-flow interaction and simultaneous satisfactions of the Bragg condition for the incident and backward-diffracted waves. An enhanced forward-propagating power is thus shown to occur over certain sections within one period due to the power coupling from the backward-diffracted waves.


Haemophilus influenzae genome evolution during persistence in the human airways in chronic obstructive pulmonary disease.
Nontypeable Haemophilus influenzae (NTHi) exclusively colonize and infect humans and are critical to the pathogenesis of chronic obstructive pulmonary disease (COPD). In vitro and animal models do not accurately capture the complex environments encountered by NTHi during human infection. We conducted whole-genome sequencing of 269 longitudinally collected cleared and persistent NTHi from a 15-y prospective study of adults with COPD. Genome sequences were used to elucidate the phylogeny of NTHi isolates, identify genomic changes that occur with persistence in the human airways, and evaluate the effect of selective pressure on 12 candidate vaccine antigens. Strains persisted in individuals with COPD for as long as 1,422 d. Slipped-strand mispairing, mediated by changes in simple sequence repeats in multiple genes during persistence, regulates expression of critical virulence functions, including adherence, nutrient uptake, and modification of surface molecules, and is a major mechanism for survival in the hostile environment of the human airways. A subset of strains underwent a large 400-kb inversion during persistence. NTHi does not undergo significant gene gain or loss during persistence, in contrast to other persistent respiratory tract pathogens. Amino acid sequence changes occurred in 8 of 12 candidate vaccine antigens during persistence, an observation with important implications for vaccine development. These results indicate that NTHi alters its genome during persistence by regulation of critical virulence functions primarily by slipped-strand mispairing, advancing our understanding of how a bacterial pathogen that plays a critical role in COPD adapts to survival in the human respiratory tract.


Early whole-brain CT perfusion for detection of patients at risk for delayed cerebral ischemia after subarachnoid hemorrhage.
OBJECT This prospective study investigated the role of whole-brain CT perfusion (CTP) studies in the identification of patients at risk for delayed ischemic neurological deficits (DIND) and of tissue at risk for delayed cerebral infarction (DCI). METHODS Forty-three patients with aneurysmal subarachnoid hemorrhage (aSAH) were included in this study. A CTP study was routinely performed in the early phase (Day 3). The CTP study was repeated in cases of transcranial Doppler sonography (TCD)-measured blood flow velocity (BFV) increase of > 50 cm/sec within 24 hours and/or on Day 7 in patients who were intubated/sedated. RESULTS Early CTP studies revealed perfusion deficits in 14 patients, of whom 10 patients (72%) developed DIND, and 6 of these 10 patients (60%) had DCI. Three of the 14 patients (21%) with early perfusion deficits developed DCI without having had DIND, and the remaining patient (7%) had neither DIND nor DCI. There was a statistically significant correlation between early perfusion deficits and occurrence of DIND and DCI (p < 0.0001). A repeated CTP was performed in 8 patients with a TCD-measured BFV increase > 50 cm/sec within 24 hours, revealing a perfusion deficit in 3 of them (38%). Two of the 3 patients (67%) developed DCI without preceding DIND and 1 patient (33%) had DIND without DCI. In 4 of the 7 patients (57%) who were sedated and/or comatose, additional CTP studies on Day 7 showed perfusion deficits. All 4 patients developed DCI. CONCLUSIONS Whole-brain CTP on Day 3 after aSAH allows early and reliable identification of patients at risk for DIND and tissue at risk for DCI. Additional CTP investigations, guided by TCD-measured BFV increase or persisting coma, do not contribute to information gain.


Evaluation of stentangioplasty in university cardiac center.
In this ongoing prospective study conducted in University Cardiac Center, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, from July 2004 to January 2006. Fifty (50) patients (mean age 56+/-7.2 years) underwent stentangioplasty were evaluated. The study group of 50 patients consisted of 42 (84%) men and 08 (16%) women. The aim of this study was to evaluate in-hospital success, failure and complications during the procedures. About risk factors 19(38%) had hypertension, 13(26%) were smoker, 11(22%) suffered from diabetes mellitus, 05(10%) had family history of ischaemic heart disease. Average left ventricular ejection fraction was 54+/-7. Target vessel percutaneous coronary angioplasty (PTCA) were done in 61 vessel, intracoronary stent implanted in 58 vessels, direct stenting were done in 35 cases, failed PTCA were in 03(6%) cases and two had dissection. The native vessels had a mean reference diameter of 2.91 mm and their luminal diameter increased significantly after percutaneous coronary intervention (PCI). All the patients were discharged by one to three days of the procedure with improvement of their clinical condition. In conclusion, intracoronary stent deployment in coronary artery stenosis following balloon angioplasty is a valid and beneficial strategy with good in-hospital results.


