Inspiratory muscle training reduces blood lactate concentration during volitional hyperpnoea

Although reduced blood lactate concentrations ([lac−]B) have been observed during whole-body exercise following inspiratory muscle training (IMT), it remains unknown whether the inspiratory muscles are the source of at least part of this reduction. To investigate this, we tested the hypothesis that IMT would attenuate the increase in [lac−]B caused by mimicking, at rest, the breathing pattern observed during high-intensity exercise. Twenty-two physically active males were matched for 85% maximal exercise minute ventilation (V˙Emax) and divided equally into an IMT or a control group. Prior to and following a 6 week intervention, participants performed 10 min of volitional hyperpnoea at the breathing pattern commensurate with 85% V˙Emax

Male reproductive health and environmental xenoestrogens

EHP is a publication of the U.S. government. Publication of EHP lies in the public domain and is therefore without copyright. Research articles from EHP may be used freely; however, articles from the News section of EHP may contain photographs or figures copyrighted by other commercial organizations and individuals that may not be used without obtaining prior approval from both the EHP editors and the holder of the copyright. Use of any materials published in EHP should be acknowledged (for example, "Reproduced with permission from Environmental Health Perspectives") and a reference provided for the article from which the material was reproduced.Male reproductive health has deteriorated in many countries during the last few decades. In the 1990s, declining semen quality has been reported from Belgium, Denmark, France, and Great Britain. The incidence of testicular cancer has increased during the same time incidences of hypospadias and cryptorchidism also appear to be increasing. Similar reproductive problems occur in many wildlife species. There are marked geographic differences in the prevalence of male reproductive disorders. While the reasons for these differences are currently unknown, both clinical and laboratory research suggest that the adverse changes may be inter-related and have a common origin in fetal life or childhood. Exposure of the male fetus to supranormal levels of estrogens, such as diethlylstilbestrol, can result in the above-mentioned reproductive defects. The growing number of reports demonstrating that common environmental contaminants and natural factors possess estrogenic activity presents the working hypothesis that the adverse trends in male reproductive health may be, at least in part, associated with exposure to estrogenic or other hormonally active (e.g., antiandrogenic) environmental chemicals during fetal and childhood development. An extensive research program is needed to understand the extent of the problem, its underlying etiology, and the development of a strategy for prevention and intervention.Supported by EU Contract BMH4-CT96-0314

From father to son: transgenerational effect of tetracycline on sperm viability

The broad-spectrum antibiotic tetracycline is used in animal production, antimicrobial therapy, and for curing arthropods infected with bacterial endosymbionts such as Wolbachia. Tetracycline inhibits mitochondrial translation, and recent evidence indicates that male reproductive traits may be particularly sensitive to this antibiotic. Here, we report the first multi-generation investigation of tetracycline's effects on ejaculate traits. In a study of the pseudoscorpion, Cordylochernes scorpioides, in which siblings were randomly assigned to control and tetracycline treatments across replicate full-sibling families, tetracycline did not affect body size in either sex, female reproduction or sperm number. However, tetracycline-treated males exhibited significantly reduced sperm viability compared to control males, and transmitted this toxic effect of tetracycline on sperm to their untreated sons but not to their F2 grandsons. These results are consistent with tetracycline-induced epigenetic changes in the male germline, and suggest the need for further investigation of transgenerational effects of tetracycline on male reproductive function

Time trends in socioeconomic inequalities in cancer mortality: results from a 35 year prospective study in British men.

BACKGROUND: Socioeconomic inequalities in cancer mortality in Britain have been shown to be present in the 1990s and early 2000s. Little is known about on-going patterns in such inequalities in cancer mortality. We examined time trends in socioeconomic inequalities in cancer mortality in Britain between 1978 and 2013. METHODS: A socially representative cohort of 7489 British men with data on longest-held occupational social class, followed up for 35 years, in whom 1484 cancer deaths occurred. RESULTS: The hazard ratio for cancer mortality for manual vs. non-manual social classes remained unchanged; among men aged 50-59 years it was 1.62 (95%CI 1.17-2.24) between 1980-1990 and 1.65 (95%CI 1.14-2.40) between 1990-2000. The absolute difference (non-manual minus manual) in probability of surviving death from cancer to 70 years remained at 3% over the follow-up. The consistency of risks over time was similar for both smoking-related and non-smoking related cancer mortality. CONCLUSION: Socioeconomic inequalities in cancer mortality in Britain remain unchanged over the last 35 years and need to be urgently addressed

