Nutrition in Spondyloarthritis and Related Immune-Mediated Disorders

Recent research on the pathogenesis of spondyloarthritis and related immune-mediated diseases associated with human leukocyte antigen class I molecule B27 (HLA-B27) has led to significant progress in terms of management and prognosis, with multiple treatments being constantly evaluated and implemented. Correlations between the genetic background of spondyloarthritis and inflammatory bowel diseases and the inflammatory processes involving gut microbiota have been established. This knowledge has allowed progress in pharmacological therapy. The role of diet in the pathogenesis and treatment of diseases pertaining to the HLA-B27 spectrum is of great significance, considering possible future applications in individualized medicine. Diet impacts the composition of gut microbiota, representing a substrate for the synthesis of metabolites affecting the mucosal immune system. Certain pro-inflammatory mediators, such as emulsifiers and microparticles, induce a more profound cytokine response, promoting inflammation. Numerous diets, including the low-starch diet, the Mediterranean diet, diets with low contents of fermentable oligosaccharides, disaccharides, monosaccharides and polyols (low-FODMAP diets), gluten-free diets and fasting, have been analysed and correlated with patients’ symptomatology and dietary adherence. The aim of this review is to provide an extensive perspective on the diets available to patients with spondyloarthritis and related immune-mediated disorders.     

Glucagon-like peptide-1 receptor dimerization differentially regulates agonist signaling but does not affect small molecule allostery

The glucagon-like peptide-1 receptor (GLP-1R) is a family B G protein-coupled receptor and an important drug target for the treatment of type II diabetes, with activation of pancreatic GLP-1Rs eliciting glucose-dependent insulin secretion. Currently, approved therapeutics acting at this receptor are peptide based, and there is substantial interest in small molecule modulators for the GLP-1R. Using a variety of resonance energy transfer techniques, we demonstrate that the GLP-1R forms homodimers and that transmembrane helix 4 (TM4) provides the primary dimerization interface. We show that disruption of dimerization using a TM4 peptide, a minigene construct encoding TM4, or by mutation of TM4, eliminates G protein-dependent high-affinity binding to GLP-1(7-36)NH₂ but has selective effects on receptor signaling. There was <10-fold decrease in potency in cAMP accumulation or ERK1/2 phosphorylation assays but marked loss of intracellular calcium mobilization by peptide agonists. In contrast, there was near-complete abrogation of the cAMP response to an allosteric agonist, compound 2, but preservation of ERK phosphorylation. Collectively, this indicates that GLP-1R dimerization is important for control of signal bias. Furthermore, we reveal that two small molecule ligands are unaltered in their ability to allosterically modulate signaling from peptide ligands, demonstrating that these modulators act in cis within a single receptor protomer, and this has important implications for small molecule drug design.     

Laser capture microdissection of cervical human papillomavirus infections: Copy number of the virus in cancerous and normal tissue and heterogeneous DNA methylation

Research on the pathogenicity of human papillomaviruses (HPVs) during cervical carcinogenesis often relies on the study of homogenized tissue or cultured cells. This approach does not detect molecular heterogeneities within the infected tissue. It is desirable to understand molecular properties in specific histological contexts. We asked whether laser capture microdissection (LCM) of archival cervical tumors in combination with real-time polymerase chain reaction and bisulfite sequencing permits (i) sensitive DNA diagnosis of small clusters of formalin-fixed cells, (ii) quantification of HPV DNA in neoplastic and normal cells, and (iii) analysis of HPV DNA methylation, a marker of tumor progression. We analyzed 26 tumors containing HPV-16 or 18. We prepared DNA from LCM dissected thin sections of 100 to 2000 cells, and analyzed aliquots corresponding to between nine and 70 cells. We detected nine to 630 HPV-16 genome copies and one to 111 HPV-18 genome copies per tumor cell, respectively. In 17 of the 26 samples, HPV DNA existed in histologically normal cells distant from the margins of the tumors, but at much lower concentrations than in the tumor, suggesting that HPVs can infect at low levels without pathogenic changes. Methylation of HPV DNA, a biomarker of integration of the virus into cellular DNA, could be measured only in few samples due to limited sensitivity, and indicated heterogeneous methylation patterns in small clusters of cancerous and normal cells. LCM is powerful to study molecular parameters of cervical HPV infections like copy number, latency and epigenetics.     

Nicotine and carcinogen exposure with smoking of progressively reduced nicotine content cigarette.