Effects of Melissa officinalis L. (lemon balm) extract on neurogenesis associated with serum corticosterone and GABA in the mouse dentate gyrus.
Lemon balm, leaves of Melissa officinalis L., has been used for anti-anxiety and spasmolytics. We observed the extract of Melissa officinalis L. (MOE) on cell proliferation and neuroblast differentiation in the hippocampal dentate gyrus (DG) of middle-aged mice (12 months of age) using Ki67 and doublecortin (DCX), respectively. We also observed changes in corticosterone, GAD67 and GABA-transaminase (GABA-T) to check their possible mechanisms related to neurogenesis. We administered 50 or 200 mg/kg MOE to the animals once a day for 3 weeks. For labeling of newly generated cells, we also administered 5-bromodeoxyuridine (BrdU) twice a day for 3 days from the day of the first MOE treatment. Administration of 50 or 200 mg/kg MOE dose-dependently increased Ki67 positive nuclei to 244.1 and 763.9% of the vehicle-treated group, respectively. In addition, 50 or 200 mg/kg MOE significantly increased DCX positive neuroblasts with well-developed (tertiary) dendrites. Furthermore, MOE administration significantly increased BrdU/calbindin D-28 k double labeled cells (integrated neurons into granule cells in the DG) to 245.2% of the vehicle-treated group. On the other hand, administration of MOE reduced corticosterone levels in serum and decreased GABA-T levels in the DG homogenates. These results suggest that MOE increases cell proliferation, neuroblast differentiation and integration into granule cells by decreasing serum corticosterone levels as well as by increasing GABA levels in the mouse DG.


Factors Influencing Physical Activity Behavior among Iranian Women with Type 2 Diabetes Using the Extended Theory of Reasoned Action.
Findings of most studies indicate that the only way to control diabetes and prevent its debilitating effects is through the continuous performance of self-care behaviors. Physical activity is a non-pharmacological method of diabetes treatment and because of its positive effects on diabetic patients, it is being increasingly considered by researchers and practitioners. This study aimed at determining factors influencing physical activity among diabetic women in Iran, using the extended theory of reasoned action in Iran. A sample of 352 women with type 2 diabetes, referring to a Diabetes Clinic in Khoy, Iran, participated in the study. Appropriate instruments were designed to measure the desired variables (knowledge of diabetes, personal beliefs, subjective norms, perceived self-efficacy, behavioral intention and physical activity behavior). The reliability and validity of the instruments were examined and approved. Statistical analyses of the study were conducted by inferential statistical techniques (independent t-test, correlations and regressions) using the SPSS package. The findings of this investigation indicated that among the constructs of the model, self efficacy was the strongest predictor of intentions among women with type 2 diabetes and both directly and indirectly affected physical activity. In addition to self efficacy, diabetic patients' physical activity also was influenced by other variables of the model and sociodemographic factors. Our findings suggest that the high ability of the theory of reasoned action extended by self-efficacy in forecasting and explaining physical activity can be a base for educational intervention. Educational interventions based on the proposed model are necessary for improving diabetics' physical activity behavior and controlling disease.


Drosophila Boi limits Hedgehog levels to suppress follicle stem cell proliferation.
Stem cells depend on signals from cells within their microenvironment, or niche, as well as factors secreted by distant cells to regulate their maintenance and function. Here we show that Boi, a Hedgehog (Hh)-binding protein, is a novel suppressor of proliferation of follicle stem cells (FSCs) in the Drosophila ovary. Hh is expressed in apical cells, distant from the FSC niche, and diffuses to reach FSCs, where it promotes FSC proliferation. We show that Boi is expressed in apical cells and exerts its suppressive effect on FSC proliferation by binding to and sequestering Hh on the apical cell surface, thereby inhibiting Hh diffusion. Our studies demonstrate that cells distant from the local niche can regulate stem cell function through ligand sequestration, a mechanism that likely is conserved in other epithelial tissues.


Impacts and responses to sea-level rise: a global analysis of the SRES scenarios over the twenty-first century.
Taking the Special Report on Emission Scenarios (SRES) climate and socio-economic scenarios (A1FI, A2, B1 and B2 'future worlds'), the potential impacts of sea-level rise through the twenty-first century are explored using complementary impact and economic analysis methods at the global scale. These methods have never been explored together previously. In all scenarios, the exposure and hence the impact potential due to increased flooding by sea-level rise increases significantly compared to the base year (1990). While mitigation reduces impacts, due to the lagged response of sea-level rise to atmospheric temperature rise, impacts cannot be avoided during the twenty-first century by this response alone. Cost-benefit analyses suggest that widespread protection will be an economically rational response to land loss due to sea-level rise in the four SRES futures that are considered. The most vulnerable future worlds to sea-level rise appear to be the A2 and B2 scenarios, which primarily reflects differences in the socio-economic situation (coastal population, Gross Domestic Product (GDP) and GDP/capita), rather than the magnitude of sea-level rise. Small islands and deltaic settings stand out as being more vulnerable as shown in many earlier analyses. Collectively, these results suggest that human societies will have more choice in how they respond to sea-level rise than is often assumed. However, this conclusion needs to be tempered by recognition that we still do not understand these choices and significant impacts remain possible. Future worlds which experience larger rises in sea-level than considered here (above 35 cm), more extreme events, a reactive rather than proactive approach to adaptation, and where GDP growth is slower or more unequal than in the SRES futures remain a concern. There is considerable scope for further research to better understand these diverse issues.