Skeeter Buster: A Stochastic, Spatially Explicit Modeling Tool for Studying Aedes aegypti Population Replacement and Population Suppression Strategies

Dengue is a viral disease that affects approximately 50 million people annually, and is estimated to result in 12,500 fatalities. Dengue viruses are vectored by mosquitoes, predominantly by the species Aedes aegypti. Because there is currently no vaccine or specific treatment, the only available strategy to reduce dengue transmission is to control the populations of these mosquitoes. This can be achieved by traditional approaches such as insecticides, or by recently developed genetic methods that propose the release of mosquitoes genetically engineered to be unable to transmit dengue viruses. The expected outcome of different control strategies can be compared by simulating the population dynamics and genetics of mosquitoes at a given location. Development of optimal control strategies can then be guided by the modeling approach. To that end, we introduce a new modeling tool called Skeeter Buster. This model describes the dynamics and the genetics of Ae. aegypti populations at a very fine scale, simulating the contents of individual houses, and even the individual water-holding containers in which mosquito larvae reside. Skeeter Buster can be used to compare the predicted outcomes of multiple control strategies, traditional or genetic, making it an important tool in the fight against dengue

The Four-Dimensional Symptom Questionnaire (4DSQ): a validation study of a multidimensional self-report questionnaire to assess distress, depression, anxiety and somatization

BACKGROUND: The Four-Dimensional Symptom Questionnaire (4DSQ) is a self-report questionnaire that has been developed in primary care to distinguish non-specific general distress from depression, anxiety and somatization. The purpose of this paper is to evaluate its criterion and construct validity. METHODS: Data from 10 different primary care studies have been used. Criterion validity was assessed by comparing the 4DSQ scores with clinical diagnoses, the GPs' diagnosis of any psychosocial problem for Distress, standardised psychiatric diagnoses for Depression and Anxiety, and GPs' suspicion of somatization for Somatization. ROC analyses and logistic regression analyses were used to examine the associations. Construct validity was evaluated by investigating the inter-correlations between the scales, the factorial structure, the associations with other symptom questionnaires, and the associations with stress, personality and social functioning. The factorial structure of the 4DSQ was assessed through confirmatory factor analysis (CFA). The associations with other questionnaires were assessed with Pearson correlations and regression analyses. RESULTS: Regarding criterion validity, the Distress scale was associated with any psychosocial diagnosis (area under the ROC curve [AUC] 0.79), the Depression scale was associated with major depression (AUC = 0.83), the Anxiety scale was associated with anxiety disorder (AUC = 0.66), and the Somatization scale was associated with the GPs' suspicion of somatization (AUC = 0.65). Regarding the construct validity, the 4DSQ scales appeared to have considerable inter-correlations (r = 0.35-0.71). However, 30–40% of the variance of each scale was unique for that scale. CFA confirmed the 4-factor structure with a comparative fit index (CFI) of 0.92. The 4DSQ scales correlated with most other questionnaires measuring corresponding constructs. However, the 4DSQ Distress scale appeared to correlate with some other depression scales more than the 4DSQ Depression scale. Measures of stress (i.e. life events, psychosocial problems, and work stress) were mainly associated with Distress, while Distress, in turn, was mainly associated with psychosocial dysfunctioning, including sick leave. CONCLUSION: The 4DSQ seems to be a valid self-report questionnaire to measure distress, depression, anxiety and somatization in primary care patients. The 4DSQ Distress scale appears to measure the most general, most common, expression of psychological problems

Prospective functional classification of all possible missense variants in PPARG.

Clinical exome sequencing routinely identifies missense variants in disease-related genes, but functional characterization is rarely undertaken, leading to diagnostic uncertainty. For example, mutations in PPARG cause Mendelian lipodystrophy and increase risk of type 2 diabetes (T2D). Although approximately 1 in 500 people harbor missense variants in PPARG, most are of unknown consequence. To prospectively characterize PPARγ variants, we used highly parallel oligonucleotide synthesis to construct a library encoding all 9,595 possible single-amino acid substitutions. We developed a pooled functional assay in human macrophages, experimentally evaluated all protein variants, and used the experimental data to train a variant classifier by supervised machine learning. When applied to 55 new missense variants identified in population-based and clinical sequencing, the classifier annotated 6 variants as pathogenic; these were subsequently validated by single-variant assays. Saturation mutagenesis and prospective experimental characterization can support immediate diagnostic interpretation of newly discovered missense variants in disease-related genes.This work was supported by grants from the National Institute of Diabetes and Digestive and Kidney Diseases (1K08DK102877-01, to A.R.M.; 1R01DK097768-01, to D.A.), NIH/Harvard Catalyst (1KL2TR001100-01, to A.R.M.), the Broad Institute (SPARC award, to A.R.M. and T.M.), and the Wellcome Trust (095564, to K.C.; 107064, to D.B.S.).This is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/ng.370

