Cultivating mindfulness in health care professionals: a review of empirical studies of mindfulness-based stress reduction (MBSR).
Demands faced by health care professionals include heavy caseloads, limited control over the work environment, long hours, as well as organizational structures and systems in transition. Such conditions have been directly linked to increased stress and symptoms of burnout, which in turn, have adverse consequences for clinicians and the quality of care that is provided to patients. Consequently, there exists an impetus for the development of curriculum aimed at fostering wellness and the necessary self-care skills for clinicians. This review will examine the potential benefits of mindfulness-based stress reduction (MBSR) programs aimed at enhancing well-being and coping with stress in this population. Empirical evidence indicates that participation in MBSR yields benefits for clinicians in the domains of physical and mental health. Conceptual and methodological limitations of the existing studies and suggestions for future research are discussed.


Scaling ethics up and down: moral craft in clinical genetics and in global health research.
This paper engages with the question of what it is to 'do good medical ethics' in two ways. It begins with an exploration of what it might mean to say that health professionals practise good medical ethics as part of practising good ethical medicine. Using the example of the Genethics Club, a well-established national ethics forum for genetics professionals in the UK, the paper develops an account of moral craftsmanship grounded in the concepts of shared moral commitments and practices, moral work, ethics and living morality. In the light of this discussion, the paper goes on to consider what it might mean for a specialist in medical ethics, a bioethicist, to do good medical ethics. Finally, a research agenda focusing on the challenges of thinking about good medical ethics in a global context and a proposal for an innovative approach to bioethics methodology is outlined.


Auricular acupuncture in the treatment of female infertility.
Following a complete gynecologic--endocrinologic workup, 45 infertile women suffering from oligoamenorrhea (n = 27) or luteal insufficiency (n = 18) were treated with auricular acupuncture. Results were compared to those of 45 women who received hormone treatment. Both groups were matched for age, duration of infertility, body mass index, previous pregnancies, menstrual cycle and tubal patency. Women treated with acupuncture had 22 pregnancies, 11 after acupuncture, four spontaneously, and seven after appropriate medication. Women treated with hormones had 20 pregnancies, five spontaneously, and 15 in response to therapy. Four women of each group had abortions. Endometriosis (normal menstrual cycles) was seen in 35% (38%) of the women of each group who failed to respond to therapy with pregnancy. Only 4% of the women who responded to acupuncture or hormone treatment with a pregnancy had endometriosis, and 7% had normal cycles. In addition, women who continued to be infertile after hormone therapy had higher body mass indices and testosterone values than the therapy responders from this group. Women who became pregnant after acupuncture suffered more often from menstrual abnormalities and luteal insufficiency with lower estrogen, thyrotropin (TSH) and dehydroepiandrosterone sulfate (DHEAS) concentrations than the women who achieved pregnancy after hormone treatment. Although the pregnancy rate was similar for both groups, eumenorrheic women treated with acupuncture had adnexitis, endometriosis, out-of-phase endometria and reduced postcoital tests more often than those receiving hormones. Twelve of the 27 women (44%) with menstrual irregularities remained infertile after therapy with acupuncture compared to 15 of the 27 (56%) controls treated with hormones, even though hormone disorders were more pronounced in the acupuncture group. Side-effects were observed only during hormone treatment. Various disorders of the autonomic nervous system normalized during acupuncture. Based on our data, auricular acupuncture seems to offer a valuable alternative therapy for female infertility due to hormone disorders.


The role of height in the sex difference in intelligence.
Recent studies conclude that men on average have higher intelligence than women by 3-5 IQ points. However, the ultimate evolutionary question of why men should have evolved to have higher intelligence than women remains. We suggest that men may have slightly higher intelligence than women through 4 mechanisms: (1) assortative mating of intelligent men and beautiful women, (2) assortative mating of tall men and beautiful women, (3) an extrinsic correlation between height and intelligence produced by Mechanisms 1 and 2, and (4) a higher-than-expected offspring sex ratio (more sons) among tall (and hence intelligent) parents. Consistent with our suggestion, we show that men may have higher IQs than women because they are taller, and once we control for height women have slightly higher IQs than men.The correlation between height and IQ and the female advantage in intelligence persist even after we control for health as a measure of genetic quality, as well as physical attractiveness, age, race, education, and earnings. Height is also strongly associated with intelligence within each sex.


Hypersecretion of ACTH and PRL from pituitary adenoma in MEN1, adequately managed by medical therapy.
A 54-year-old man had gastrinoma, parathyroid hyperplasia and pituitary tumor. His family history indicated that he might have multiple endocrine neoplasia type 1 (MEN1). MEN1 gene analysis revealed a heterozygous germline mutation (Gly156Arg). Therefore, we diagnosed him with MEN1. Endocrinological tests revealed that his serum prolactin (PRL) and plasma adrenocorticotropic hormone (ACTH) levels were elevated to 1699 ng/mL and 125 pg/mL respectively. Immunohistochemical analysis of the resected pancreatic tumors revealed that the tumors did not express ACTH. Overnight 0.5 and 8 mg dexamethasone suppression tests indicated that his pituitary tumor was a PRL-ACTH-producing plurihormonal tumor. Before transsphenoidal surgery, cabergoline was initiated. Despite no decrease in the volume of the pituitary tumor, PRL and ACTH levels decreased to 37.8 ng/mL and 57.6 pg/mL respectively. Owing to the emergence of metastatic gastrinoma in the liver, octreotide was initiated. After that, PRL and ACTH levels further decreased to 5.1 ng/mL and 19.7 pg/mL respectively. He died from liver dysfunction, and an autopsy of the pituitary tumor was performed. In the autopsy study, histopathological and immunohistochemical (IHC) analysis showed that the tumor was single adenoma and the cells were positive for ACTH, growth hormone (GH), luteinizing hormone (LH) and PRL. RT-PCR analysis showed that the tumor expressed mRNA encoding all anterior pituitary hormones, pituitary transcription factor excluding estrogen receptor (ER) β, somatostatin receptor (SSTR) 2, SSTR5 and dopamine receptor D (D2R). PRL-ACTH-producing tumor is a very rare type of pituitary tumor, and treatment with cabergoline and octreotide may be useful for controlling hormone levels secreted from a plurihormonal pituitary adenoma, as seen in this case of MEN1. Although plurihormonal pituitary adenomas were reported to be more frequent in patients with MEN1 than in those without, the combination of PRL and ACTH is rare.RT-PCR analysis showed that the pituitary tumor expressed various pituitary transcription factors and IHC analysis revealed that the tumor was positive for PRL, ACTH, GH and LH.Generally, the effectiveness of dopamine agonist and somatostatin analog in corticotroph adenomas is low; however, if the plurihormonal pituitary adenoma producing ACTH expresses SSTR2, SSTR5 and D2R, medical therapy for the pituitary adenoma may be effective.


Increasing destructiveness of tropical cyclones over the past 30 years.
Theory and modelling predict that hurricane intensity should increase with increasing global mean temperatures, but work on the detection of trends in hurricane activity has focused mostly on their frequency and shows no trend. Here I define an index of the potential destructiveness of hurricanes based on the total dissipation of power, integrated over the lifetime of the cyclone, and show that this index has increased markedly since the mid-1970s. This trend is due to both longer storm lifetimes and greater storm intensities. I find that the record of net hurricane power dissipation is highly correlated with tropical sea surface temperature, reflecting well-documented climate signals, including multi-decadal oscillations in the North Atlantic and North Pacific, and global warming. My results suggest that future warming may lead to an upward trend in tropical cyclone destructive potential, and--taking into account an increasing coastal population--a substantial increase in hurricane-related losses in the twenty-first century.


Cyclic dermal BMP signalling regulates stem cell activation during hair regeneration.
In the age of stem cell engineering it is critical to understand how stem cell activity is regulated during regeneration. Hairs are mini-organs that undergo cyclic regeneration throughout adult life, and are an important model for organ regeneration. Hair stem cells located in the follicle bulge are regulated by the surrounding microenvironment, or niche. The activation of such stem cells is cyclic, involving periodic beta-catenin activity. In the adult mouse, regeneration occurs in waves in a follicle population, implying coordination among adjacent follicles and the extrafollicular environment. Here we show that unexpected periodic expression of bone morphogenetic protein 2 (Bmp2) and Bmp4 in the dermis regulates this process. This BMP cycle is out of phase with the WNT/beta-catenin cycle, thus dividing the conventional telogen into new functional phases: one refractory and the other competent for hair regeneration, characterized by high and low BMP signalling, respectively. Overexpression of noggin, a BMP antagonist, in mouse skin resulted in a markedly shortened refractory phase and faster propagation of the regenerative wave. Transplantation of skin from this mutant onto a wild-type host showed that follicles in donor and host can affect their cycling behaviours mutually, with the outcome depending on the equilibrium of BMP activity in the dermis. Administration of BMP4 protein caused the competent region to become refractory. These results show that BMPs may be the long-sought 'chalone' inhibitors of hair growth postulated by classical experiments. Taken together, results presented in this study provide an example of hierarchical regulation of local organ stem cell homeostasis by the inter-organ macroenvironment. The expression of Bmp2 in subcutaneous adipocytes indicates physiological integration between these two thermo-regulatory organs. Our findings have practical importance for studies using mouse skin as a model for carcinogenesis, intra-cutaneous drug delivery and stem cell engineering studies, because they highlight the acute need to differentiate supportive versus inhibitory regions in the host skin.


Phantom pain is associated with preserved structure and function in the former hand area.
Phantom pain after arm amputation is widely believed to arise from maladaptive cortical reorganization, triggered by loss of sensory input. We instead propose that chronic phantom pain experience drives plasticity by maintaining local cortical representations and disrupting inter-regional connectivity. Here we show that, while loss of sensory input is generally characterized by structural and functional degeneration in the deprived sensorimotor cortex, the experience of persistent pain is associated with preserved structure and functional organization in the former hand area. Furthermore, consistent with the isolated nature of phantom experience, phantom pain is associated with reduced inter-regional functional connectivity in the primary sensorimotor cortex. We therefore propose that contrary to the maladaptive model, cortical plasticity associated with phantom pain is driven by powerful and long-lasting subjective sensory experience, such as triggered by nociceptive or top-down inputs. Our results prompt a revisiting of the link between phantom pain and brain organization.