Vulnerability of Jews to affective disorders.
Psychiatric literature over the past 100 years suggests that Jews are at higher risk for affective disorders than numbers of other religious groups. To examine these claims, the authors analyzed data from the National Institute of Mental Health Epidemiologic Catchment Area (ECA) study. In addition, the relationships among gender, alcoholism, and major depression were investigated. The period prevalence and lifetime rates of DSM-III major depression among Jews, Catholics, Protestants, individuals in other religious groups, and individuals with no religious affiliation were examined in the Los Angeles and New Haven, Conn., ECA data. Logistic regression with covariates for site, gender, marital status, and socioeconomic status was used to estimate odds ratios and 95% confidence intervals. The calculated rates, based on the combined data from ECA study waves 1 and 2 for the white population, were weighted according to the 1980 U.S. population census. Female-to-male rate ratios and rates of alcohol abuse/dependence were also obtained. While no differences were found among females, Jewish males had significantly higher rates of major depression than Catholics, Protestants, and all non-Jews combined. Jews had a 1:1 female-to-male ratio for major depression, in contrast to the other religious groups, which approached the universal 2:1 ratio. Rates of alcohol abuse/dependence were inversely related to rates of major depression. The results support only in part the earlier reports that Jews have higher rates of depression. The equal gender distribution of major depression among Jews may be associated with the lower rate of alcoholism among Jewish males.


Signals from Eph and ephrin proteins: a developmental tool kit.
Interactions between Eph receptors and their ligands the ephrin proteins are critically important in many key developmental processes. Emerging evidence also supports a role for these molecules in postembryonic tissues, particularly in pathological processes, including tissue injury and tumor metastasis. We review the signaling mechanisms that allow the 14 Eph and nine ephrin proteins to deliver intracellular signals that regulate cell shape and movement. What emerges is that the initiation of these signals is critically dependent on which Eph and ephrin proteins are expressed, the level of their expression, and, in some cases, which splice variants are expressed. Diversity at the level of initial interaction and in the downstream signaling processes regulated by Eph-ephrin signaling provides a subtle, versatile system of regulation of intercellular adhesion, cell shape, and cell motility.


Disruption of Immune Homeostasis in Human Dendritic Cells via Regulation of Autophagy and Apoptosis by Porphyromonas gingivalis.
As fundamental processes of immune homeostasis, autophagy, and apoptosis must be maintained to mitigate risk of chronic inflammation and autoimmune diseases. Periodontitis is a chronic inflammatory disease characterized by oral microbial dysbiosis, and dysregulation of dendritic cell (DC) and T cell responses. The aim of this study was to elucidate the underlying mechanisms by which the oral microbe Porphyromonas gingivalis (P. gingivalis) manipulates dendritic cell signaling to perturb both autophagy and apoptosis. Using a combination of Western blotting, flow cytometry, qRT-PCR and immunofluorescence analysis, we show a pivotal role for the minor (Mfa1) fimbriae of P. gingivalis in nuclear/cytoplasmic shuttling of Akt and FOXO1 in human monocyte-derived DCs. Mfa1-induced Akt nuclear localization and activation ultimately induced mTOR. Activation of the Akt/mTOR axis downregulated intracellular LC3II, also known as Atg8, required for autophagosome formation and maturation. Use of allosteric panAkt inhibitor MK2206 and mTOR inhibitor rapamycin confirmed the role of Akt/mTOR signaling in autophagy inhibition by P. gingivalis in DCs. Interestingly, this pathway was also linked to induction of the anti-apoptotic protein Bcl2, decreased caspase-3 cleavage and decreased expression of pro-apoptotic proteins Bax and Bim, thus promoting longevity of host DCs. Addition of ABT-199 peptide to disrupt the interaction of antiapoptotic Bcl2 and its proapoptotic partners BAK/BAX restored apoptotic death to P. gingivalis-infected DC cells. In summary, we have identified the underlying mechanism by which P. gingivalis promotes its own survival and that of its host DCs.


THE SOURCE OF LIPID ACCUMULATION IN L CELLS.
Strain L cells accumulate lipid, concurrent with cessation of protein synthesis, in the stationary phase of growth from the extracellular medium and as a result of de novo synthesis. Cells which have been more severely damaged with an amino acid analogue also accumulate lipid from the extracellular medium, but synthesize very little lipid from labeled acetate. The possible roles which lipid accumulation may play in the cell are discussed.


