Reply to Lipworth et al.

We thank Dr. Lipworth and colleagues for their interest in our work published recently in the Journal (1). They rightly point out that the biology of asthma attacks is more complex than blood eosinophils alone and that corticosteroids have a wide range of other potentially relevant antiinflammatory effects. However, local treatment with inhaled corticosteroids (ICS) is usually the mainstay of patients with frequent eosinophilic exacerbations, and therefore in the great majority of patients, the key question is what oral corticosteroids (OCS) add to ICS in an acute attack (2) and whether this effect is seen with benralizumab. We suggest that depletion of circulating eosinophils is the only effect OCS are likely to have that are not shared with ICS (3)

Assessment of intelligibility in dysarthria: development of a Maltese word and phrase list

This paper describes the development of the Maltese Intelligibility Lists (MIL) for the assessment of word and phrase intelligibility in dysarthria. Two main tools were employed: the Frenchay Dysarthria Assessment-2 (FDA), and the Maltese Language Resource Server (MLRS). Three main criteria served as the basis for the construction of the word and phrase lists: frequency of occurrence of Maltese phonemes, word frequency and an analysis of syllable types and structures. The most common 500 words in the MLRS corpus (Korpus Malti v. 3) were broadly transcribed and an analysis of different types of syllables and their frequency of occurrence was carried out. Based on this analysis, the relevant proportion of different syllable types required for the word and phrase lists for Maltese was calculated in line with the number of items present in the FDA-2. With regards to phoneme frequency, the words chosen demonstrate a similar short-vowel and consonant distribution as reported in a previous large-scale study. The MIL consists of 116 words and 50 phrases which are representative of Standard Maltese and can be used in the clinic to assess speech intelligibility in Maltese individuals with dysarthria

Appetite and gut hormone responses to moderate-intensity continuous exercise versus high-intensity interval exercise, in normoxic and hypoxic conditions.

This study investigated the effects of continuous moderate-intensity exercise (MIE) and high-intensity interval exercise (HIIE) in combination with short exposure to hypoxia on appetite and plasma concentrations of acylated ghrelin, peptide YY (PYY), and glucagon-like peptide-1 (GLP-1). Twelve healthy males completed four, 2.6 h trials in a random order: 1) MIE-normoxia, 2) MIE-hypoxia, 3) HIIE-normoxia, and 4) HIIE-hypoxia. Exercise took place in an environmental chamber. During MIE, participants ran for 50 min at 70% of altitude-specific maximal oxygen uptake ( 2max) and during HIIE performed 6 x 3 min running at 90% 2max interspersed with 6 x 3 min active recovery at 50% 2max with a 7 min warm-up and cool-down at 70% 2max (50 min total). In hypoxic trials, exercise was performed at a simulated altitude of 2,980 m (14.5% O2). Exercise was completed after a standardised breakfast. A second meal standardised to 30% of participants’ daily energy requirements was provided 45 min after exercise. Appetite was suppressed more in hypoxia than normoxia during exercise, post-exercise, and for the full 2.6 h trial period (linear mixed modelling, p 0.05). These findings demonstrate that short exposure to hypoxia causes suppressions in appetite and plasma acylated ghrelin concentrations. Furthermore, appetite responses to exercise do not appear to be influenced by exercise modality

Regulatory evaluation of Glybera in Europe-two committees, one mission

publishersversionPeer reviewe

Divergence in Sex Steroid Hormone Signaling between Sympatric Species of Japanese Threespine Stickleback

Sex steroids mediate the expression of sexually dimorphic or sex-specific traits that are important both for mate choice within species and for behavioral isolation between species. We investigated divergence in sex steroid signaling between two sympatric species of threespine stickleback (Gasterosteus aculeatus): the Japan Sea form and the Pacific Ocean form. These sympatric forms diverge in both male display traits and female mate choice behaviors, which together contribute to asymmetric behavioral isolation in sympatry. Here, we found that plasma levels of testosterone and 17β-estradiol differed between spawning females of the two sympatric forms. Transcript levels of follicle-stimulating hormone-β (FSHβ) gene were also higher in the pituitary gland of spawning Japan Sea females than in the pituitary gland of spawning Pacific Ocean females. By contrast, none of the sex steroids examined were significantly different between nesting males of the two forms. However, combining the plasma sex steroid data with testis transcriptome data suggested that the efficiency of the conversion of testosterone into 11-ketotestosterone has likely diverged between forms. Within forms, plasma testosterone levels in males were significantly correlated with male body size, a trait important for female mate choice in the two sympatric species. These results demonstrate that substantial divergence in sex steroid signaling can occur between incipient sympatric species. We suggest that investigation of the genetic and ecological mechanisms underlying divergence in hormonal signaling between incipient sympatric species will provide a better understanding of the mechanisms of speciation in animals