Clonal evolution of preleukemic hematopoietic stem cells precedes human acute myeloid leukemia.
Given that most bone marrow cells are short-lived, the accumulation of multiple leukemogenic mutations in a single clonal lineage has been difficult to explain. We propose that serial acquisition of mutations occurs in self-renewing hematopoietic stem cells (HSCs). We investigated this model through genomic analysis of HSCs from six patients with de novo acute myeloid leukemia (AML). Using exome sequencing, we identified mutations present in individual AML patients harboring the FLT3-ITD (internal tandem duplication) mutation. We then screened the residual HSCs and detected some of these mutations including mutations in the NPM1, TET2, and SMC1A genes. Finally, through single-cell analysis, we determined that a clonal progression of multiple mutations occurred in the HSCs of some AML patients. These preleukemic HSCs suggest the clonal evolution of AML genomes from founder mutations, revealing a potential mechanism contributing to relapse. Such preleukemic HSCs may constitute a cellular reservoir that should be targeted therapeutically for more durable remissions.


Association between the insulin-like growth factor axis in serum and periodontitis in the Study of Health in Pomerania: an exploratory study.
To evaluate the association of Insulin-like Growth Factor (IGF) I-related variables with periodontitis in the population-based Study of Health in Pomerania (SHIP). From the cross-sectional SHIP, 2293 subjects with clinical attachment loss (CAL) data and 2398 subjects with tooth count data aged 20-59 years were analysed. Serum IGF-I and IGF-binding protein (BP)-3 levels were determined by chemiluminescence immunoassays. Linear and logistic regressions with fractional polynomials were used to study associations between IGF-related variables and mean CAL or high tooth loss. For non-linear relations between IGFBP-3 and mean CAL, graphical presentations of fractional polynomials were used to deduce knots for linear splines. In fully adjusted models, for serum IGFBP-3 values ≤1200 ng/ml, mean CAL increased significantly for decreasing serum IGFBP-3 levels [B = -0.027 (95% CI, -0.049; -0.005), p = 0.02]. The odds for high tooth loss decreased significantly for high serum IGFBP-3 values [OR = 0.97 (0.95; 0.99), p = 0.02]. Serum IGF-I levels and the IGF-I/IGFBP-3 ratio were not related to mean CAL or tooth loss after full adjustment. Low serum IGFBP-3 levels might be associated with higher levels of periodontal disease. Neither serum IGF-I nor IGF-I/IGFBP-3 ratios were associated with periodontitis.


Temporal order is coded temporally in the brain: early event-related potential latency shifts underlying prior entry in a cross-modal temporal order judgment task.
The speeding-up of neural processing associated with attended events (i.e., the prior-entry effect) has long been proposed as a viable mechanism by which attention can prioritize our perception and action. In the brain, this has been thought to be regulated through a sensory gating mechanism, increasing the amplitudes of early evoked potentials while leaving their latencies unaffected. However, the majority of previous research has emphasized speeded responding and has failed to emphasize fine temporal discrimination, thereby potentially lacking the sensitivity to reveal putative modulations in the timing of neural processing. In the present study, we used a cross-modal temporal order judgment task while shifting attention between the visual and tactile modalities to investigate the mechanisms underlying selective attention electrophysiologically. Our results indicate that attention can indeed speed up neural processes during visual perception, thereby providing the first electrophysiological support for the existence of prior entry.


Immunogenicity of the tuberculosis vaccine MVA85A is reduced by coadministration with EPI vaccines in a randomized controlled trial in Gambian infants.
New tuberculosis vaccines are urgently needed to curtail the current epidemic. MVA85A is a subunit vaccine that could enhance immunity from BCG vaccination. To determine MVA85A safety and immunogenicity as well as interactions with other routine vaccines administered in infancy, we randomized healthy 4-month-old infants who had received Bacille Calmette-Guérin at birth to receive Expanded Program on Immunization (EPI) vaccines alone, EPI and MVA85A simultaneously, or MVA85A alone. Adverse events were monitored throughout. Blood samples obtained before vaccination and at 1, 4, and 20 weeks after vaccination were used to assess safety and immunogenicity. The safety profile of both low and standard doses was comparable, but the standard dose was more immunogenic and therefore was selected for the second stage of the study. In total, 72 (first stage) and 142 (second stage) infants were enrolled. MVA85A was safe and well tolerated and induced a potent cellular immune response. Coadministration of MVA85A with EPI vaccines was associated with a significant reduction in MVA85A immunogenicity, but did not affect humoral responses to the EPI vaccines. These results provide important information regarding timing of immunizations, which is required for the design of infant efficacy trials with MVA85A, and suggest that modifications to the standard EPI schedule may be required to incorporate a new generation of T cell-inducing vaccines.


Importance of acupuncture on premenstrual syndrome.
Premenstrual syndrome (PMS) is a complex group of symptoms. The clear reasons for PMS have not been understood completely. PMS includes emotional symptoms but mostly physical symptoms. The study was carried out on 11 patients (23-40 age range) diagnosed as having PMS. DSM IV was taken into account as the criteria for diagnosis. Ren2, Ren6, Ren12, LI4, LI11, P6, Liv3, Sp6, St36 and Du20 points were used on patients for the effects of acupuncture. The treatment of acupuncture was applied for three menses. Furthermore, NOx, MDA and GSH values in blood were studied. The complaints of patients were observed to decrease or disappear completely. The most obvious changes were observed in myalgia, mastalgia and dysmenorrheal complaints (p < 0.000). Moreover, before starting the treatment of acupuncture, former blood values of NOx, MDA and GSH were compared with blood values of NOx, MDA and GSH after three cycles. An increase was observed for NOx levels after acupuncture treatment (p < 0.05). While there was no change in the oxidant stress indicator, MDA, an increase in antioxidant indicator GSH levels was observed (p < or = 0.05). Acupuncture to treat premenstrual syndrome can be considered as an effective treatment modality.


Response inhibition is linked to emotional devaluation: behavioural and electrophysiological evidence.
To study links between the inhibition of motor responses and emotional evaluation, we combined electrophysiological measures of prefrontal response inhibition with behavioural measures of affective evaluation. Participants first performed a Go-Nogo task in response to Asian and Caucasian faces (with race determining their Go or Nogo status), followed by a trustworthiness rating for each face. Faces previously seen as Nogo stimuli were rated as less trustworthy than previous Go stimuli. To study links between the efficiency of response inhibition in the Go-Nogo task and subsequent emotional evaluations, the Nogo N2 component was quantified separately for faces that were later judged to be high versus low in trustworthiness. Nogo N2 amplitudes were larger in response to low-rated as compared to high-rated faces, demonstrating that trial-by-trial variations in the efficiency of response inhibition triggered by Nogo faces, as measured by the Nogo N2 component, co-vary with their subsequent affective evaluation. These results suggest close links between inhibitory processes in top-down motor control and emotional responses.


Pharmacological FMRI in the development of new analgesic compounds.
Chronic pain is a major problem for the individual and for society. Despite a range of drugs being available to treat chronic pain, only inadequate pain relief can be achieved for many patients. There is therefore a need for the development of new analgesic compounds. The assessment of pain depends to date entirely on the subjective report of the patient, in contrast to many other clinical conditions where biomarkers that help determine the severity and stage of the disease enable the physician to monitor the course of the disease and treatment effects longitudinally. In this article, we illustrate that magnetic resonance-based imaging techniques have the potential to provide sensitive and specific biomarkers of the pain experience, as well as clarifying disease mechanisms. Functional magnetic resonance imaging (FMRI) is particularly suited to investigating the effects of pharmacological agents on pain processing within the human central nervous system. Combination of FMRI and drug administration is termed pharmacological FMRI (phFMRI). In addition to outlining several methodological considerations that have to be taken into account when performing phFMRI, we discuss phFMRI studies that have already used this technique to study the effects of analgesic compounds. These studies provide promising data for the use of phFMRI as sensitive tool in assessing a potential drug effect. Such pharmacodynamic readouts obtained early in the process of drug development would not only save the pharmaceutical industry substantial amounts of money, but would also avoid the unnecessary exposure of patients to molecules with limited or no therapeutic value. We are therefore optimistic that phFMRI will be used as a tool with high sensitivity and specificity for evaluating analgesic agents in early drug development and clinical studies.


Identification of the BCAR1-CFDP1-TMEM170A locus as a determinant of carotid intima-media thickness and coronary artery disease risk.
Carotid intima-media thickness (cIMT) is a widely accepted marker of subclinical atherosclerosis. To date, large-scale investigations of genetic determinants of cIMT are sparse. To identify cIMT-associated genes and genetic variants, a discovery analysis using the Illumina 200K CardioMetabochip was conducted in 3430 subjects with detailed ultrasonographic determinations of cIMT from the IMPROVE (Carotid Intima Media Thickness [IMT] and IMT-Progression as Predictors of Vascular Events in a High Risk European Population) study. Segment-specific IMT measurements of common carotid, bifurcation, and internal carotid arteries, and composite IMT variables considering the whole carotid tree (IMT(mean), IMT(max), and IMT(mean-max)), were analyzed. A replication stage investigating 42 single-nucleotide polymorphisms for association with common carotid IMT was undertaken in 5 independent European cohorts (total n=11,590). A locus on chromosome 16 (lead single-nucleotide polymorphism rs4888378, intronic in CFDP1) was associated with cIMT at significance levels passing multiple testing correction at both stages (array-wide significant discovery P=6.75 × 10(-7) for IMT(max); replication P=7.24×10(-6) for common cIMT; adjustments for sex, age, and population substructure where applicable; minor allele frequency 0.43 and 0.41, respectively). The protective minor allele was associated with lower carotid plaque score in a replication cohort (P=0.04, n=2120) and lower coronary artery disease risk in 2 case-control studies of subjects with European ancestry (odds ratio [95% confidence interval] 0.83 [0.77-0.90], P=6.53 × 10(-6), n=13 591; and 0.95 [0.92-0.98], P=1.83 × 10(-4), n=82 297, respectively). Queries of human biobank data sets revealed associations of rs4888378 with nearby gene expression in vascular tissues (n=126-138). This study identified rs4888378 in the BCAR1-CFDP1-TMEM170A locus as a novel genetic determinant of cIMT and coronary artery disease risk in individuals of European descent.