Zwittermicin A resistance gene from Bacillus cereus.
Zwittermicin A is a novel aminopolyol antibiotic produced by Bacillus cereus that is active against diverse bacteria and lower eukaryotes (L.A. Silo-Suh, B.J. Lethbridge, S.J. Raffel, H. He, J. Clardy, and J. Handelsman, Appl. Environ. Microbiol. 60:2023-2030, 1994). To identify a determinant for resistance to zwittermicin A, we constructed a genomic library from B. cereus UW85, which produces zwittermicin A, and screened transformants of Escherichia coli DH5alpha, which is sensitive to zwittermicin A, for resistance to zwittermicin A. Subcloning and mutagenesis defined a genetic locus, designated zmaR, on a 1.2-kb fragment of DNA that conferred zwittermicin A resistance on E. coli. A DNA fragment containing zmaR hybridized to a corresponding fragment of genomic DNA from B. cereus UW85. Corresponding fragments were not detected in mutants of B. cereus UW85 that were sensitive to zwittermicin A, and the plasmids carrying zmaR restored resistance to the zwittermicin A-sensitive mutants, indicating that zmaR was deleted in the zwittermicin A-sensitive mutants and that zmaR is functional in B. cereus. Sequencing of the 1.2-kb fragment of DNA defined an open reading frame, designated ZmaR. Neither the nucleotide sequence nor the predicted protein sequence had significant similarity to sequences in existing databases. Cell extracts from an E. coli strain carrying zmaR contained a 43.5-kDa protein whose molecular mass and N-terminal sequence matched those of the protein predicted by the zmaR sequence. The results demonstrate that we have isolated a gene, zmaR, that encodes a zwIttermicin A resistance determinant that is functional in both B. cereus and E. coli.


CORRELATION OF SERUM VITAMIN D LEVEL WITH TYPE 1 DIABETES MELLITUS IN CHILDREN: A META-ANALYSIS.
to assess the relationship between serums vitamin D level and type 1 diabetes mellitus (T1DM) in children. the following electronic databases were searched until Sep 2014 to identify relevant studies that assessed the relationship between serum vitamin D with T1DM: PubMed\EMbase\Medline\Central Register of Controlled Trials\CBM\Chinese National Knowledge Infrastructure (CNKI)\wangfang; The NOS scale was used to evaluate the quality of studies, and the statistical tests were performed by Stata 11.0 software. a total of 10 studies were included in this study. Our results showed that serum vitamin D was significantly lower in children with T1DM than in healthy controls (MD = -0.60, P < 0.05). No evidence support publication bias in present study. the meta-analysis suggests that serum vitamin D level is associated with T1DM in children.


Risk factors for incidence of sexually transmitted infections among women in South Africa, Tanzania, and Zambia: results from HPTN 055 study.
To determine risk factors for sexually transmitted infections (STIs) among women in Durban and Hlabisa (South Africa), Moshi (Tanzania), and Lusaka (Zambia). Between 2003 and 2004, 958 women at risk of STIs were enrolled in a 1-year prospective study. They were interviewed at each monthly visit, and samples for STI testing were collected during quarterly and other visits when clinically indicated. The incidence of infections as measured in person-years at risk (PYAR) was as follows: overall trichomoniasis, 31.9/100 PYAR; chlamydial infection in South Africa, 19.5/100 PYAR; chlamydial infection in Tanzania and Zambia, 4.9/100 PYAR; gonorrhea in South Africa, 16.5/100 PYAR; gonorrhea in Tanzania and Zambia, 5.3/100 PYAR; overall syphilis, 7.5/100 PYAR; and overall HIV, 3.8/100 PYAR. The incidence of most STIs was highest among the South African sites, where chlamydial infection and gonorrhea were detected by using a more sensitive assay. Independent risk factors included age, hormonal contraceptive methods, and measures of sexual behavior, including number of sex partners and occurrence of anal sex in the past 3 months. Women with incident HIV infection were at increased risk of chlamydial infection [odds ratio (OR) = 5.5, 95% confidence interval (CI): 2.0-15.2]and gonorrhea (OR = 5.7, 95% CI: 1.9-17.0) in South African sites. Despite ongoing counseling during the study, high-risk sexual behaviors were common, and consistent condom use remained low. The incidence of STIs, including HIV, was high among women in this study. These findings highlight the urgent need for effective HIV/STI prevention programs in this population.


Revisiting old drugs as novel agents for retinoblastoma: in vitro and in vivo antitumor activity of cardenolides.
Intra-arterial delivery of chemotherapeutic agents offers a new and exciting opportunity for the treatment of advanced intraocular retinoblastoma. It allows local delivery of relatively high doses of chemotherapy agents while bypassing general blood circulation. For this reason, this study was undertaken to revisit some of the FDA-approved drugs for the treatment of retinoblastoma. High-throughput screening (HTS) of 2640 approved drugs and bioactive compounds resulted in the identification of cytotoxic agents with potent activity toward both the Y79 and RB355 human retinoblastoma cell lines. Subsequent profiling of the drug candidates was performed in a panel of ocular cancer cell lines. Induction of apoptosis in Y79 cells was assessed by immunofluorescence detection of activated caspase-3. Therapeutic effect was evaluated in a xenograft model of retinoblastoma. Several FDA-approved drugs were identified that showed potent cytotoxic activity toward retinoblastoma cell lines in vitro. Among them were several cardiac glycosides, a class of cardenolides historically associated with the prevention and treatment of congestive heart failure. Caspase-3 activation studies provided an insight into the mechanism of action of cardenolides in retinoblastoma cells. When tested in a xenograft model of retinoblastoma, the cardenolide ouabain induced complete tumor regression in the treated mice. Cardenolides were identified as a new class of antitumor agents for the treatment of retinoblastoma. Members of this class of cardiotonic drugs could be repositioned for retinoblastoma if administered locally via direct intra-arterial infusion.