Attitudes towards fibromyalgia: A survey of Canadian chiropractic, naturopathic, physical therapy and occupational therapy students

<p>Abstract</p> <p>Background</p> <p>The frequent use of chiropractic, naturopathic, and physical and occupational therapy by patients with fibromyalgia has been emphasized repeatedly, but little is known about the attitudes of these therapists towards this challenging condition.</p> <p>Methods</p> <p>We administered a cross-sectional survey to 385 senior Canadian chiropractic, naturopathic, physical and occupational therapy students in their final year of studies, that inquired about attitudes towards the diagnosis and management of fibromyalgia.</p> <p>Results</p> <p>336 students completed the survey (response rate 87%). While they disagreed about the etiology (primarily psychological 28%, physiological 23%, psychological and physiological 15%, unsure 34%), the majority (58%) reported that fibromyalgia was difficult to manage. Respondants were also conflicted in whether treatment should prioritize symptom relief (65%) or functional gains (85%), with the majority (58%) wanting to do both. The majority of respondents (57%) agreed that there was effective treatment for fibromyalgia and that they possessed the required clinical skills to manage patients (55%).</p> <p>Chiropractic students were most skeptical in regards to fibromyalgia as a useful diagnostic entity, and most likely to endorse a psychological etiology. In our regression model, only training in naturopathic medicine (unstandardized regression coefficient = 0.33; 95% confidence interval = 0.11 to 0.56) and the belief that effective therapies existed (unstandardized regression coefficient = 0.42; 95% confidence interval = 0.30 to 0.54) were associated with greater confidence in managing patients with fibromyalgia.</p> <p>Conclusion</p> <p>The majority of senior Canadian chiropractic, naturopathic, physical and occupational therapy students, and in particular those with naturopathic training, believe that effective treatment for fibromyalgia exists and that they possess the clinical skillset to effectively manage this disorder. The majority place high priority on both symptom relief and functional gains when treating fibromyalgia.</p

Receptor and secreted targets of Wnt-1/β-catenin signalling in mouse mammary epithelial cells

BACKGROUND: Deregulation of the Wnt/ β-catenin signal transduction pathway has been implicated in the pathogenesis of tumours in the mammary gland, colon and other tissues. Mutations in components of this pathway result in β-catenin stabilization and accumulation, and the aberrant modulation of β-catenin/TCF target genes. Such alterations in the cellular transcriptional profile are believed to underlie the pathogenesis of these cancers. We have sought to identify novel target genes of this pathway in mouse mammary epithelial cells. METHODS: Gene expression microarray analysis of mouse mammary epithelial cells inducibly expressing a constitutively active mutant of β-catenin was used to identify target genes of this pathway. RESULTS: The differential expression in response to ΔNβ-catenin for five putative target genes, Autotaxin, Extracellular Matrix Protein 1 (Ecm1), CD14, Hypoxia-inducible gene 2 (Hig2) and Receptor Activity Modifying Protein 3 (RAMP3), was independently validated by northern blotting. Each of these genes encodes either a receptor or a secreted protein, modulation of which may underlie the interactions between Wnt/β-catenin tumour cells and between the tumour and its microenvironment. One of these genes, Hig2, previously shown to be induced by both hypoxia and glucose deprivation in human cervical carcinoma cells, was strongly repressed upon ΔNβ-catenin induction. The predicted N-terminus of Hig2 contains a putative signal peptide suggesting it might be secreted. Consistent with this, a Hig2-EGFP fusion protein was able to enter the secretory pathway and was detected in conditioned medium. Mutation of critical residues in the putative signal sequence abolished its secretion. The expression of human HIG2 was examined in a panel of human tumours and was found to be significantly downregulated in kidney tumours compared to normal adjacent tissue. CONCLUSIONS: HIG2 represents a novel non-cell autonomous target of the Wnt pathway which is potentially involved in human cancer