Utilisation of gonadotrophin-releasing hormone (GnRH) analogue to differentiate ovarian from adrenal hyperandrogenism in postmenopausal women.
Postmenopausal hyperandrogenism is a relatively rare diagnosis resulting from excess androgen production from the adrenals or ovaries. The exclusion of malignant causes is a priority. Laboratory tests and imaging are utilised to help differentiate the source of excess androgens. We report two cases of postmenopausal hyperandrogenism in women aged 75 and 67 years. Both cases presented with clinical features suggestive of hyperandrogenism which had developed gradually over the previous 2 years. Laboratory investigations confirmed a significant elevation in their serum testosterone levels. In both cases, imaging did not reveal any abnormality of the adrenals or ovaries. To help differentiate an adrenal vs ovarian source a single-dose GnRH analogue was given with measurement of testosterone and gonadotrophin levels pre and post. The reduction in gonadotrophins achieved by the GnRH analogue resulted in suppression of testosterone levels which suggested an ovarian source. Both patients proceeded to bilateral oophorectomy. Histology revealed a benign hilus cell tumour in one case and a benign Leydig cell tumour in the other. Learning points: A key part of the work-up of postmenopausal hyperandrogenism is to differentiate between an adrenal or an ovarian source of excess androgens; Imaging may not identify small ovarian tumours or hyperthecosis and may also identify incidental adrenal masses which are non-functioning; Current guidelines suggest ovarian and adrenal venous sampling when imaging is inconclusive but this requires technical expertise and has a high failure rate; GnRH analogue use can successfully confirm ovarian source and should be considered as a diagnostic tool in this setting.


Deficiency in Kelch protein Klhl31 causes congenital myopathy in mice.
Maintenance of muscle structure and function depends on the precise organization of contractile proteins into sarcomeres and coupling of the contractile apparatus to the sarcoplasmic reticulum (SR), which serves as the reservoir for calcium required for contraction. Several members of the Kelch superfamily of proteins, which modulate protein stability as substrate-specific adaptors for ubiquitination, have been implicated in sarcomere formation. The Kelch protein Klhl31 is expressed in a muscle-specific manner under control of the transcription factor MEF2. To explore its functions in vivo, we created a mouse model of Klhl31 loss of function using the CRISPR-Cas9 system. Mice lacking Klhl31 exhibited stunted postnatal skeletal muscle growth, centronuclear myopathy, central cores, Z-disc streaming, and SR dilation. We used proteomics to identify several candidate Klhl31 substrates, including Filamin-C (FlnC). In the Klhl31-knockout mice, FlnC protein levels were highly upregulated with no change in transcription, and we further demonstrated that Klhl31 targets FlnC for ubiquitination and degradation. These findings highlight a role for Klhl31 in the maintenance of skeletal muscle structure and provide insight into the mechanisms underlying congenital myopathies.


Attendance of men at the familial cancer clinic: what they value from the consultation.
This study examined what men from high-risk breast/ovarian cancer families valued from attending a familial cancer clinic. One hundred men from families with a BRCA1 or BRCA2 mutation completed a self-administered questionnaire. Seventy- two percent (72%) of men attended the familial cancer clinic at the request of a family member. Multivariate analyses showed that men with a preference for a collaborative decision-making style (B = -4.651, 95% CI = -9.014 to -0.289, P = 0.04), those with lower levels of education (B = -4.850, 95% CI = -9.16 to -0.537, P = 0.03), and those with higher levels of cancer-related anxiety (intrusion) (B = 0.920, 95% CI = 0.441-1.399, P < 0.001) were more likely to value emotional support from the clinic. Men with a collaborative decision-making style (B = -2.68, 95% CI = -4.91 to -0.467, P = 0.02) were less likely, and those with higher total levels of cancer-related anxiety (intrusion and avoidance) (B = 0.393, 95% CI = 0.008-0.779, P = 0.04) were more likely to value receiving information from the clinic. A preference for collaborative decision making and cancer-related anxiety predicted men valuing information and emotional support from the consultation. The finding that men's attendance is initiated by family members highlights the value men place on family responsibility.


Independent guidance of retinal axons in the developing visual system of Drosophila.
The development of the adult visual system of Drosophila requires the establishment of precise retinotopic connections between retinal photoreceptor cell axons and their synaptic partners in the optic lobe of the brain. To assess the role of axon-axon interactions in retinal axon guidance, we used genetic methods to disrupt the normal spatiotemporal order of retinal axon ingrowth. We examined retinal axon projections to the developing first optic ganglion, the lamina, in two mutants in which reduced numbers of ommatidia develop in the eye imaginal disk. We find that in the developing lamina of these mutants, sine oculis and Ellipse, retinal axons project to proper dorsoventral positions despite the absence of the usual array of neighboring retinal axons. In a second approach, we examined animals that were somatic mosaics for the mutation, glass. In glass- animals, retinal axons project aberrantly and the larval optic nerve is absent. We find that in the developing lamina of glass mosaic animals, wild-type retinal axons project to proper dorsoventral positions despite the misrouted projections of neighboring glass- retinal axons. In addition, wild-type retinal axons project normally in the absence of the larval optic nerve, indicating that the latter is not an essential pioneer for retinal axon navigation. Our observations support the proposal that axon fascicles can make at least some pathfinding decisions independently of other retinal axon fascicles. We suggest that positional guidance cues that might label axon pathways and target destinations contribute to retinotopic pattern formation in the Drosophila visual system.


Effects of 3,4-methylenedioxyamphetamine and 3,4-methylenedioxymethamphetamine isomers on central serotonergic, dopaminergic and nigral neurotensin systems of the rat.
This study demonstrates that the isomers of 3,4-methylenedioxyamphetamine (MDA) and 3,4-methylenedioxymethamphetamine (MDMA) are different in their ability to induce changes in serotonergic parameters and nigral concentrations of neurotensin-like immunoreactivity. With five successive doses (3.5 mg/kg) the d-MDA isomer was more potent than the l-MDA in its ability to decrease the concentrations of serotonin in the frontal cortex and hippocampus. The same difference occurred in the ability to decrease the hippocampal activity of tryptophan hydroxylase as well as the hippocampal and neostriatal 5-hydroxyindoleacetic acid concentrations. However, both isomers of MDMA were equipotent in their ability to decrease serotonergic parameters in the brain areas examined. When the doses were increased to 5 and 10 mg/kg, both isomers of MDA were equipotent in their effects on the serotonin system, whereas the l-MDMA was significantly less potent than its d isomeric counterpart in causing a decrease in serotonergic parameters of the different brain areas. In contrast, treatments with any of the isomers appeared to have a minimal impact on neostriatal dopaminergic parameters. However, treatment with MDA or MDMA caused increases in the nigral concentrations of neurotensin, with the d isomer of both compounds having substantially greater effects on this neuropeptide system. These increases are suspected to result from drug-released dopamine. This study demonstrates that at selected doses, the d isomers of MDA and MDMA are more potent than their l forms in affecting neurochemical systems, whereas high doses of either isomer of MDA share a common ability to induce changes in the serotonergic system that are likely associated with neuronal damage.


Human papillomavirus (HPV) vaccines as an option for preventing cervical malignancies: (how) effective and safe?
We carried out a systematic review of HPV vaccine pre- and post-licensure trials to assess the evidence of their effectiveness and safety. We find that HPV vaccine clinical trials design, and data interpretation of both efficacy and safety outcomes, were largely inadequate. Additionally, we note evidence of selective reporting of results from clinical trials (i.e., exclusion of vaccine efficacy figures related to study subgroups in which efficacy might be lower or even negative from peer-reviewed publications). Given this, the widespread optimism regarding HPV vaccines long-term benefits appears to rest on a number of unproven assumptions (or such which are at odd with factual evidence) and significant misinterpretation of available data. For example, the claim that HPV vaccination will result in approximately 70% reduction of cervical cancers is made despite the fact that the clinical trials data have not demonstrated to date that the vaccines have actually prevented a single case of cervical cancer (let alone cervical cancer death), nor that the current overly optimistic surrogate marker-based extrapolations are justified. Likewise, the notion that HPV vaccines have an impressive safety profile is only supported by highly flawed design of safety trials and is contrary to accumulating evidence from vaccine safety surveillance databases and case reports which continue to link HPV vaccination to serious adverse outcomes (including death and permanent disabilities). We thus conclude that further reduction of cervical cancers might be best achieved by optimizing cervical screening (which carries no such risks) and targeting other factors of the disease rather than by the reliance on vaccines with questionable efficacy and safety profiles.


Gamma Knife surgery for convexity, parasagittal, and falcine meningiomas.
The aim of this study was to evaluate the outcomes in patients with convexity, parasagittal, or falcine meningiomas treated using Gamma Knife surgery (GKS) and to determine management strategy considering a risk of radiation-induced edema. One hundred twelve patients who harbored 125 convexity, parasagittal, or falcine meningiomas were assessed. Forty-six patients underwent GKS as the initial treatment. The median tumor diameter was 25 mm, and median tumor volume was 8 cm(3). The median maximum and margin doses were 30 and 16 Gy, respectively. The median follow-up period was 72 months. The actuarial 5- and 10-year progression-free survival rates were 78% and 55%, respectively. The actuarial 5- and 10-year local tumor control rates were 87% and 71%, respectively. Of 29 tumors that developed postradiosurgical edema, 7 were symptomatic. The actuarial symptomatic radiation-induced edema rate was 7%. The incidence of this complication was significantly higher in patients who underwent GKS as the initial treatment. Six of 46 patients for whom GKS was the initial treatment had preradiosurgical edema. Of these 6 patients, 4 developed severe panhemispheric edema after GKS (2 patients with parasagittal tumors, 1 with a falx tumor, and 1 with a convexity tumor). Gamma Knife surgery is an effective treatment for convexity, parasagittal, and falcine meningiomas as the initial or adjuvant treatment. However, GKS should be restricted to small- to medium-sized tumors, particularly in patients with primary tumors, because radiation-induced edema is more common in convexity, parasagittal, and falcine meningiomas than skull base meningiomas.