An enhanced individual placement and support (IPS) intervention based on the Model of Human Occupation (MOHO); a prospective cohort study.
Employment is good for physical and mental health, however people with severe mental illness (SMI) are often excluded from employment. Standard Individual Placement and Support (IPS) is effective in supporting around 55% of people with SMI into employment or education. Current research considers enhancements to IPS to improve outcomes for those requiring more complex interventions. Clinicians need to better understand who will benefit from these enhanced IPS interventions. This study offers a new enhanced IPS intervention and an approach to predicting who may achieve successful outcomes. This prospective cohort study included people with SMI who participated in an enhanced IPS service and had prolonged absence from employment. Secondary data analysis was conducted of data gathered in routine clinical practice. Univariate analysis coupled with previous research and clinical consultation was used to select variables to be included in the initial model, followed by a backward stepwise approach to model building for the final multiple logistic regression model with an outcome of successful or unsuccessful goal attainment (employment or education). Sixty-three percent of participants in the enhanced IPS successfully attained employment or education. Significant relationships from bivariate analyses were identified between outcomes (employment or education) and seven psychosocial variables. Adapting Routines to Minimise Difficulties, Work Related Goals, and Living in an Area of Lesser Deprivation were found to be significant in predicting employment or education in the final multiple logistic regression model R2 = 0.16 (Hosmer-Lemeshow), 0.19 (Cox-Snell), 0.26 (Nagelkerke). Model χ2(7) = 41.38 p < .001. An enhanced IPS service had a 63% rate success in achieving employment or education, higher than comparable studies and provides an alternative to IPS-Lite and IPS-standard for more complex populations. Motivational and habitual psychosocial variables are helpful in predicting who may benefit from an enhanced IPS intervention supporting people after prolonged absence from employment. NCT04083404 Registered 05 September 2019 (retrospectively registered).


Differential expression of gonadotropin and estrogen receptors and oocyte cytology during follicular maturation associated with egg viability in European eel (Anguilla anguilla).
In captivity, oogenesis and ovarian follicle maturation in European eel can be induced experimentally using hormonal therapy. The follicle's ability to respond effectively to the induction of maturation and ovulation, resulting in viable eggs, depends on the oocyte stage at the time of induction. We hypothesized that variation in the expression of key hormone receptors in the ovary and size of oocyte lipid droplets are associated with changes in oocyte stage. Thus, we induced ovarian follicle maturation using a priming dose of fish pituitary extract followed by the administration of a 17α, 20β-dihydroxy-4-pregnen-3-one (DHP) injection. Females were then strip-spawned, the eggs were fertilized in vitro, incubated and larval survival was recorded at 3 days post hatch (dph). The expression of gonadotropin receptors (fshr, lhcgr1 and lhcgr2) and estrogen receptors (esr1, esr2a, esr2b, gpera and gperb) was quantified and the size of oocyte lipid droplets measured. Larval survival at 3 dph was used to differentiate high- and low-quality egg batches. Results showed significantly higher abundance of lhcgr1 and esr2a at priming for high-quality egg batches whereas fshr and gperb transcripts were significantly higher at DHP injection for low-quality egg batches. Therefore, high levels of lhcgr1 and esr2a may be important for attaining follicular maturational competence, while high fshr and gperb mRNA levels may indicate inadequate maturational competence. Furthermore, lipid droplet size at DHP and in ovulated eggs was significantly smaller in high-quality egg batches than in low-quality, which indicates that droplet size may be a useful marker of follicular maturational stage.


The p38 MAPK pathway is essential for skeletogenesis and bone homeostasis in mice.
Nearly every extracellular ligand that has been found to play a role in regulating bone biology acts, at least in part, through MAPK pathways. Nevertheless, much remains to be learned about the contribution of MAPKs to osteoblast biology in vivo. Here we report that the p38 MAPK pathway is required for normal skeletogenesis in mice, as mice with deletion of any of the MAPK pathway member-encoding genes MAPK kinase 3 (Mkk3), Mkk6, p38a, or p38b displayed profoundly reduced bone mass secondary to defective osteoblast differentiation. Among the MAPK kinase kinase (MAP3K) family, we identified TGF-beta-activated kinase 1 (TAK1; also known as MAP3K7) as the critical activator upstream of p38 in osteoblasts. Osteoblast-specific deletion of Tak1 resulted in clavicular hypoplasia and delayed fontanelle fusion, a phenotype similar to the cleidocranial dysplasia observed in humans haploinsufficient for the transcription factor runt-related transcription factor 2 (Runx2). Mechanistic analysis revealed that the TAK1-MKK3/6-p38 MAPK axis phosphorylated Runx2, promoting its association with the coactivator CREB-binding protein (CBP), which was required to regulate osteoblast genetic programs. These findings reveal an in vivo function for p38beta and establish that MAPK signaling is essential for bone formation in vivo. These results also suggest that selective p38beta agonists may represent attractive therapeutic agents to prevent bone loss associated with osteoporosis and aging.