BRCA2 polymorphic stop codon K3326X and the risk of breast, prostate, and ovarian cancers

Background: The K3326X variant in BRCA2 (BRCA2*c.9976A>T; p.Lys3326*; rs11571833) has been found to be associated with small increased risks of breast cancer. However, it is not clear to what extent linkage disequilibrium with fully pathogenic mutations might account for this association. There is scant information about the effect of K3326X in other hormone-related cancers. Methods: Using weighted logistic regression, we analyzed data from the large iCOGS study including 76 637 cancer case patients and 83 796 control patients to estimate odds ratios (ORw) and 95% confidence intervals (CIs) for K3326X variant carriers in relation to breast, ovarian, and prostate cancer risks, with weights defined as probability of not having a pathogenic BRCA2 variant. Using Cox proportional hazards modeling, we also examined the associations of K3326X with breast and ovarian cancer risks among 7183 BRCA1 variant carriers. All statistical tests were two-sided. Results: The K3326X variant was associated with breast (ORw = 1.28, 95% CI = 1.17 to 1.40, P = 5.9x10- 6) and invasive ovarian cancer (ORw = 1.26, 95% CI = 1.10 to 1.43, P = 3.8x10-3). These associations were stronger for serous ovarian cancer and for estrogen receptor–negative breast cancer (ORw = 1.46, 95% CI = 1.2 to 1.70, P = 3.4x10-5 and ORw = 1.50, 95% CI = 1.28 to 1.76, P = 4.1x10-5, respectively). For BRCA1 mutation carriers, there was a statistically significant inverse association of the K3326X variant with risk of ovarian cancer (HR = 0.43, 95% CI = 0.22 to 0.84, P = .013) but no association with breast cancer. No association with prostate cancer was observed. Conclusions: Our study provides evidence that the K3326X variant is associated with risk of developing breast and ovarian cancers independent of other pathogenic variants in BRCA2. Further studies are needed to determine the biological mechanism of action responsible for these associations

Effect of Mouth Rinsing and Ingestion of Carbohydrate Solutions on Mood and Perceptual Responses During Exercise

Background: The aim of this study was to investigate whether mouth rinsing or ingesting carbohydrate (CHO) solutions impact on perceptual responses during exercise. Methods: Nine moderately trained male cyclists underwent a 90-min glycogen-reducing exercise, and consumed a low CHO meal, prior to completing an overnight fast. A 1-h cycle time trial was performed the following morning. Four trials, each separated by 7days, were conducted in a randomized, counterbalanced study design: 15% CHO mouth rinse (CHOR), 7.5% CHO ingestion (CHOI), placebo mouth rinse (PLAR) and placebo ingestion (PLAI). Solution volumes (1.5ml·g-1 ingestion trials and 0.33ml·kg-1 rinsing trials) were provided after every 12.5% of completed exercise. Perceptual scales were used to assess affective valence (feeling scale, FS), arousal (felt arousal scale, FAS), exertion (ratings of perceived exertion, RPE) and mood (profile of mood states, POMS) before, during and immediately after exercise. Results: There was no difference in RPE (CHOI, 14.0±9; CHOR, 14.2±.7; PLAI, 14.6±1.8; PLAR, 14.6±2.0; P=0.35), FS (CHOI, 0.0±1.7; CHOR, -0.2±1.5; PLAI, -0.8±1.4; PLAR, -0.8±1.6; P0.15), or FAS (CHOI, 3.6±1.1; CHOR, 3.5±1.0; PLAI, 3.4±1.4; PLAR, 3.3±1.3; P=725) scores between trials. While overall POMS score did not appear to differ between trials, the 'vigour' subscale indicated that CHOI may facilitate the maintenance of 'vigour' scores over time, in comparison to the steady decline witnessed in other trials (P=0.04). There was no difference in time trial performance between trials (CHOI, 65.3±4.8min; CHOR, 68.4±3.9min; PLAI, 68.7±5.3min; PLAR, 68.3±5.2min; P=0.21) but power output was higher in CHOI (231.0±33.2 W) relative to other trials (221-223.6 W; Plt0.01). Conclusions: In a CHO-reduced state, mouth rinsing with a CHO solution did not impact on perceptual responses during high-intensity exercise in trained cyclists and triathletes. On the other hand CHO ingestion improved perceived ratings of vigour and increased power output during exercise