Time from HIV-1 seroconversion to AIDS and death before widespread use of highly-active antiretroviral therapy: a collaborative re-analysis. Collaborative Group on AIDS Incubation and HIV Survival including the CASCADE EU Concerted Action. Concerted Action on SeroConversion to AIDS and Death in Europe.
We used data from Europe, North America, and Australia to assess the effect of exposure category on the AIDS incubation period and HIV-1 survival and whether the effect of age at seroconversion varies with exposure category and with time since seroconversion. 38 studies of HIV-1-infected individuals whose dates of seroconversion could be reliably estimated were included in the analysis. Individual data on 13030 HIV-1-infected individuals from 15 countries were collated, checked, and analysed centrally. We calculated estimates of mortality and AIDS incidence rates and estimated the proportions of individuals surviving and developing AIDS at each year after seroconversion from the numbers of observed deaths or cases of AIDS and the corresponding person-years at risk. Analyses were adjusted for age at seroconversion, time since seroconversion, and other factors as appropriate. Mortality and AIDS incidence increased strongly with time since seroconversion and age at seroconversion. Median survival varied from 12.5 years (95% CI 12.1-12.9) for those aged 15-24 years at seroconversion to 7.9 years (7.4-8.5) for those aged 45-54 years at seroconversion, whereas for development of AIDS the corresponding values were 11.0 years (10.7-11.7) and 7.7 years (7.1-8.6). There was no appreciable effect of exposure category on survival. For AIDS incidence, the exposure category effect that we noted was explained by the high incidence of Kaposi's sarcoma in those infected through sex between men. We estimated that among people aged 25-29 years at seroconversion 90% (89-91) and 60% (57-62) survived to 5 years and 10 years, respectively, after seroconversion, whereas 13% (12-15) and 46% (44-49), respectively, developed AIDS (excluding Kaposi's sarcoma). Before widespread use of highly-active antiretroviral therapy (before 1996), time since seroconversion and age at seroconversion were the major determinants of survival and development of AIDS in Europe, North America, and Australia.


Characterisation of a syndrome of autoimmune adult onset focal epilepsy and encephalitis.
We report a series of patients with a clinical syndrome characterised by the explosive onset in adulthood of recurrent focal seizures of frontotemporal onset and features suggestive of autoimmune encephalitis. We propose that this presentation of "autoimmune adult onset focal epilepsy and encephalitis" is a recognisable clinical syndrome, and provide evidence it may be associated with heterogeneous immunological targets. Between 2008 and 2011 we encountered six patients with new-onset epilepsy in whom we suspected an autoimmune aetiology. We first characterised the clinical, electroencephalographic, cerebrospinal fluid (CSF), imaging, and pathological findings of this syndrome. We subsequently tested them for antibodies against both intracellular and neuronal cell surface antigens. All patients presented with recurrent seizures with focal frontotemporal onset, refractory to multiple anticonvulsants. Four had focal T2-weighted hyperintensities on MRI. CSF mononuclear cells were variably elevated with positive oligoclonal bands in four. Brain biopsy in one patient demonstrated perivascular lymphocytic infiltration. Two were treated with immunosuppression and went on to achieve complete seizure control and return to baseline cognition. Three of four patients who received only pulsed steroids or no treatment had ongoing frequent seizures, with two dying of sudden unexpected death in epilepsy. Subsequently, three had antibodies identified against neuronal cell surface antigens including N-methyl-D-aspartate receptor and leucine-rich glioma inactivated 1. We suggest that patients with such a presentation should be carefully evaluated for a suspected autoimmune aetiology targeting cell surface antigens and have a therapeutic trial of immunosuppression as this may improve their long-term outcome.


Bee products prevent agrichemical-induced oxidative damage in fish.
In southern South America and other parts of the world, aquaculture is an activity that complements agriculture. Small amounts of agrichemicals can reach aquaculture ponds, which results in numerous problems caused by oxidative stress in non-target organisms. Substances that can prevent or reverse agrichemical-induced oxidative damage may be used to combat these effects. This study includes four experiments. In each experiment, 96 mixed-sex, 6-month-old Rhamdia quelen (118±15 g) were distributed into eight experimental groups: a control group that was not exposed to contaminated water, three groups that were exposed to various concentrations of bee products, three groups that were exposed to various concentrations of bee products plus tebuconazole (TEB; Folicur 200 CE™) and a group that was exposed to 0.88 mg L(-1) of TEB alone (corresponding to 16.6% of the 96-h LC50). We show that waterborne bee products, including royal jelly (RJ), honey (H), bee pollen (BP) and propolis (P), reversed the oxidative damage caused by exposure to TEB. These effects were likely caused by the high polyphenol contents of these bee-derived compounds. The most likely mechanism of action for the protective effects of bee products against tissue oxidation and the resultant damage is that the enzymatic activities of superoxide dismutase (SOD), catalase (CAT) and glutathione-S-transferase (GST) are increased.


Structure and dynamics of the deoxyguanosine-sensing riboswitch studied by NMR-spectroscopy.
The mfl-riboswitch regulates expression of ribonucleotide reductase subunit in Mesoplasma florum by binding to 2'-deoxyguanosine and thereby promoting transcription termination. We characterized the structure of the ligand-bound aptamer domain by NMR spectroscopy and compared the mfl-aptamer to the aptamer domain of the closely related purine-sensing riboswitches. We show that the mfl-aptamer accommodates the extra 2'-deoxyribose unit of the ligand by forming a more relaxed binding pocket than these found in the purine-sensing riboswitches. Tertiary structures of the xpt-aptamer bound to guanine and of the mfl-aptamer bound to 2'-deoxyguanosine exhibit very similar features, although the sequence of the mfl-aptamer contains several alterations compared to the purine-aptamer consensus sequence. These alterations include the truncation of a hairpin loop which is crucial for complex formation in all purine-sensing riboswitches characterized to date. We further defined structural features and ligand binding requirements of the free mfl-aptamer and found that the presence of Mg(2+) is not essential for complex formation, but facilitates ligand binding by promoting pre-organization of key structural motifs in the free aptamer.


HLA-B27-mediated activation of TNAP phosphatase promotes pathogenic syndesmophyte formation in ankylosing spondylitis.
Ankylosing spondylitis (AS) is a type of axial inflammation. Over time, some patients develop spinal ankylosis and permanent disability; however, current treatment strategies cannot arrest syndesmophyte formation completely. Here, we used mesenchymal stem cells (MSCs) from AS patients (AS MSCs) within the enthesis involved in spinal ankylosis to delineate that the HLA-B27-mediated spliced X-box-binding protein 1 (sXBP1)/retinoic acid receptor-β (RARB)/tissue-nonspecific alkaline phosphatase (TNAP) axis accelerated the mineralization of AS MSCs, which was independent of Runt-related transcription factor 2 (Runx2). An animal model mimicking AS pathological bony appositions was established by implantation of AS MSCs into the lumbar spine of NOD-SCID mice. We found that TNAP inhibitors, including levamisole and pamidronate, inhibited AS MSC mineralization in vitro and blocked bony appositions in vivo. Furthermore, we demonstrated that the serum bone-specific TNAP (BAP) level was a potential prognostic biomarker to predict AS patients with a high risk for radiographic progression. Our study highlights the importance of the HLA-B27-mediated activation of the sXBP1/RARB/TNAP axis in AS syndesmophyte pathogenesis and provides a new strategy for the diagnosis and prevention of radiographic progression of AS.


Bone marrow-derived stromal cells home to and remain in the infarcted rat heart but fail to improve function: an in vivo cine-MRI study.
Basic and clinical studies have shown that bone marrow cell therapy can improve cardiac function following infarction. In experimental animals, reported stem cell-mediated changes range from no measurable improvement to the complete restoration of function. In the clinic, however, the average improvement in left ventricular ejection fraction is around 2% to 3%. A possible explanation for the discrepancy between basic and clinical results is that few basic studies have used the magnetic resonance (MR) imaging (MRI) methods that were used in clinical trials for measuring cardiac function. Consequently, we employed cine-MR to determine the effect of bone marrow stromal cells (BMSCs) on cardiac function in rats. Cultured rat BMSCs were characterized using flow cytometry and labeled with iron oxide particles and a fluorescent marker to allow in vivo cell tracking and ex vivo cell identification, respectively. Neither label affected in vitro cell proliferation or differentiation. Rat hearts were infarcted, and BMSCs or control media were injected into the infarct periphery (n = 34) or infused systemically (n = 30). MRI was used to measure cardiac morphology and function and to determine cell distribution for 10 wk after infarction and cell therapy. In vivo MRI, histology, and cell reisolation confirmed successful BMSC delivery and retention within the myocardium throughout the experiment. However, no significant improvement in any measure of cardiac function was observed at any time. We conclude that cultured BMSCs are not the optimal cell population to treat the infarcted heart.


Interrater reliability of a method to assess hypothalamic involvement in pediatric adamantinomatous craniopharyngioma.
Pediatric adamantinomatous craniopharyngiomas (ACPs) are histologically benign brain tumors that confer significant neuroendocrine morbidity. Previous studies have demonstrated that injury to the hypothalamus is associated with worsened quality of life and a shorter lifespan. This insight helps many surgeons define the goals of surgery for patients with ACP. Puget and colleagues proposed a 3-tiered preoperative and postoperative grading system based on the degree of hypothalamic involvement identified on MRI. In a prospective cohort from their institution, the authors found that use of the system to guide operative goals was associated with decreased morbidity. To date, however, the Puget system has not been externally validated. Here, the authors present an interrater reliability study that assesses the generalizability of this system for surgeons planning initial operative intervention for children with craniopharyngiomas. A panel of 6 experts, consisting of pediatric neurosurgeons and pediatric neuroradiologists, graded 30 preoperative and postoperative MRI scans according to the Puget system. Interrater reliability was calculated using Fleiss' κ and Krippendorff's α statistics. Interrater reliability in the preoperative context demonstrated moderate agreement (κ = 0.50, α = 0.51). Interrater reliability in the postoperative context was 0.27 for both methods of statistical evaluation. Interrater reliability for the system as defined is moderate. Slight refinements of the Puget MRI grading system, such as collapsing the 3 grades into 2, may improve its reliability, making the system more generalizable.


Napping facilitates word learning in early lexical development.
Little is known about the role that night-time sleep and daytime naps play in early cognitive development. Our aim was to investigate how napping affects word learning in 16-month-olds. Thirty-four typically developing infants were assigned randomly to nap and wake groups. After teaching two novel object-word pairs to infants, we tested their initial performance with an intermodal preferential looking task in which infants are expected to increase their target looking time compared to a distracter after hearing its auditory label. A second test session followed after approximately a 2-h delay. The delay contained sleep for the nap group or no sleep for the wake group. Looking behaviour was measured with an automatic eye-tracker. Vocabulary size was assessed using the Oxford Communicative Development Inventory. A significant interaction between group and session was found in preferential looking towards the target picture. The performance of the nap group increased after the nap, whereas that of the wake group did not change. The gain in performance correlated positively with the expressive vocabulary size in the nap group. These results indicate that daytime napping helps consolidate word learning in infancy.