The role of intra-operative cell salvage in patient blood management for revision hip arthroplasty: a prospective cohort study.
Cell salvage is an important component of blood management in patients undergoing revision hip arthroplasty surgery. However concerns regarding efficacy and patient selection remain. The aims of this study were to describe intra-operative blood loss, cell salvage re-infusion volumes and red blood cell transfusion rates for revision hip procedures and to identify factors associated with the ability to salvage sufficient blood intra-operatively to permit processing and re-infusion. Data were collected from a prospective cohort of 664 consecutive patients undergoing revision hip surgery at a single tertiary centre from 31 March 2015 to 1 April 2018. Indications for revision surgery were aseptic (n = 393 (59%)) fracture (n = 160 (24%)) and infection (n = 111 (17%)). Salvaged blood was processed and re-infused when blood loss exceeded 500 ml. Mean (SD) intra-operative blood loss was 1038 (778) ml across all procedures. Salvaged blood was re-infused in 505 of 664 (76%) patients. Mean (SD) re-infusion volume was 253 (169) ml. In total, 246 of 664 (37%) patients received an allogeneic red blood cell transfusion within 72 h of surgery. Patients undergoing femoral component revision only (OR (95%CI) 0.41 (0.23-0.73)) or acetabular component revision only (0.53 (0.32-0.87)) were less likely to generate sufficient blood salvage volume for re-infusion compared with revision of both components. Compared with aseptic indications, patients undergoing revision surgery for infection (1.87 (1.04-3.36)) or fracture (4.43 (2.30-8.55)) were more likely to generate sufficient blood salvage volume for re-infusion. Our data suggest that cell salvage is efficacious in this population. Cases where the indication is infection or fracture and where both femoral and acetabular components are to be revised should be prioritised.


Serotype emergence and genotype distribution among macrolide-resistant invasive Streptococcus pneumoniae isolates in the postconjugate vaccine (PCV-7) era.
We conducted population-based surveillance for pneumococcal bacteremia within a 5-county region surrounding Philadelphia from October 2001 through September 2008, the period following introduction of the seven-valent pneumococcal conjugate vaccine. Erythromycin resistance increased from 14.7% in 2001-2002 to 20.3% in 2007-2008, while the resistance rate to penicillin (MIC, ≥2 μg/ml) decreased from 7.2% to 4.2% during the same period. The most predominant serotypes associated with erythromycin resistance in 2007-2008 included 19A (29.7%), 15A (29.2%), 6C (10.1%), 3 (5.6%), and 6A (4.5%). The molecular mechanisms for the increasing erythromycin resistance were mainly due to the growing presence of mef(A) negative erm(B)(+) and mef(A)(+) erm(B)(+) genotypes, which increased from 20.0% to 46.1% and from 1.8% to 19.1%, respectively, from 2001-2002 to 2007-2008. However, mef(A)-mediated erythromycin resistance decreased from 72.7% in 2001-2002 to 34.8% in 2007-2008. Serotypes related to the erm(B) gene were 15A (45.6%), 19A (20.9%), 3 (10.1%), and 6B (6.3%); serotypes related to the mef(A) gene were 6A (18.6%), 19A (15.0%), 6C (9.3%), and 14(8.4%); serotypes associated with the presence of both erm(B) and mef(A) were 19A (81.5%), 15A (7.7%), and 19F (6.2%). Pulsed-field gel electrophoresis analysis demonstrated that erythromycin-resistant isolates within the 19A serotype were genetically diverse and related to several circulating international clones. In contrast, erythromycin-resistant isolates within the 15A serotype consisted of clonally identical or closely related isolates.


Determinants of readiness to adopt mHealth in a rural community of Bangladesh.
Evidence in favor of mHealth for healthcare delivery in settings where trained health workforce is limited or unavailable is accumulating. With rapid growth in access to mobile phones and an acute shortage of health workforce in Bangladesh, mHealth initiatives are increasing with more than 20 current initiatives in place. "Readiness" is a crucial prerequisite to the successful implementation of telehealth programs. However, systematic assessment of the community readiness for mHealth-based services in the country is lacking. We report on a recent study describing the influence of community readiness for mHealth of a rural Bangladesh community. A conceptual framework for mHealth readiness was developed, which included three categories: technological, motivational and resource readiness. This guided the questionnaire development for the survey conducted in the Chakaria sub-district of Bangladesh from November 2012 to April 2013. Multivariate logistic regression was used to examine ownership of mobile phones, use of the technology, and knowledge regarding awareness of mHealth services as predictors of the community readiness to adopt mHealth. A total of 4915 randomly selected household members aged 18 years and over completed the survey. The data explained the sub-categories of the readiness dimensions. In terms of access, 45% of respondents owned a mobile phone with ownership higher among males, younger participants and those in the highest socioeconomic quintiles. Results related to technological readiness showed that among mobile phone owners, 50% were aware of SMS but only sending and receiving SMS. Only 37% generally read the received SMS. Only 5% of respondents used the internet capabilities on their phone and 25% used voice messages. The majority (73%) of the participants were interested in joining mHealth programs in the future. Multivariate analysis showed that ownership of a mobile phone (aOR 1.3, 95% CI 1.1-1.5), younger age (aOR 2.6, 95% CI 2.1-3.3), males (aOR 1.8, 95% CI 1.6-2.1), educated respondents (11 years or more education) (aOR 11.1, 95% CI 6.2-19.2) and those belonging to the highest socio-economic group (aOR 3.7, 95% CI 2.9-4.7) were significantly independently associated with knowledge regarding awareness of current mHealth services. We developed a conceptual framework to assess community readiness for mHealth. We described three high level dimensions of readiness and have partially tested the conceptual framework in a rural sub-district in Bangladesh. We found that the community has some technological readiness but inequity was observed for human resource readiness and technological capabilities. The study population is motivated to use mHealth. Our conceptual framework is a promising tool to assist policy-makers in planning and implementing mHealth programs.


