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Journal: Clinical science (London, England : 1979)


In PCOS women, hyperinsulinemia stimulates ovarian cytochrome P450c17α activity that, in turn, stimulates ovarian androgen production. Our objective was to compare whether timed caloric intake differentially influences insulin resistance and hyperandrogenism in lean PCOS women. Sixty lean PCOS women (BMI 23.7±0.2kg/m2) were randomized into two isocaloric (~1800kcal) maintenance diets with different meal timing distribution: a breakfast diet (BF) (980kcal breakfast, 640kcal lunch, 190kcal dinner) or a dinner diet (D) group (190kcal breakfast, 640kcal lunch, 980kcal dinner) for 90 days. In the BF group, a significant decrease was observed in both AUCglucose and AUCinsulin, by 7 and 54%, respectively. In the BF group, free testosterone decreased by 50% and SHBG increased by 105%. GnRH-stimulated peak serum 17α hydroxyprogesterone decreased by 39%. No change in these parameters was observed in the D group. In addition, women in the BF group presented increased ovulation rate. In lean PCOS women, a high caloric intake at breakfast with reduced intake at dinner results in improved insulin sensitivity indices and reduced cytochrome P450c17α activity, which ameliorates hyperandrogenism and improves ovulation rate. Meal timing and distribution should be considered as a therapeutic option for women with PCOS.

Concepts: Estrogen, Luteinizing hormone, Metformin, Polycystic ovary syndrome


Although weight loss can usually be achieved by restricting food intake, the majority of dieters regain weight over the long-term. In the hypothalamus, hormonal signals from the gastrointestinal tract, adipose tissue and other peripheral sites are integrated to influence appetite and energy expenditure. Diet-induced weight loss is accompanied by several physiological changes which encourage weight regain, including alterations in energy expenditure, substrate metabolism and hormone pathways involved in appetite regulation, many of which persist beyond the initial weight loss period. Safe effective long-term strategies to overcome these physiological changes are needed to help facilitate maintenance of weight loss. The present review, which focuses on data from human studies, begins with an outline of body weight regulation to provide the context for the subsequent discussion of short- and long-term physiological changes which accompany diet-induced weight loss.

Concepts: Metabolism, Nutrition, Obesity, Weight loss, Dieting, Puberty, Appetite, Leptin


Long-term tobacco smokers with chronic obstructive pulmonary disease (COPD) or chronic bronchitis display an excessive accumulation of neutrophils in the airways; an inflammation that responds poorly to established therapy. Thus, there is a need to identify new molecular targets for the development of effective therapy. Here, we hypothesized that the neutrophil-mobilizing cytokine interleukin (IL)-26 (IL-26) is involved in airway inflammation amongst long-term tobacco smokers with or without COPD, chronic bronchitis or colonization by pathogenic bacteria. By analyzing bronchoalveolar lavage (BAL), bronchail wash (BW) and induced sputum (IS) samples, we found increased extracellular IL-26 protein in the airways of long-term smokers in vivo without further increase amongst those with clinically stable COPD. In human alveolar macrophages (AM) in vitro, the exposure to water-soluble tobacco smoke components (WTC) enhanced IL-26 gene and protein. In this cell model, the same exposure increased gene expression of the IL-26 receptor complex (IL10R2 and IL20R1) and nuclear factor κ B (NF-κB); a proven regulator of IL-26 production. In the same cell model, recombinant human IL-26 in vitro caused a concentration-dependent increase in the gene expression of NF-κB and several pro-inflammatory cytokines. In the long-term smokers, we also observed that extracellular IL-26 protein in BAL samples correlates with measures of lung function, tobacco load, and several markers of neutrophil accumulation. Extracellular IL-26 was further increased in long-term smokers with exacerbations of COPD (IS samples), with chronic bronchitis (BAL samples ) or with colonization by pathogenic bacteria (IS and BW samples). Thus, IL-26 in the airways emerges as a promising target for improving the understanding of the pathogenic mechanisms behind several pulmonary morbidities in long-term tobacco smokers.


Data showing a remarkable gender difference in life expectancy and mortality, including survival to extreme age, are reviewed starting from clinical and demographic data and stressing the importance of a comprehensive historical perspective and a gene-environment/lifestyle interaction. Gender difference regarding prevalence and incidence of the most important age-related diseases, such as cardiovascular and neurodegenerative diseases, cancer, Type 2 diabetes, disability, autoimmunity and infections, are reviewed and updated with particular attention to the role of the immune system and immunosenescence. On the whole, gender differences appear to be pervasive and still poorly considered and investigated despite their biomedical relevance. The basic biological mechanisms responsible for gender differences in aging and longevity are quite complex and still poorly understood. The present review focuses on centenarians and their offspring as a model of healthy aging and summarizes available knowledge on three basic biological phenomena, i.e. age-related X chromosome inactivation skewing, gut microbiome changes and maternally inherited mitochondrial DNA genetic variants. In conclusion, an appropriate gender-specific medicine approach is urgently needed and should be systematically pursued in studies on healthy aging, longevity and age-related diseases, in a globalized world characterized by great gender differences which have a high impact on health and diseases.

