Association between nasal and bronchial symptoms in subjects with persistent allergic rhinitis

BACKGROUND: The association between nasal and bronchial symptoms, and the course of bronchial responsiveness and airway inflammation in house dust mite sensitive persistent rhinitis over a prolonged time period has not been thoroughly explored. OBJECTIVE: To determine if nasal symptoms were associated with bronchial symptoms in persistent rhinitic subjects, and to assess their bronchial responsiveness and airway inflammation in comparison to nonrhinitic, nonatopic controls. The additional impact of pollen sensitivity on the lower airways in rhinitic subjects was also addressed. METHODS: Rhinitics and controls answered telephone symptom questionnaires once every 2 weeks for 1 year. Every 3 months, exhaled nitric oxide (eNO) and bronchial responsiveness to histamine were measured. RESULTS: Thirty-seven rhinitics and 19 controls completed the study. High nasal symptom scores in rhinitic subjects were associated with bronchial symptoms (OR = 1.7, 95% CI 1.2-2.5). Bronchial hyper-responsiveness was present in 32.4% of rhinitic subjects on at least one clinical visit during the year. Pollen allergy caused seasonal variation in eNO (P = 0.03). CONCLUSION: In persistent rhinitic subjects, high nasal symptom scores were associated with bronchial symptoms, and many subjects experienced bronchial hyper-responsiveness during the year. Persistent rhinitic subjects were more at risk than healthy adults of bronchial symptoms and airway inflammation, which are likely risk factors for asthma.     

Impact of intratumoral heterogeneity of breast cancer tissue on quantitative metabolomics using high‐resolution magic angle spinning 1H NMR spectroscopy

High‐resolution magic angle spinning (HR MAS) nuclear magnetic resonance (NMR) spectroscopy is increasingly being used to study metabolite levels in human breast cancer tissue, assessing, for instance, correlations with prognostic factors, survival outcome or therapeutic response. However, the impact of intratumoral heterogeneity on metabolite levels in breast tumor tissue has not been studied comprehensively. More specifically, when biopsy material is analyzed, it remains questionable whether one biopsy is representative of the entire tumor. Therefore, multi‐core sampling (n = 6) of tumor tissue from three patients with breast cancer, followed by lipid (0.9‐ and 1.3‐ppm signals) and metabolite quantification using HR MAS ¹H NMR, was performed, resulting in the quantification of 32 metabolites. The mean relative standard deviation across all metabolites for the six tumor cores sampled from each of the three tumors ranged from 0.48 to 0.74. This was considerably higher when compared with a morphologically more homogeneous tissue type, here represented by murine liver (0.16–0.20). Despite the seemingly high variability observed within the tumor tissue, a random forest classifier trained on the original sample set (training set) was, with one exception, able to correctly predict the tumor identity of an independent series of cores (test set) that were additionally sampled from the same three tumors and analyzed blindly. Moreover, significant differences between the tumors were identified using one‐way analysis of variance (ANOVA), indicating that the intertumoral differences for many metabolites were larger than the intratumoral differences for these three tumors. That intertumoral differences, on average, were larger than intratumoral differences was further supported by the analysis of duplicate tissue cores from 15 additional breast tumors. In summary, despite the observed intratumoral variability, the results of the present study suggest that the analysis of one, or a few, replicates per tumor may be acceptable, and supports the feasibility of performing reliable analyses of patient tissue.     

Durable HIV RNA resuppression after virologic failure while remaining on a first‐line regimen: a cohort study

Adherence interventions are a recommended strategy to salvage failing antiretroviral therapy without regimen change. We assessed the durability of resuppression when using this approach. Of 300 patients who resuppressed on the same regimen (41% of all those with virologic failure), 148 (45%) remained suppressed during follow‐up for a median of 2.4 years (interquartile range [IQR]: 1.1, 4.0). Resuppression can be durable following viraemia without a switch in antiretroviral therapy regimen.     

Catecholamine-induced lipolysis causes mTOR complex dissociation and inhibits glucose uptake in adipocytes