Preliminary Investigation of a Mindfulness-Based Intervention for Social Anxiety Disorder That Integrates Compassion Meditation and Mindful Exposure.
This study evaluated the feasibility and initial efficacy of a 12-week group mindfulness-based intervention tailored for persons with social anxiety disorder (MBI-SAD). The intervention includes elements of the standard mindfulness-based stress reduction program, explicit training in self-compassion aimed at cultivating a more accepting and kinder stance toward oneself, and use of exposure procedures to help participants practice responding mindfully to internal experiences evoked by feared social situations. Participants were randomly assigned to the MBI-SAD (n = 21) or a waitlist (WL) (n = 18) control group. Feasibility was assessed by the number of participants who completed at least 75% of the 12 weekly group sessions. Primary efficacy outcomes were clinician- and self-rated measures of social anxiety. Other outcomes included clinician ratings of illness severity and self-rated depression, social adjustment, mindfulness, and self-compassion. The MBI-SAD was acceptable and feasible, with 81% of participants attending at least 75% of sessions. The MBI-SAD fared better than WL in improving social anxiety symptom severity (p ≤ 0.0001), depression (p ≤ 0.05), and social adjustment (p ≤ 0.05). The intervention also enhanced self-compassion (p ≤ 0.05), and facets of mindfulness (observe and aware; p ≤ .05). MBI-SAD treatment gains were maintained at 3-month follow-up. These preliminary findings suggest that an MBI that integrates explicit training in self-compassion and mindful exposure is a feasible and promising intervention for social anxiety disorder. The next step is to compare the MBI-SAD to the gold standard of cognitive-behavior therapy to determine equivalence or noninferiority and to explore mediators and moderators of treatment outcome.


Reciprocal inhibition between the muscles of the human forearm.
Peripheral and central mechanisms of reciprocal inhibition between antagonist muscles in the forearm have been studied in ten human subjects. H reflexes were evoked in flexor muscles by stimulating the median nerve with single shocks at around motor threshold intensity. Peripheral inhibition of the flexor H reflex was produced by motor threshold stimulation with a single shock of the radial nerve supplying the extensor muscles. The conditioning radial nerve stimulus produced inhibition of the flexor H reflex consisting of three phases. In some individuals, an H reflex could be evoked in extensor muscles of the forearm. Stimulation of the median nerve produced inhibition of the extensor H reflex with a similar time course to that from extensors to flexors. The first phase of inhibition was apparent when the test median nerve shock was given from 1 ms before to 3 ms after the conditioning radial nerve shock. It was abrupt in onset and short in duration and could be evoked with a conditioning stimulus intensity as low as 0.75 X motor threshold. The second and third phases of inhibition were evident when the conditioning radial nerve stimulus preceded the median nerve test shock by 5 to 50, and 50 to 500 ms respectively. The characteristics of these later phases of inhibition are to be the subject of a separate report. The difference in timing of the peak initial short-latency inhibition from extensor to flexor and from flexor to extensor muscles enabled an estimate to be made of the central synaptic delay of the inhibitory process. This method yielded a central delay of 0.95 ms in excess of that of the H reflex. We conclude that the first phase of inhibition is mediated via large group I afferents acting through a single inhibitory interneurone . Central inhibition of the flexor H reflex was demonstrated with the radial nerve anaesthetized by injection of local anaesthetic at the elbow. Subjects were asked to try to contract the paralysed extensor muscles. Under this condition, attempted voluntary wrist extension inhibited the flexor H reflex even though no movement occurred. A shock was delivered to the radial nerve at a site proximal to the anaesthetic block. When the shock was applied in conjunction with an attempted voluntary contraction of the paralysed extensor muscles, the depth of inhibition was greater than that predicted from the effect of either a shock or a willed contraction acting independently.(ABSTRACT TRUNCATED AT 400 WORDS)