Impact of Apolipoprotein(a) Isoform Size on Lipoprotein(a) Lowering in the HPS2-THRIVE Study.
Genetic studies have shown lipoprotein(a) (Lp[a]) to be an important causal risk factor for coronary disease. Apolipoprotein(a) isoform size is the chief determinant of Lp(a) levels, but its impact on the benefits of therapies that lower Lp(a) remains unclear. HPS2-THRIVE (Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events) is a randomized trial of niacin-laropiprant versus placebo on a background of simvastatin therapy. Plasma Lp(a) levels at baseline and 1 year post-randomization were measured in 3978 participants from the United Kingdom and China. Apolipoprotein(a) isoform size, estimated by the number of kringle IV domains, was measured by agarose gel electrophoresis and the predominantly expressed isoform identified. Allocation to niacin-laropiprant reduced mean Lp(a) by 12 (SE, 1) nmol/L overall and 34 (6) nmol/L in the top quintile by baseline Lp(a) level (Lp[a] ≥128 nmol/L). The mean proportional reduction in Lp(a) with niacin-laropiprant was 31% but varied strongly with predominant apolipoprotein(a) isoform size (PTrend=4×10-29) and was only 18% in the quintile with the highest baseline Lp(a) level and low isoform size. Estimates from genetic studies suggest that these Lp(a) reductions during the short term of the trial might yield proportional reductions in coronary risk of ≈2% overall and 6% in the top quintile by Lp(a) levels. Proportional reductions in Lp(a) were dependent on apolipoprotein(a) isoform size. Taking this into account, the likely benefits of niacin-laropiprant on coronary risk through Lp(a) lowering are small. Novel therapies that reduce high Lp(a) levels by at least 80 nmol/L (≈40%) may be needed to produce worthwhile benefits in people at the highest risk because of Lp(a). URL: https://clinicaltrials.gov. Unique identifier: NCT00461630.


Bi-specific splice-switching PMO oligonucleotides conjugated via a single peptide active in a mouse model of Duchenne muscular dystrophy.
The potential for therapeutic application of splice-switching oligonucleotides (SSOs) to modulate pre-mRNA splicing is increasingly evident in a number of diseases. However, the primary drawback of this approach is poor cell and in vivo oligonucleotide uptake efficacy. Biological activities can be significantly enhanced through the use of synthetically conjugated cationic cell penetrating peptides (CPPs). Studies to date have focused on the delivery of a single SSO conjugated to a CPP, but here we describe the conjugation of two phosphorodiamidate morpholino oligonucleotide (PMO) SSOs to a single CPP for simultaneous delivery and pre-mRNA targeting of two separate genes, exon 23 of the Dmd gene and exon 5 of the Acvr2b gene, in a mouse model of Duchenne muscular dystrophy. Conjugations of PMOs to a single CPP were carried out through an amide bond in one case and through a triazole linkage ('click chemistry') in the other. The most active bi-specific CPP-PMOs demonstrated comparable exon skipping levels for both pre-mRNA targets when compared to individual CPP-PMO conjugates both in cell culture and in vivo in the mdx mouse model. Thus, two SSOs with different target sequences conjugated to a single CPP are biologically effective and potentially suitable for future therapeutic exploitation.


Political diversity will improve social psychological science.
Psychologists have demonstrated the value of diversity--particularly diversity of viewpoints--for enhancing creativity, discovery, and problem solving. But one key type of viewpoint diversity is lacking in academic psychology in general and social psychology in particular: political diversity. This article reviews the available evidence and finds support for four claims: (1) Academic psychology once had considerable political diversity, but has lost nearly all of it in the last 50 years. (2) This lack of political diversity can undermine the validity of social psychological science via mechanisms such as the embedding of liberal values into research questions and methods, steering researchers away from important but politically unpalatable research topics, and producing conclusions that mischaracterize liberals and conservatives alike. (3) Increased political diversity would improve social psychological science by reducing the impact of bias mechanisms such as confirmation bias, and by empowering dissenting minorities to improve the quality of the majority's thinking. (4) The underrepresentation of non-liberals in social psychology is most likely due to a combination of self-selection, hostile climate, and discrimination. We close with recommendations for increasing political diversity in social psychology.


Fundoplication versus post-operative medication for gastro-oesophageal reflux in children with neurological impairment undergoing gastrostomy.
Children with neurological impairments (NI) frequently experience feeding difficulties which can lead to malnutrition and growth failure. Gastrostomy feeding is now the preferred method of providing nutritional support to children with NI who are unable to feed adequately by mouth. Complications may arise as a result of gastrostomy placement and the development or worsening of gastro-oesophageal reflux (GOR) has been widely reported. This has led to the frequent use of surgical anti-reflux treatment in the form of a fundoplication, or other Anti-Reflux Procedures. Fundoplication is associated with a high recurrence rate, surgical failure and significant morbidity and mortality. Since Proton Pump Inhibitors (PPIs) were introduced in the 1990s they have come to play a larger part in the medical management of GOR in children with NI. Uncontrolled studies suggest that PPIs may be a safe, appropriate treatment for GOR. Other agents currently used include milk thickeners, acid suppression drugs, acid buffering agents, gut motility stimulants and sodium alginate preparations. There are risks and benefits associated with both surgical and medical interventions and further comparison is necessary to determine the optimal treatment choice. To compare the effectiveness of anti-reflux surgery and anti-reflux medications for children with NI and GOR who are undergoing placement of a gastrostomy feeding tube. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) up to Issue 2, 2006, MEDLINE (1966 to June 2006), EMBASE (1980 to week 33, 2006), CINAHL (1982 -to May, week 4, 2006), LILACS (1982 to June 2006), ISI Web of Science (1970 to June 2006) and the Child Health Library (searched June 2006). We also performed online searches of trial registries, medical journals, conference proceedings, dissertations and theses. Specialists in the medical and industry setting were contacted for knowledge of completed or ongoing trials. We sought to include only randomised controlled trials that recruited children up to the age of 18 years with NI and GOR who were undergoing gastrostomy tube insertion. Two reviewers worked independently on selected trials and performed data extraction and assessment of trial quality. No trials were identified that satisfied the criteria for this review. There remains considerable uncertainty regarding the optimal treatment when faced with the decision of fundoplication surgery versus anti-reflux medications for gastro-oesophageal-reflux in the child with neurological impairment who is undergoing gastrostomy insertion. There is a need for robust scientific evidence in order to provide data on the comparable risks or benefits of the two interventions.


Working with Concepts: The Role of Community in International Collaborative Biomedical Research.
The importance of communities in strengthening the ethics of international collaborative research is increasingly highlighted, but there has been much debate about the meaning of the term 'community' and its specific normative contribution. We argue that 'community' is a contingent concept that plays an important normative role in research through the existence of morally significant interplay between notions of community and individuality. We draw on experience of community engagement in rural Kenya to illustrate two aspects of this interplay: (i) that taking individual informed consent seriously involves understanding and addressing the influence of communities in which individuals' lives are embedded; (ii) that individual participation can generate risks and benefits for communities as part of the wider implications of research. We further argue that the contingent nature of a community means that defining boundaries is generally a normative process itself, with ethical implications. Community engagement supports the enactment of normative roles; building mutual understanding and trust between researchers and community members have been important goals in Kilifi, requiring a broad range of approaches. Ethical dilemmas are continuously generated as part of these engagement activities, including the risks of perverse outcomes related to existing social relations in communities and conditions of 'half knowing' intrinsic to processes of developing new understandings.


Global atmospheric black carbon inferred from AERONET.
AERONET, a network of well calibrated sunphotometers, provides data on aerosol optical depth and absorption optical depth at >250 sites around the world. The spectral range of AERONET allows discrimination between constituents that absorb most strongly in the UV region, such as soil dust and organic carbon, and the more ubiquitously absorbing black carbon (BC). AERONET locations, primarily continental, are not representative of the global mean, but they can be used to calibrate global aerosol climatologies produced by tracer transport models. We find that the amount of BC in current climatologies must be increased by a factor of 2-4 to yield best agreement with AERONET, in the approximation in which BC is externally mixed with other aerosols. The inferred climate forcing by BC, regardless of whether it is internally or externally mixed, is approximately 1 W/m2, most of which is probably anthropogenic. This positive forcing (warming) by BC must substantially counterbalance cooling by anthropogenic reflective aerosols. Thus, especially if reflective aerosols such as sulfates are reduced, it is important to reduce BC to minimize global warming.


Magnesium supplementation improves indicators of low magnesium status and inflammatory stress in adults older than 51 years with poor quality sleep.
Low magnesium status has been associated with numerous conditions characterized as having a chronic inflammatory stress component. Some animal findings indicate that a moderate magnesium deficiency, similar to which apparently commonly occurs in humans, may enhance inflammatory or oxidative stress induced by other factors, including disrupted sleep/sleep deprivation. Thus, an experiment was performed with 100 adults (22 males and 78 females) aged 59 ± 8 years (range 51 to 85 years) with poor sleep quality revealed by a Pittsburg Sleep Quality Index (PSQI) score higher than five. The participants were randomly assigned to two groups matched by gender, age, and overall PSQI score. After baseline assessment (week one) of body mass index (BMI), diet, blood and urine biochemical variables, and sleep quality, one group was given a 320 mg magnesium/day supplement as magnesium citrate and the other group a sodium citrate placebo for seven weeks. Final assessments were made five and seven weeks (which were combined for statistical analysis to reduce intra-individual variation) after supplement initiation for the 96 participants who completed the study as designed. Based on food diaries, 58% of the participants were consuming less than the US. Estimated Average Requirement (EAR) for magnesium. Consuming less than the EAR was associated with a significantly higher BMI and plasma C-reactive protein (CRP) concentration. Only 40 participants had plasma CRP concentrations higher than 3.0 mg/L (an indication of chronic inflammatory stress). Overall PSQI scores improved (10.4 to 6.6, p < 0.0001) and erythrocyte magnesium increased (4.75 to 5.05 pg/cell, p = 0.01) regardless of magnesium or placebo supplementation. Magnesium vs placebo supplementation did not significantly affect serum magnesium when all participants were included in the analysis. When only the 37 participants with serum magnesium concentrations < 1.8 mg/dL (indication of deficient magnesium status) were analyzed, magnesium supplementation, but not the placebo, increased serum magnesium concentrations. Magnesium supplementation vs placebo decreased plasma CRP in participants with baseline values > 3.0 mg/L. The findings show that many individuals have a low magnesium status associated with increased chronic inflammatory stress that could be alleviated by increased magnesium intake. Because dietary magnesium intake did not change during the experimental period, another factor, possibly a placebo effect, improved sleep quality, which resulted in increased erythrocyte magnesium. This factor prevented the determination of whether magnesium deficiency contributes to poor sleep quality. The findings, however, suggest an association between magnesium status and sleep quality that needs further study to definitively determine whether a low magnesium status is a cause or an effect of poor sleep quality.