Anabolic and catabolic signaling oppose one another in adipose tissue to maintain cellular and organismal homeostasis, but these pathways are often dysregulated in metabolic disorders. Although it has long been established that stimulation of the β-adrenergic receptor inhibits insulin-stimulated glucose uptake in adipocytes, the mechanism has remained unclear. Here we report that β-adrenergic–mediated inhibition of glucose uptake requires lipolysis. We also show that lipolysis suppresses glucose uptake by inhibiting the mammalian target of rapamycin (mTOR) complexes 1 and 2 through complex dissociation. In addition, we show that products of lipolysis inhibit mTOR through complex dissociation in vitro. These findings reveal a previously unrecognized intracellular signaling mechanism whereby lipolysis blocks the phosphoinositide 3-kinase–Akt–mTOR pathway, resulting in decreased glucose uptake. This previously unidentified mechanism of mTOR regulation likely contributes to the development of insulin resistance.Adipose tissue plays an essential role in maintaining whole-body energy homeostasis by storing or releasing nutrients. This balance is controlled by opposing signaling pathways where anabolic processes are activated by insulin (INS) and catabolic actions are activated by catecholamines. An important unanswered question in adipose biology is how catecholamine-induced β-adrenergic signaling opposes insulin-stimulated glucose uptake (1–6). Surprisingly, the underlying mechanism for this well-established physiological response in adipocytes is still unknown.When nutrients are plentiful, insulin is released by the pancreas and stimulates the absorption of glucose and fatty acids in adipose tissue, where they are packaged and stored as triacylglycerol (TAG) in cellular lipid droplets. Insulin signaling in adipocytes is mediated by the phosphoinositide 3-kinase (PI3K)–Akt–mTOR pathway. mTOR is a highly conserved serine/threonine protein kinase that functions in either of two distinct multiprotein complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). mTORC1 is defined primarily by the association of mTOR with raptor, whereas mTORC2 includes mTOR with rictor (7). Importantly, mTORC2 phosphorylation of Akt at S473 is required for Akt activity on AS160, which is necessary for glucose uptake in response to insulin (8–11). Of note, for both mTORC1 and mTORC2, the integrity of these protein complexes is essential for kinase substrate specificity and proper signaling (12, 13).During periods of fasting or stress, catecholamines are released by the sympathetic nervous system to activate lipolysis. Stimulation of the β-adrenergic receptor on adipocytes activates adenylyl cyclase (AC), leading to elevated cAMP and protein kinase A (PKA) activity. PKA initiates lipolysis by direct phosphorylation of hormone-sensitive lipase (HSL) and perilipin (14–16) and indirect activation of adipose triglyceride lipase (ATGL) (17–19). Lipolysis involves hydrolysis of TAG stored in the lipid droplet to produce diacylglycerol (DAG), monoacylglycerol (MAG), fatty acids, and glycerol. These lipolytic products are important energy substrates that can act as precursors for other lipids and impact cellular signaling. However, their potential role as signaling molecules has been underappreciated (20).In this study, we provide insight into the mechanisms that link β-adrenergic stimulation to the inhibition of insulin-stimulated glucose uptake. Namely, we show that activation of lipolysis is crucial. Moreover, we find that products of lipolysis themselves cause mTOR inhibition by complex dissociation, which inhibits glucose uptake in adipocytes. This mechanism of mTOR regulation (i.e., by complex dissociation) has major implications in the regulation of cellular metabolism and likely contributes to stress-induced hyperglycemia and obesity-induced insulin resistance.     

Acceptability of neonatal male circumcision in Lusaka, Zambia

Neonatal male circumcision (NMC) is being scaled up in Zambia and elsewhere in Southern Africa as a long-term HIV prevention strategy. We conducted 12 focus group discussions with 129 parents and grandparents in Lusaka, recruited from two sites providing free NMC services and information about NMC, to explore the acceptability of circumcising newborn boys. Most participants recognized the benefits of circumcision for HIV prevention, and the advantages of circumcising their children and grandchildren at a young age. Fear of negative outcomes, concerns about pain, and issues around cultural identity may challenge NMC uptake. To effectively promote the service, the upper age limit for NMC must be emphasized, and fathers must be targeted by messaging campaigns.     

Asthma and obesity: a known association but unknown mechanism

The obese asthma phenotype is an increasingly common encounter in our clinical practice. Epidemiological data indicate that obesity increases the prevalence and incidence of asthma, and evidence that obesity precedes the development of asthma raises the possibility of a causal association. Obese patients with asthma experience more symptoms and increased morbidity compared with non-obese asthma patients. Despite more than a decade of research into this association, the exact mechanisms that underlie the interaction of obesity with asthma remain unclear. It is unlikely that the asthma-obesity association is simply due to comorbidities such as obstructive sleep apnoea or gastroesophageal reflux disease. Although inflammatory pathways are purported to play a role, there is scant direct evidence in humans that systemic inflammation modulates the behaviour of the asthmatic airway or the expression of symptoms in the obese. The role of non-eosinophilic airway inflammation also requires further study. Obesity results in important changes to the mechanical properties of the respiratory system, and these obesity-related factors appear to exert an additive effect to the asthma-related changes seen in the airways. An understanding of the various physiological perturbations that might be contributing to symptoms in obese patients with asthma will allow for a more targeted and rational treatment approach for these patients.     

Successful use of “Hour 1” transfer of sperm microinjected oocytes in natural cycles of poor responder women: a prospective randomized controlled pilot study

The aim of the study is to demonstrate the successful use of “Hour 1” transfer of sperm microinjected oocytes in natural cycles of poor responder women. Seventy women were selected from 92 consecutive poor responders undergoing intracytoplasmatic sperm injection (ICSI) in a natural cycle at our Sterility and Assisted Reproduction Unit from September 2009 to July 2013, and randomly distributed in two homogeneous groups: Group A or B. Women in Group A (35) underwent transfer within 1 h after ICSI; Group B (35, control group) underwent transfer 3 days after ICSI. In Group A, seven clinical pregnancy and one miscarriage occurred; in Group B, eight clinical pregnancies and two miscarriages were observed. Pregnancy, miscarriage, term pregnancy and overall live birth rates’ difference between the two groups was not statistically significant (p?>?0.05). Difference between the two groups in terms of timing, type of delivery and newborn birthweight was not observed. Neither ectopic pregnancy nor multiple pregnancies occurred. “Hour 1” uterine transfer of ICSI oocytes, still to be considered with caution because of the relatively low number of observations of the pilot study, deserves further attention on a larger scale, and might be evaluated for clinical and financial effectiveness in other clinical settings.