Exercise augmentation compared to usual care for Post Traumatic Stress Disorder: A Randomised Controlled Trial (The REAP study: Randomised Exercise Augmentation for PTSD)

<p>Abstract</p> <p>Background</p> <p>The physical wellbeing of people with mental health conditions can often be overlooked in order to treat the primary mental health condition as a priority. Exercise however, can potentially improve both the primary psychiatric condition as well as physical measures that indicate risk of other conditions such as diabetes mellitus and cardiovascular disease. Evidence supports the role of exercise as an important component of treatment for depression and anxiety, yet no randomised controlled trials (RCT's) have been conducted to evaluate the use of exercise in the treatment of people with post traumatic stress disorder (PTSD).</p> <p>This RCT will investigate the effects of structured, progressive exercise on PTSD symptoms, functional ability, body composition, physical activity levels, sleep patterns and medication usage.</p> <p>Methods and design</p> <p>Eighty participants with a Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) diagnosis of PTSD will be recruited. Participants will have no contraindications to exercise and will be cognitively able to provide consent to participate in the study.</p> <p>The primary outcome measures will be PTSD symptoms, measured through the PTSD Checklist Civilian (PCL-C) scale. Secondary outcome measures will assess depression and anxiety, mobility and strength, body composition, physical activity levels, sleep patterns and medication usage. All outcomes will be assessed by a health or exercise professional masked to group allocation at baseline and 12 weeks after randomisation.</p> <p>The intervention will be a 12 week individualised program, primarily involving resistance exercises with the use of exercise bands. A walking component will also be incorporated. Participants will complete one supervised session per week, and will be asked to perform at least two other non-supervised exercise sessions per week. Both intervention and control groups will receive all usual non-exercise interventions including psychotherapy, pharmaceutical interventions and group therapy.</p> <p>Discussion</p> <p>This study will determine the effect of an individualised and progressive exercise intervention on PTSD symptoms, depression and anxiety, mobility and strength, body composition, physical activity levels, sleep patterns and medication usage among people with a DSM-IV diagnosis of PTSD.</p> <p>Trial Registration</p> <p><a href="http://www.anzctr.org.au/ACTRN12605000567628.aspx">ACTRN12610000579099</a></p

Aged PROP1 Deficient Dwarf Mice Maintain ACTH Production

Humans with PROP1 mutations have multiple pituitary hormone deficiencies (MPHD) that typically advance from growth insufficiency diagnosed in infancy to include more severe growth hormone (GH) deficiency and progressive reduction in other anterior pituitary hormones, eventually including adrenocorticotropic hormone (ACTH) deficiency and hypocortisolism. Congenital deficiencies of GH, prolactin, and thyroid stimulating hormone have been reported in the Prop1null (Prop1-/-) and the Ames dwarf (Prop1df/df) mouse models, but corticotroph and pituitary adrenal axis function have not been thoroughly investigated. Here we report that the C57BL6 background sensitizes mutants to a wasting phenotype that causes approximately one third to die precipitously between weaning and adulthood, while remaining homozygotes live with no signs of illness. The wasting phenotype is associated with severe hypoglycemia. Circulating ACTH and corticosterone levels are elevated in juvenile and aged Prop1 mutants, indicating activation of the pituitary-adrenal axis. Despite this, young adult Prop1 deficient mice are capable of responding to restraint stress with further elevation of ACTH and corticosterone. Low blood glucose, an expected side effect of GH deficiency, is likely responsible for the elevated corticosterone level. These studies suggest that the mouse model differs from the human patients who display progressive hormone loss and hypocortisolism

Mutational processes molding the genomes of 21 breast cancers

All cancers carry somatic mutations. The patterns of mutation in cancer genomes reflect the DNA damage and repair processes to which cancer cells and their precursors have been exposed. To explore these mechanisms further, we generated catalogs of somatic mutation from 21 breast cancers and applied mathematical methods to extract mutational signatures of the underlying processes. Multiple distinct single- and double-nucleotide substitution signatures were discernible. Cancers with BRCA1 or BRCA2 mutations exhibited a characteristic combination of substitution mutation signatures and a distinctive profile of deletions. Complex relationships between somatic mutation prevalence and transcription were detected. A remarkable phenomenon of localized hypermutation, termed "kataegis," was observed. Regions of kataegis differed between cancers but usually colocalized with somatic rearrangements. Base substitutions in these regions were almost exclusively of cytosine at TpC dinucleotides. The mechanisms underlying most of these mutational signatures are unknown. However, a role for the APOBEC family of cytidine deaminases is proposed