Ganglioside-Dependent Neural Stem Cell Proliferation in Alzheimer's Disease Model Mice.
The aggregation and formation of amyloid plaques by amyloid β-peptides (Aβs) is believed to be one of the pathological hallmarks of Alzheimer's disease (AD). Intriguingly, Aβs have also been shown to possess proliferative effects on neural stem cells (NSCs). Many essential cellular processes in NSCs, such as fate determination and proliferation, are heavily influenced by cell surface glycoconjugates, including gangliosides. It has recently been shown that Aβ1-42 alters several key glycosyltransferases and glycosidases. To further define the effects of Aβs and to clarify the potential mechanisms of action of those peptides on NSCs, NSCs were cultured from embryonic brains of the double-transgenic mouse model of AD [B6C3-Tg(APPswe,PSEN1dE9)85Dbo/J] coexpressing mutants of amyloid precursor protein (APPswe) and presenilin1 (PSEN1dE9). We found that Aβs not only promoted cell proliferation but also altered expression of several key glycogenes for glycoconjugate metabolism, such as sialyltransferases II and III (ST-II & -III) in AD NSCs. In addition, we found upregulation of epidermal growth factor receptor and Notch1 intracellular domain. Moreover, the increased expression of ST-II and -III coincided with the elevated levels of c-series gangliosides (A2B5+ antigens) in AD NSCs. Further, we revealed that epidermal growth factor signaling and gangliosides are necessary components on Aβ-stimulated NSC proliferation. Our present study has thus provided a novel mechanism for the upregulation of c-series ganglioside expression and increases in several NSC markers to account for the proliferative effect of Aβs on NSCs in AD mouse brain. These observations support the potential beneficial effects of Aβs and gangliosides in promoting neurogenesis in AD brain.


Clinical applications of PET in oncology.
Positron emission tomography (PET) provides metabolic information that has been documented to be useful in patient care. The properties of positron decay permit accurate imaging of the distribution of positron-emitting radiopharmaceuticals. The wide array of positron-emitting radiopharmaceuticals has been used to characterize multiple physiologic and pathologic states. PET is used for characterizing brain disorders such as Alzheimer disease and epilepsy and cardiac disorders such as coronary artery disease and myocardial viability. The neurologic and cardiac applications of PET are not covered in this review. The major utilization of PET clinically is in oncology and consists of imaging the distribution of fluorine 18 fluorodeoxyglucose (FDG). FDG, an analogue of glucose, accumulates in most tumors in a greater amount than it does in normal tissue. FDG PET is being used in diagnosis and follow-up of several malignancies, and the list of articles supporting its use continues to grow. In this review, the physics and instrumentation aspects of PET are described. Many of the clinical applications in oncology are mature and readily covered by third-party payers. Other applications are being used clinically but have not been as carefully evaluated in the literature, and these applications may not be covered by third-party payers. The developing applications of PET are included in this review.


The small-molecule TNF-alpha modulator, UTL-5g, reduces side effects induced by cisplatin and enhances the therapeutic effect of cisplatin in vivo.
We investigated a small-molecule modulator of tumor necrosis factor alpha (TNF-alpha), UTL-5g (also referred to as GBL-5g), as a potential chemoprotective agent against cisplatin-induced side effects including nephrotoxicity, hepatotoxicity and hematotoxicity. Pretreatment of UTL-5g i.p. in BDF1 mice reduced the levels of blood urea nitrogen (BUN) and creatinine induced by cisplatin treatment. The levels of both aspartate transaminase (AST) and alanine transaminase (ALT) in these animals were also reduced by UTL-5g. Pretreatment of UTL-5g did not significantly affect the number of white blood cells (WBC) under current experimental conditions, yet it markedly increased blood platelet counts by more than threefold. Therapeutic assessment in SCID mice inoculated with human HCT-15 tumor cells showed that UTL-5g did not attenuate the anti-tumor effect of cisplatin but increased the therapeutic efficacy of cisplatin. The LD50 of UTL-5g was determined to be > 2,000 mg/kg by an acute toxicity study. In summary, our studies showed that 1) UTL-5g significantly reduces nephrotoxicity and hepatotoxicity induced by cisplatin in mice, presumably by lowering the levels of TNF-alpha, 2) UTL-5g markedly increased blood platelet counts in mice and 3) UTL-5g treatment increased the therapeutic efficacy of cisplatin against HCT-15 cells inoculated in SCID mice.


Receptors for the incretin glucagon-like peptide-1 are expressed on neurons in the central nervous system.
Glucagon-like-peptide-1 is an incretin hormone that also has neuroprotective properties. Here we analyse where glucagon-like-peptide-1 receptors are expressed in the brain. The receptor is found only on neurons, not on glia cells. The pyramidal cell layer of the CA region and the granule cell layer of the dentate gyrus in the hippocampus show intense staining. In the neocortex, larger pyramidal neurons express the receptor. In the cerebellum, only Purkinje neurons express the receptor. Dendrites of larger neurons were stained; in particular, pyramidal cells in area CA and dendrites of Purkinje cells. The fact that the receptor is located on neurons and dendrites suggests that the neuroprotective action is caused by the modulation of neuronal excitation.