A high fat diet increases mitochondrial fatty acid oxidation and uncoupling to decrease efficiency in rat heart.
Elevated levels of cardiac mitochondrial uncoupling protein 3 (UCP3) and decreased cardiac efficiency (hydraulic power/oxygen consumption) with abnormal cardiac function occur in obese, diabetic mice. To determine whether cardiac mitochondrial uncoupling occurs in non-genetic obesity, we fed rats a high fat diet (55% kcal from fat) or standard laboratory chow (7% kcal from fat) for 3 weeks, after which we measured cardiac function in vivo using cine MRI, efficiency in isolated working hearts and respiration rates and ADP/O ratios in isolated interfibrillar mitochondria; also, measured were medium chain acyl-CoA dehydrogenase (MCAD) and citrate synthase activities plus uncoupling protein 3 (UCP3), mitochondrial thioesterase 1 (MTE-1), adenine nucleotide translocase (ANT) and ATP synthase protein levels. We found that in vivo cardiac function was the same for all rats, yet oxygen consumption was 19% higher in high fat-fed rat hearts, therefore, efficiency was 21% lower than in controls. We found that mitochondrial fatty acid oxidation rates were 25% higher, and MCAD activity was 23% higher, in hearts from rats fed the high fat diet when compared with controls. Mitochondria from high fat-fed rat hearts had lower ADP/O ratios than controls, indicating increased respiratory uncoupling, which was ameliorated by GDP, a UCP3 inhibitor. Mitochondrial UCP3 and MTE-1 levels were both increased by 20% in high fat-fed rat hearts when compared with controls, with no significant change in ATP synthase or ANT levels, or citrate synthase activity. We conclude that increased cardiac oxygen utilisation, and thereby decreased cardiac efficiency, occurs in non-genetic obesity, which is associated with increased mitochondrial uncoupling due to elevated UCP3 and MTE-1 levels.


The Involvement of the McsB Arginine Kinase in Clp-Dependent Degradation of the MgsR Regulator in Bacillus subtilis.
Regulated ATP-dependent proteolysis is a common feature of developmental processes and plays also a crucial role during environmental perturbations such as stress and starvation. The Bacillus subtilis MgsR regulator controls a subregulon within the stress- and stationary phase σB regulon. After ethanol exposition and a short time-window of activity, MgsR is ClpXP-dependently degraded with a half-life of approximately 6 min. Surprisingly, a protein interaction analysis with MgsR revealed an association with the McsB arginine kinase and an in vivo degradation assay confirmed a strong impact of McsB on MgsR degradation. In vitro phosphorylation experiments with arginine (R) by lysine (K) substitutions in McsB and its activator McsA unraveled all R residues, which are essentially needed for the arginine kinase reaction. Subsequently, site directed mutagenesis of the MgsR substrate was used to substitute all arginine residues with glutamate (R-E) to mimic arginine phosphorylation and to test their influence on MgsR degradation in vivo. It turned out, that especially the R33E and R94/95E residues (RRPI motif), the latter are adjacently located to the two redox-sensitive cysteines in a 3D model, have the potential to accelerate MgsR degradation. These results imply that selective arginine phosphorylation may have favorable effects for Clp dependent degradation of short-living regulatory proteins. We speculate that in addition to its kinase activity and adaptor function for the ClpC ATPase, McsB might also serve as a proteolytic adaptor for the ClpX ATPase in the degradation mechanism of MgsR.


Gene array of VHL mutation and hypoxia shows novel hypoxia-induced genes and that cyclin D1 is a VHL target gene.
Gene expression analysis was performed on a human renal cancer cell line (786-0) with mutated VHL gene and a transfectant with wild-type VHL to analyse genes regulated by VHL and to compare with the gene programme regulated by hypoxia. There was a highly significant concordance of the global gene response to hypoxia and genes suppressed by VHL. Cyclin D1 was the most highly inducible transcript and 14-3-3 epsilon was downregulated. There were some genes regulated by VHL but not hypoxia in the renal cell line, suggesting a VHL role independent of hypoxia. However in nonrenal cell lines they were hypoxia regulated. These included several new pathways regulated by hypoxia, including RNase 6PL, collagen type 1 alpha 1, integrin alpha 5, ferritin light polypeptide, JM4 protein, transgelin and L1 cell adhesion molecule. These were not found in a recent SAGE analysis of the same cell line. Hypoxia induced downregulation of Cyclin D1 in nonrenal cells via an HIF independent pathway. The selective regulation of Cyclin D1 by hypoxia in renal cells may therefore contribute to the tissue selectivity of VHL mutation.


The complete mitochondrial genome of the common vole, Microtus arvalis (Rodentia: Arvicolinae).
The common vole, Microtus arvalis belongs to the genus Microtus in the subfamily Arvicolinae. In this study, the complete mitochondrial genome of M. arvalis was recovered using shotgun sequencing and an iterative mapping approach using three related species. Phylogenetic analyses using the sequence of 21 arvicoline species place the common vole as a sister species to the East European vole (Microtus levis), but as opposed to previous results we find no support for the recognition of the genus Neodon within the subfamily Arvicolinae, as this is, as well as the genus Lasiopodomys, found within the Microtus genus.


An integrated model of eicosanoid metabolism and signaling based on lipidomics flux analysis.
There is increasing evidence for a major and critical involvement of lipids in signal transduction and cellular trafficking, and this has motivated large-scale studies on lipid pathways. The Lipid Metabolites and Pathways Strategy consortium is actively investigating lipid metabolism in mammalian cells and has made available time-course data on various lipids in response to treatment with KDO(2)-lipid A (a lipopolysaccharide analog) of macrophage RAW 264.7 cells. The lipids known as eicosanoids play an important role in inflammation. We have reconstructed an integrated network of eicosanoid metabolism and signaling based on the KEGG pathway database and the literature and have developed a kinetic model. A matrix-based approach was used to estimate the rate constants from experimental data and these were further refined using generalized constrained nonlinear optimization. The resulting model fits the experimental data well for all species, and simulated enzyme activities were similar to their literature values. The quantitative model for eicosanoid metabolism that we have developed can be used to design experimental studies utilizing genetic and pharmacological perturbations to probe fluxes in lipid pathways.


How health technology assessment agencies address the issue of unpublished data.
Reporting bias potentially threatens the validity of results in health technology assessment (HTA) reports. Our study aimed to explore policies and practices of HTA agencies regarding strategies to include previously unpublished data in their assessments, focusing on requests to industry for unpublished data. We included international HTA agencies with publicly available methods papers as well as HTA reports. From the methods papers and recent reports we extracted information on requests to industry and on searches in trial registries, regulatory authority Web sites and for conference abstracts. Eighteen HTA agencies and seventy-three reports were included. Agencies' methods papers showed variability regarding requests to industry (requests are routinely carried out in seven cases, not mentioned in six, at the discretion of HTA authors in three, and based on manufacturer applications in two), which were reflected in the reports investigated. As reporting of requests was limited, it often remained unclear whether unpublished data had been received. Searches in trial registries, at regulatory authorities or for conference abstracts are described as a routine or optional part of the search strategy in the methods papers of 9, 11, and 8 included agencies, respectively. A total of 52 percent, 39 percent, and 16 percent of reports described searches in trial registries, at regulatory agencies, and hand searching of conference proceedings. International HTA agencies currently differ considerably in their efforts to address the issue of unpublished data. Requests to industry may constitute one strategy to access and include unpublished data, while agencies can learn from each other concerning successful practice.


Do aluminum vaccine adjuvants contribute to the rising prevalence of autism?
Autism spectrum disorders (ASD) are serious multisystem developmental disorders and an urgent global public health concern. Dysfunctional immunity and impaired brain function are core deficits in ASD. Aluminum (Al), the most commonly used vaccine adjuvant, is a demonstrated neurotoxin and a strong immune stimulator. Hence, adjuvant Al has the potential to induce neuroimmune disorders. When assessing adjuvant toxicity in children, two key points ought to be considered: (i) children should not be viewed as "small adults" as their unique physiology makes them much more vulnerable to toxic insults; and (ii) if exposure to Al from only few vaccines can lead to cognitive impairment and autoimmunity in adults, is it unreasonable to question whether the current pediatric schedules, often containing 18 Al adjuvanted vaccines, are safe for children? By applying Hill's criteria for establishing causality between exposure and outcome we investigated whether exposure to Al from vaccines could be contributing to the rise in ASD prevalence in the Western world. Our results show that: (i) children from countries with the highest ASD prevalence appear to have the highest exposure to Al from vaccines; (ii) the increase in exposure to Al adjuvants significantly correlates with the increase in ASD prevalence in the United States observed over the last two decades (Pearson r=0.92, p<0.0001); and (iii) a significant correlation exists between the amounts of Al administered to preschool children and the current prevalence of ASD in seven Western countries, particularly at 3-4 months of age (Pearson r=0.89-0.94, p=0.0018-0.0248). The application of the Hill's criteria to these data indicates that the correlation between Al in vaccines and ASD may be causal. Because children represent a fraction of the population most at risk for complications following exposure to Al, a more rigorous evaluation of Al adjuvant safety seems warranted.