Concepts: Immune system, DNA, Medicine, Genetics, Epidemiology, Demography, Population, X-inactivation


Quitting smoking is the most important step smokers can take to improve their health. Nonetheless, there is little information on long-term improvements in lung function and/or respiratory symptoms after smoking cessation. Here we illustrate long-term changes in spirometric indices as well as in respiratory symptoms in smokers invited to quit or reduce their cigarette consumption by switching to electronic cigarettes. Prospective evaluation of cigarette consumption, spirometry and symptoms was performed in a 1-year randomized controlled trial of smokers receiving electronic cigarette containing 2.4%, 1.8%, or 0% nicotine. Spirometric data are presented on the basis of participants' pooled continuous smoking phenotype classification (Quitters, Reducers, Failures), whereas respiratory symptoms on point prevalence-smoking phenotype. Smoking phenotype classification (Quitters, Reducers, Failures) had no significant effect on spirometric indices (FEV1, FVC, and FEV1/FVC) with the exception of FEF25-75%, which significantly (p=0.034) increased over the time among Quitters; their FEF25-75% (% predicted) improving from (means±SD) 85.7±15.6% at baseline to 100.8±14.6%. High prevalence of cough/phlegm (43.1%) and shortness of breath (34.8%) was reported at baseline with substantial reduction in their frequency at subsequent follow-up visits. These symptoms virtually disappeared very quickly in both quitters and reducers. Smokers invited to switch to electronic cigarettes who completely abstained from smoking showed steady progressive improvements in their FEF25-75% Normalization of peripheral airways function was associated with improvement in respiratory symptoms, adding to the notion that abstaining from smoking can reverse tobacco harm in the lung.

Concepts: Pulmonology, Smoking, Tobacco, Cigarette, Nicotine, Smoking cessation, Electronic cigarette, Spirometry


The physical and immunological properties of the human intestinal epithelial barrier in ageing are largely unknown. Ileal biopsies from young (7-12 years), adult (20-40y) and ageing (67-77y) individuals not showing symptoms of gastrointestinal pathologies were used to assess levels of inflammatory cytokines, barrier integrity, and cytokine production in response to microbial challenges. Increased expression of IL-6, but not IFNg, TNF-a and IL-1b was observed during ageing; further analysis showed that CD11c+ dendritic cells (DCs) are one of the major sources of IL-6 in the ageing gut and expressed higher levels of CD40. Up-regulated production of IL-6 was accompanied by increased expression of Claudin-2 leading to reduced transepithelial electric resistance (TEER); TEER could be restored in in vitro and ex-vivo cultures by neutralizing anti-IL-6 antibody. In contrast, expression of Zonula occludens-1, Occludin and Junctional-Adhesion Molecule-A1 did not vary with age and overall permeability to macromolecules was not affected. Finally, cytokine production to different microbial stimuli was assessed in a polarized in vitro organ culture. IL-8 production in response to flagellin declined progressively with age although the expression and distribution of TLR-5 on intestinal epithelial cells remained unchanged. Also, flagellin-induced production of IL-6 was less pronounced in ageing. In contrast, TNF-a production in response to probiotics (VSL#3) did not decline with age; however, in our experimental model probiotics did not down-regulate the production of IL- 6 and expression of Claudin 2. These data suggested that ageing affects properties of the intestinal barrier likely to impact on age-associated disturbances both locally and systemically.

Concepts: Immune system, Antibody, Bacteria, Cytokine, Digestive system, Epithelium, Small intestine, Intestinal epithelium


Fully-sedated patients, being treated in the ICU, experience substantial skeletal muscle loss. Consequently, survival rate is reduced and full recovery after awakening is compromised. Neuromuscular electrical stimulation (NMES) represents an effective method to stimulate muscle protein synthesis and alleviate muscle disuse atrophy in healthy subjects. We investigated the efficacy of twice-daily NMES to alleviate muscle loss in six fully-sedated ICU patients admitted for acute critical illness (n=3 males, n=3 females; age 63±6 y; APACHE II disease severity-score: 29±2). One leg was subjected to twice-daily NMES of the quadriceps muscle for a period of 7±1 d while the other leg acted as non-stimulated control (CON). Directly before the first and on the morning after the final NMES session, quadriceps muscle biopsies were collected from both legs to assess muscle fiber-type specific cross-sectional area (CSA). Furthermore, phosphorylation status of key proteins involved in the regulation of muscle protein synthesis was assessed, and mRNA expression of selected genes was measured. In the CON leg, type I and type II muscle fiber CSA decreased by 16±9 and 24±7%, respectively (P<0.05). No muscle atrophy was observed in the stimulated leg. NMES increased mTOR phosphorylation by 19% when compared to baseline (P<0.05), with no changes in the CON leg. Furthermore, mRNA expression of key genes involved in muscle protein breakdown either declined (FOXO1; P<0.05) or remained unchanged (MAFBx and MuRF1), with no differences between legs. In conclusion, NMES represents an effective and feasible interventional strategy to prevent skeletal muscle atrophy in critically ill, comatose patients.

Concepts: DNA, Protein, Messenger RNA, Muscle, Muscle atrophy, Sarcopenia, Skeletal muscle, Atrophy


T helper (Th)17 immune response participates in allergic lung inflammation and asthma is reduced in the absence of interleukin (IL)-17 in mice. Since IL-17A and IL-17F are induced and bind the shared receptor IL-17RA, we asked whether both IL-17A and IL-17F contribute to house dust mite (HDM) induced asthma. We report that allergic lung inflammation is attenuated in absence of either IL-17A or IL-17F with reduced airway hyperreactivity, eosinophilic inflammation, goblet cell hyperplasia, cytokine and chemokine production as found in absence of IL-17RA. Furthermore, specific antibody neutralization of either IL-17A or IL-17F given during the sensitization phase attenuated allergic lung inflammation and airway hyperreactivity. In vitro activation by HDM of primary dendritic cells revealed a comparable induction of CXCL1 and IL-6 expression and the response to IL-17A and IL-17F relied on IL-17RA signaling via the adaptor protein act1 in fibroblasts. Therefore, HDM-induced allergic respiratory response depends on IL-17RA via act1 signaling and inactivation of either IL-17A or IL-17F is sufficient to attenuate allergic asthma in mice.

Concepts: Immune system, Inflammation, Asthma, Immunology, Allergy, Chemokine, Mucus, House dust mite


Cardiovascular disease (CVD) is the most prevalent cause of mortality among patients with Type 1 or Type 2 diabetes, due to accelerated atherosclerosis. Recent evidence suggests a strong link between atherosclerosis and insulin resistance, due to impaired insulin receptor (IR) signalling. Here we demonstrate that inhibiting the activity of protein tyrosine phosphatase 1B (PTP1B), the major negative regulator of the IR prevents and reverses atherosclerotic plaque formation in LDLR(-/-) mouse model of atherosclerosis. Acute (single dose) or chronic PTP1B inhibitor (trodusquemine) treatment of LDLR(-/-) mice decreased weight gain and adiposity, improved glucose homeostasis and attenuated atherosclerotic plaque formation. This was accompanied with a reduction in both, circulating total cholesterol and triglycerides, a decrease in aortic monocyte chemoattractant protein-1 (MCP-1) expression levels, and hyperphosphorylation of aortic Akt/PKB and AMPKα. Our findings are the first to demonstrate that PTP1B inhibitors could be used in prevention and reversal of atherosclerosis development and reduction of CVD risk.

Concepts: Cholesterol, Myocardial infarction, Atherosclerosis, Insulin, Diabetes mellitus, Insulin resistance, Metabolic syndrome, Inhibitor


Energy balance is not a simple algebraic sum of energy expenditure and energy intake as often depicted in communications. Energy balance is a dynamic process and there exist reciprocal effects between food intake and energy expenditure. An important distinction is that of metabolic and behavioural components of energy expenditure. These components not only contribute to the energy budget directly, but also by influencing the energy intake side of the equation. It has recently been demonstrated that resting metabolic rate (RMR) is a potential driver of energy intake, and evidence is accumulating on the influence of physical activity (behavioural energy expenditure) on mechanisms of satiety and appetite control. These effects are associated with changes in leptin and insulin sensitivity, and in the plasma levels of gastrointestinal (GI) peptides such as glucagon-like peptide-1 (GLP-1), ghrelin and cholecystokinin (CCK). The influence of fat-free mass on energy expenditure and as a driver of energy intake directs attention to molecules emanating from skeletal tissue as potential appetite signals. Sedentariness (physical inactivity) is positively associated with adiposity and is proposed to be a source of overconsumption and appetite dysregulation. The molecular signals underlying these effects are not known but represent a target for research.

Concepts: Metabolism, Nutrition, Energy, Diabetes mellitus, Obesity, Adipose tissue, Appetite, Basal metabolic rate