Cost-minimisation analysis versus cost-effectiveness analysis, revisited.
We aim to establish whether it is ever appropriate to conduct cost-minimisation analysis (CMA) rather than cost-effectiveness analysis.We perform a literature review to examine how the use of CMA has changed since Briggs & O'Brien announced its death in 2001. Examples of simulated and trial data are presented: firstly to illustrate the advantages and disadvantages of CMA in the context of non-inferiority trials and those finding no significant difference in efficacy and secondly to assess whether CMA gives biased results.We show that CMA is still used and will bias measures of uncertainty, causing overestimation or underestimation of the value of information and the probability that treatment is cost-effective. Although bias will be negligible for non-inferiority studies comparing treatments that differ enormously in cost, it is generally necessary to collect and analyse data on costs and efficacy (including utilities) to assess this bias. Cost-effectiveness analysis (including evaluation of the joint distribution of costs and benefits) is almost always required to avoid biased estimation of uncertainty. The remit of CMA in trial-based economic evaluation is therefore even narrower than previously thought, suggesting that CMA is not only dead but should also be buried.


Purinergic P2X4 receptors and mitochondrial ATP production regulate T cell migration.
T cells must migrate in order to encounter antigen-presenting cells (APCs) and to execute their varied functions in immune defense and inflammation. ATP release and autocrine signaling through purinergic receptors contribute to T cell activation at the immune synapse that T cells form with APCs. Here, we show that T cells also require ATP release and purinergic signaling for their migration to APCs. We found that the chemokine stromal-derived factor-1α (SDF-1α) triggered mitochondrial ATP production, rapid bursts of ATP release, and increased migration of primary human CD4+ T cells. This process depended on pannexin-1 ATP release channels and autocrine stimulation of P2X4 receptors. SDF-1α stimulation caused localized accumulation of mitochondria with P2X4 receptors near the front of cells, resulting in a feed-forward signaling mechanism that promotes cellular Ca2+ influx and sustains mitochondrial ATP synthesis at levels needed for pseudopod protrusion, T cell polarization, and cell migration. Inhibition of P2X4 receptors blocked the activation and migration of T cells in vitro. In a mouse lung transplant model, P2X4 receptor antagonist treatment prevented the recruitment of T cells into allograft tissue and the rejection of lung transplants. Our findings suggest that P2X4 receptors are therapeutic targets for immunomodulation in transplantation and inflammatory diseases.


Telephone-Based Cognitive Behavioral Intervention Improves Dementia Caregivers' Quality of Life.
The present study examined the effects of a telephone-based cognitive behavioral intervention on dementia caregivers' quality of life (QoL). A total of 273 caregivers were randomly assigned to an intervention or control group. The intervention comprised 12 telephone sessions of individual cognitive behavioral therapy (CBT) over 6 months. At baseline, postintervention, and 6-month follow-up, QoL was assessed with the World Health Organization QoL-BREF, which measures perceived QoL for the domains physical health, psychological health, social relationships, and environment as well as overall QoL and satisfaction with general health. Intention-to-treat analyses using latent change models were performed. At postintervention, intervention group participants reported better overall QoL and satisfaction with general health as well as better physical and psychological health compared to control group participants. Together with existing evidence, the results suggest that the telephone CBT intervention does not only reduce impairments but also fosters improvements in health-related QoL.


Risk factors for cancers of unknown primary site: Results from the prospective EPIC cohort.
Cancer of unknown primary site (CUP) may be called an "orphan" disease, as it is diagnosed when metastases are detected while the primary tumor typically remains undetected, and because little research has been done on its primary causes. So far, few epidemiological studies, if any, have addressed possible risk factors for CUP. We analyzed data from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort (N=476,940). During prospective follow-up, a total of 651 cases of incident cases of CUP were detected (ICD-O-2 code C809). Proportional hazards models were conducted to examine the associations of lifetime history of smoking habits, alcohol consumption, levels of education and anthropometric indices of adiposity with risk of being diagnosed with CUP. Risk of being diagnosed with CUP was strongly related to smoking, with a relative risk of 3.66 [95% C.I., 2.24-5.97] for current, heavy smokers (26+ cigarettes/day) compared to never smokers (adjusted for alcohol consumption, body mass index, waist circumference and level of education) and a relative risk of 5.12 [3.09-8.47] for cases with CUP who died within 12 months. For alcohol consumption and level of education, weaker associations were observed but attenuated and no longer statistically significant after adjusting for smoking and indices of obesity. Finally, risk of CUP was increased by approximately 30 per cent for subjects in the highest versus lowest quartiles of waist circumference. Our analyses provide further documentation, in addition to autopsy studies, that a substantial proportion of cancers of unknown primary site may have their origin in smoking-related tumors, in particular.


International standards for newborn weight, length, and head circumference by gestational age and sex: the Newborn Cross-Sectional Study of the INTERGROWTH-21st Project.
In 2006, WHO published international growth standards for children younger than 5 years, which are now accepted worldwide. In the INTERGROWTH-21(st) Project, our aim was to complement them by developing international standards for fetuses, newborn infants, and the postnatal growth period of preterm infants. INTERGROWTH-21(st) is a population-based project that assessed fetal growth and newborn size in eight geographically defined urban populations. These groups were selected because most of the health and nutrition needs of mothers were met, adequate antenatal care was provided, and there were no major environmental constraints on growth. As part of the Newborn Cross-Sectional Study (NCSS), a component of INTERGROWTH-21(st) Project, we measured weight, length, and head circumference in all newborn infants, in addition to collecting data prospectively for pregnancy and the perinatal period. To construct the newborn standards, we selected all pregnancies in women meeting (in addition to the underlying population characteristics) strict individual eligibility criteria for a population at low risk of impaired fetal growth (labelled the NCSS prescriptive subpopulation). Women had a reliable ultrasound estimate of gestational age using crown-rump length before 14 weeks of gestation or biparietal diameter if antenatal care started between 14 weeks and 24 weeks or less of gestation. Newborn anthropometric measures were obtained within 12 h of birth by identically trained anthropometric teams using the same equipment at all sites. Fractional polynomials assuming a skewed t distribution were used to estimate the fitted centiles. We identified 20,486 (35%) eligible women from the 59,137 pregnant women enrolled in NCSS between May 14, 2009, and Aug 2, 2013. We calculated sex-specific observed and smoothed centiles for weight, length, and head circumference for gestational age at birth. The observed and smoothed centiles were almost identical. We present the 3rd, 10th, 50th, 90th, and 97th centile curves according to gestational age and sex. We have developed, for routine clinical practice, international anthropometric standards to assess newborn size that are intended to complement the WHO Child Growth Standards and allow comparisons across multiethnic populations. Bill & Melinda Gates Foundation.


Quantitative analysis of culture using millions of digitized books.
We constructed a corpus of digitized texts containing about 4% of all books ever printed. Analysis of this corpus enables us to investigate cultural trends quantitatively. We survey the vast terrain of 'culturomics,' focusing on linguistic and cultural phenomena that were reflected in the English language between 1800 and 2000. We show how this approach can provide insights about fields as diverse as lexicography, the evolution of grammar, collective memory, the adoption of technology, the pursuit of fame, censorship, and historical epidemiology. Culturomics extends the boundaries of rigorous quantitative inquiry to a wide array of new phenomena spanning the social sciences and the humanities.


Common syndromes of orthostatic intolerance.
The autonomic nervous system, adequate blood volume, and intact skeletal and respiratory muscle pumps are essential components for rapid cardiovascular adjustments to upright posture (orthostasis). Patients lacking sufficient blood volume or having defective sympathetic adrenergic vasoconstriction develop orthostatic hypotension (OH), prohibiting effective upright activities. OH is one form of orthostatic intolerance (OI) defined by signs, such as hypotension, and symptoms, such as lightheadedness, that occur when upright and are relieved by recumbence. Mild OI is commonly experienced during intercurrent illnesses and when standing up rapidly. The latter is denoted "initial OH" and represents a normal cardiovascular adjustment to the blood volume shifts during standing. Some people experience episodic acute OI, such as postural vasovagal syncope (fainting), or chronic OI, such as postural tachycardia syndrome, which can significantly reduce quality of life. The lifetime incidence of ≥1 fainting episodes is ∼40%. For the most part, these episodes are benign and self-limited, although frequent syncope episodes can be debilitating, and injury may occur from sudden falls. In this article, mechanisms for OI having components of adrenergic hypofunction, adrenergic hyperfunction, hyperpnea, and regional blood volume redistribution are discussed. Therapeutic strategies to cope with OI are proposed.


The trans-Saharan slave trade - clues from interpolation analyses and high-resolution characterization of mitochondrial DNA lineages.
A proportion of 1/4 to 1/2 of North African female pool is made of typical sub-Saharan lineages, in higher frequencies as geographic proximity to sub-Saharan Africa increases. The Sahara was a strong geographical barrier against gene flow, at least since 5,000 years ago, when desertification affected a larger region, but the Arab trans-Saharan slave trade could have facilitate enormously this migration of lineages. Till now, the genetic consequences of these forced trans-Saharan movements of people have not been ascertained. The distribution of the main L haplogroups in North Africa clearly reflects the known trans-Saharan slave routes: West is dominated by L1b, L2b, L2c, L2d, L3b and L3d; the Center by L3e and some L3f and L3w; the East by L0a, L3h, L3i, L3x and, in common with the Center, L3f and L3w; while, L2a is almost everywhere. Ages for the haplogroups observed in both sides of the Saharan desert testify the recent origin (holocenic) of these haplogroups in sub-Saharan Africa, claiming a recent introduction in North Africa, further strengthened by the no detection of local expansions. The interpolation analyses and complete sequencing of present mtDNA sub-Saharan lineages observed in North Africa support the genetic impact of recent trans-Saharan migrations, namely the slave trade initiated by the Arab conquest of North Africa in the seventh century. Sub-Saharan people did not leave traces in the North African maternal gene pool for the time of its settlement, some 40,000 years ago.


White matter integrity of the descending pain modulatory system is associated with interindividual differences in placebo analgesia.
The ability for endogenous pain control varies considerably among individuals. The mechanisms underlying this interindividual difference are incompletely understood. We used placebo analgesia as a classic model of endogenous pain modulation in combination with diffusion tensor magnetic resonance imaging to test the hypothesis of a structural predisposition for the individual capacity of endogenous pain control. Specifically we determined white matter integrity within and between regions of the descending pain modulatory system. Twenty-four healthy participants completed a placebo paradigm and underwent diffusion tensor magnetic resonance imaging. The individual placebo analgesic effect was correlated with white matter integrity indexed by fractional anisotropy. The individual placebo analgesic effect was positively correlated with FA in the right dorsolateral prefrontal cortex, left rostral anterior cingulate cortex, and the periaqueductal grey. Probabilistic tractography seeded in these regions showed that stronger placebo analgesic responses were associated with increased mean fractional anisotropy values within white matter tracts connecting the periaqueductal grey with pain control regions such as the rostral anterior cingulate cortex and the dorsolateral prefrontal cortex. Our findings provide the first evidence that the white matter integrity within and between regions of the descending pain modulatory network is critically linked with the individual ability for endogenous pain control.


Behavioral and Neural Markers of Flexible Attention over Working Memory in Aging.
Working memory (WM) declines as we age and, because of its fundamental role in higher order cognition, this can have highly deleterious effects in daily life. We investigated whether older individuals benefit from flexible orienting of attention within WM to mitigate cognitive decline. We measured magnetoencephalography (MEG) in older adults performing a WM precision task with cues during the maintenance period that retroactively predicted the location of the relevant items for performance (retro-cues). WM performance of older adults significantly benefitted from retro-cues. Whereas WM maintenance declined with age, retro-cues conferred strong attentional benefits. A model-based analysis revealed an increase in the probability of recalling the target, a lowered probability of retrieving incorrect items or guessing, and an improvement in memory precision. MEG recordings showed that retro-cues induced a transient lateralization of alpha (8-14 Hz) and beta (15-30 Hz) oscillatory power. Interestingly, shorter durations of alpha/beta lateralization following retro-cues predicted larger cueing benefits, reinforcing recent ideas about the dynamic nature of access to WM representations. Our results suggest that older adults retain flexible control over WM, but individual differences in control correspond to differences in neural dynamics, possibly reflecting the degree of preservation of control in healthy aging.


Three-dimensional architecture and biogenesis of membrane structures associated with hepatitis C virus replication.
All positive strand RNA viruses are known to replicate their genomes in close association with intracellular membranes. In case of the hepatitis C virus (HCV), a member of the family Flaviviridae, infected cells contain accumulations of vesicles forming a membranous web (MW) that is thought to be the site of viral RNA replication. However, little is known about the biogenesis and three-dimensional structure of the MW. In this study we used a combination of immunofluorescence- and electron microscopy (EM)-based methods to analyze the membranous structures induced by HCV in infected cells. We found that the MW is derived primarily from the endoplasmic reticulum (ER) and contains markers of rough ER as well as markers of early and late endosomes, COP vesicles, mitochondria and lipid droplets (LDs). The main constituents of the MW are single and double membrane vesicles (DMVs). The latter predominate and the kinetic of their appearance correlates with kinetics of viral RNA replication. DMVs are induced primarily by NS5A whereas NS4B induces single membrane vesicles arguing that MW formation requires the concerted action of several HCV replicase proteins. Three-dimensional reconstructions identify DMVs as protrusions from the ER membrane into the cytosol, frequently connected to the ER membrane via a neck-like structure. In addition, late in infection multi-membrane vesicles become evident, presumably as a result of a stress-induced reaction. Thus, the morphology of the membranous rearrangements induced in HCV-infected cells resemble those of the unrelated picorna-, corona- and arteriviruses, but are clearly distinct from those of the closely related flaviviruses. These results reveal unexpected similarities between HCV and distantly related positive-strand RNA viruses presumably reflecting similarities in cellular pathways exploited by these viruses to establish their membranous replication factories.


Linking secondary school physical education with community sport and recreation for girls: a process evaluation.
The purpose of this study was to undertake a process evaluation to examine the reach, adoption and implementation of a school-community linked physical activity (PA) program for girls aged 12 - 15 years (School Years 7 - 9) using the RE-AIM framework. Various approaches were used to assess 'reach', 'adoption' and implementation: (a) a school environment survey of intervention schools (n = 6); (b) teacher feedback regarding the professional development component (91.1% response rate) and lesson implementation (60.8% response rate); and (c) post-intervention focus group interviews with physical education (PE) teachers (n = 29), students (n = 125), coaches (n = 13) and instructors (n = 8) regarding program experiences. Reach and Adoption: Seven schools (n = 1491 Year 7-9 female student enrolment; 70% adoption rate), five tennis clubs, eight football clubs and five leisure centres participated in the program during 2011. Program design and professional development opportunities (training, resource manual and opportunities to work with coaches and instructors during PE classes) supported implementation and student engagement in PA. However, there was a lack of individual and organisational readiness to adopt program principles. For some deliverers there were deeply embedded ideologies that were not aligned with the Game Sense teaching approach upon which the program was based. Further, cognitive components of the program such as self-management were not widely adopted as other components of the program tended to be prioritised. The program design and resources supported the success of the program, however, some aspects were not implemented as intended, which may have affected the likelihood of achieving further positive outcomes. Barriers to program implementation were identified and should be considered when designing school-community linked interventions. In particular, future programs should seek to assess and adjust for organizational readiness within the study design. For example, shared commitment and abilities of program deliverers to implement the program needs to be determined to support program implementation. ACTRN12614000446662. April 30th 2014.


Reliability exercise for the polymyalgia rheumatica classification criteria study: the oranjewoud ultrasound substudy.
Objective. A study supported by the EULAR and the ACR being conducted to establish classification criteria for polymyalgia rheumatica (PMR) will include ultrasound examination of the shoulders and hips. Ultrasound (US) depicts glenohumeral joint effusion, biceps tenosynovitis, subdeltoid bursitis, hip joint synovitis, and trochanteric bursitis in PMR. These findings may aid in distinguishing PMR from other diseases. The purpose of this study was to assess standards and US interreader agreement of participants in the PMR classification criteria study. Methods. Sixteen physicians in four groups examined shoulders and hips of 4 patients and 4 healthy adults with ultrasound. Overall agreement and interobserver agreement were calculated. Results. The overall agreement (OA) between groups was 87%. The OA for healthy shoulders was 88.8%, for healthy hips 100%, for shoulders with pathology 85.2%, and 74.3% for hips with pathology, respectively. Conclusion. There was a high degree of agreement found for the examination of healthy shoulders and pathologic hips. Agreement was moderate for pathologic shoulders and perfect for healthy hips. US of shoulder and hips performed by different examiners is a reliable and feasible tool for assessment of PMR related disease pathology and can be incorporated into a classification criteria study.


Cannabis use in patients with fibromyalgia: effect on symptoms relief and health-related quality of life.
The aim of this study was to describe the patterns of cannabis use and the associated benefits reported by patients with fibromyalgia (FM) who were consumers of this drug. In addition, the quality of life of FM patients who consumed cannabis was compared with FM subjects who were not cannabis users. Information on medicinal cannabis use was recorded on a specific questionnaire as well as perceived benefits of cannabis on a range of symptoms using standard 100-mm visual analogue scales (VAS). Cannabis users and non-users completed the Fibromyalgia Impact Questionnaire (FIQ), the Pittsburgh Sleep Quality Index (PSQI) and the Short Form 36 Health Survey (SF-36). Twenty-eight FM patients who were cannabis users and 28 non-users were included in the study. Demographics and clinical variables were similar in both groups. Cannabis users referred different duration of drug consumption; the route of administration was smoking (54%), oral (46%) and combined (43%). The amount and frequency of cannabis use were also different among patients. After 2 hours of cannabis use, VAS scores showed a statistically significant (p<0.001) reduction of pain and stiffness, enhancement of relaxation, and an increase in somnolence and feeling of well being. The mental health component summary score of the SF-36 was significantly higher (p<0.05) in cannabis users than in non-users. No significant differences were found in the other SF-36 domains, in the FIQ and the PSQI. The use of cannabis was associated with beneficial effects on some FM symptoms. Further studies on the usefulness of cannabinoids in FM patients as well as cannabinoid system involvement in the pathophysiology of this condition are warranted.


Euglycemic diabetic ketoacidosis: a diagnostic and therapeutic dilemma.
Euglycemic diabetic ketoacidosis (EDKA) is a clinical triad comprising increased anion gap metabolic acidosis, ketonemia or ketonuria and normal blood glucose levels <200 mg/dL. This condition is a diagnostic challenge as euglycemia masquerades the underlying diabetic ketoacidosis. Thus, a high clinical suspicion is warranted, and other diagnosis ruled out. Here, we present two patients on regular insulin treatment who were admitted with a diagnosis of EDKA. The first patient had insulin pump failure and the second patient had urinary tract infection and nausea, thereby resulting in starvation. Both of them were aggressively treated with intravenous fluids and insulin drip as per the protocol for the blood glucose levels till the anion gap normalized, and the metabolic acidosis reversed. This case series summarizes, in brief, the etiology, pathophysiology and treatment of EDKA. Euglycemic diabetic ketoacidosis is rare.Consider ketosis in patients with DKA even if their serum glucose levels are normal.High clinical suspicion is required to diagnose EDKA as normal blood sugar levels masquerade the underlying DKA and cause a diagnostic and therapeutic dilemma.Blood pH and blood or urine ketones should be checked in ill patients with diabetes regardless of blood glucose levels.


Chronic perfluorooctanesulphonic acid (PFOS) exposure produces estrogenic effects in zebrafish.
Perfluorooctanesulphonic acid (PFOS) is a ubiquitous contaminant in the aquatic environment and our earlier studies demonstrated that chronic PFOS exposures lead to a female-biased sex ratio and decreased sperm quality in male zebrafish. The underlying mechanism for these reproductive effects is unknown. In the present study, 8 h post-fertilization (hpf) zebrafish were exposed to PFOS at 250 μg/L for 5 months, and the levels of sex hormones, expression of sex determination related genes, and histological and ultrastructural changes of gonads were fully characterized. During the sex differentiation period, we observed elevated estradiol (E2) and decreased testosterone (T) levels in whole tissue homogenates from PFOS exposed juveniles. In fully mature adult male fish, serum E2 levels were slightly increased, however, the estrogen receptor alpha (esr1) was significantly elevated in PFOS treated male gonads. Histological and electron microscopic examinations revealed structural changes in the gonads of PFOS exposed male and female adult zebrafish. In summary, chronic PFOS exposure disrupts sex hormone level and related gene expression and impairs gonadal development, which may contribute to the previously reported PFOS reproductive toxicity.