BACKGROUND: Reducing the nicotine content of cigarettes to make them non-addictive has been widely discussed as a potential strategy for tobacco regulation. A major concern with nicotine reduction is that smokers will compensate for reduced nicotine by smoking more cigarettes and/or smoking more intensively, thereby increasing their exposure to tobacco smoke toxins. This study examined whether gradual reduction in nicotine exposure increases exposure to tobacco smoke toxins. METHODS: This 10-week longitudinal study of 20 healthy smokers involved smoking their usual brand followed by different types of research cigarettes with progressively lower nicotine content, each smoked for 1 week. Subjects were followed for 4 weeks after returning to smoking their usual brand (or quitting). Smoking behaviors, chemical biomarkers of tobacco smoke exposure, and cardiovascular effect biomarkers were measured. FINDINGS: Intake of nicotine declined progressively as the nicotine content of cigarettes was reduced, with little evidence of compensation. Cigarette consumption and markers of exposure to carbon monoxide and polycyclic aromatic hydrocarbons, as well as cardiovascular biomarkers remained stable, whereas urinary 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol excretion decreased. Twenty-five percent of participants had spontaneously quit smoking 4 weeks after completing the research cigarette taper. IMPLICATIONS: Our findings with reduced nicotine content cigarettes differ from those of commercial low yields for which compensatory smoking for lower nicotine delivery is substantial. Our data suggest that the degree of nicotine dependence of smokers can be lowered without increasing their exposure to tobacco smoke toxins. Gradual reduction of nicotine content of cigarettes seems to be feasible and should be further evaluated as a national tobacco regulatory strategy.     

Cytotoxicity and DNA-damage in human lung epithelial cells exposed to respirable alpha-quartz.

Occupational exposure to respirable crystalline silica is associated with the development of silicosis, lung cancer and airways diseases. In order to assess cytotoxic effects and direct-oxidative DNA damage induced by short-term exposure to different doses of respirable alpha-quartz (NIST SRM1878a), we conducted a study using A549 cells. The cells were exposed to alpha-quartz at 25, 50, 100 microg/ml for 4 h and analysed by scanning electron microscope (SEM) and LDH release assay for cytotoxic effect evaluation. Cells were also exposed to 10, 25, 50, 100 microg/ml of alpha-quartz for 2 h and 4 h and analysed by Fpg comet test to evaluate direct and oxidative DNA damage. SEM observations of treated cells showed bleb development at lower doses and alterations of microvilli morphology at the highest dose. A slight LDH release was found only at 100 microg/ml. Fpg comet test showed a dose-related oxidative DNA damage in cells exposed for 2 h to quartz. Cells exposed for 4h at the same concentrations showed a dose-related direct DNA damage and the presence of oxidative DNA damage at lower doses. The bleb induction on cell surface evidenced by SEM at lower doses correlates with the presence of oxidative DNA damage at 4 h. The cell surface modifications observed by SEM at 100 microg/ml indicate that high doses of quartz induce more evident cytotoxic effects confirmed by LDH analysis and correlate with the genotoxicity showed by comet assay.     

Sexual behaviors and their correlates among young people in Mauritius: a cross-sectional study

Background  

Little is known about the HIV/AIDS epidemic in the Indian Ocean region, including Mauritius. National records suggest a prevalence of HIV in Mauritius of < 1% in the general population, which is one of the lowest prevalence rates in southern Africa. However, HIV-positive cases have been increasing recently in Mauritius. We conducted a cross-sectional survey in January 2003 to assess the prevalence of HIVrelated sexual behaviors and their correlates among young people aged 15–24 years in Mauritius.     

Injectable hormone contraception and bone density: results from a prospective study

BACKGROUND: Depot medroxyprogesterone acetate (DMPA) injectable contraception may decrease bone density and increase the risk for osteoporosis in later life. Prospective data are scarce, especially of the effects of DMPA discontinuation on bone. METHODS: Between 1994 and 1999, we conducted a population-based prospective cohort study among women enrollees of a Washington State health maintenance organization. We enrolled 457 nonpregnant women, ages 18-39 years (183 DMPA users and 274 non-users). Bone density was measured by dual-energy x-ray absorptiometry every 6 months for 3 years. RESULTS: Bone density decreased notably among DMPA-exposed women at the spine (adjusted mean bone density was -0.0053 gm/cm for DMPA users compared with +0.0023 gm/cm for non-users for each 6-month interval) and total hip (-0.0060 compared with -0.0002 gm/cm ). This represents an annualized mean rate of change at the spine of -0.87% compared with +0.40% and, at the hip, -1.12% compared with -0.05%. Discontinuers of this method (N = 110) showed sizable increases in bone density over comparison women (for each 6-month interval, adjusted mean spine bone density was +0.0067 gm/cm compared with +0.0023 gm/cm, respectively; adjusted mean hip bone density was +0.0035 compared with -0.0002 gm/cm ). Estimated annualized mean rates of change were +1.41% compared with +0.40% [corrected] at the spine and +1.03% [corrected] compared with -0.05% at the hip. After 30 months, mean bone density for discontinuers was similar to that of non-users. CONCLUSIONS: In this study, DMPA use was strongly associated with bone density loss. Substantial postdiscontinuation recovery of bone provides evidence that the effects may be largely reversible.     

Waterborne outbreak of Norwalk-like virus gastroenteritis at a tourist resort,Italy

In July 2000, an outbreak of gastroenteritis occurred at a tourist resort in the Gulf of Taranto in southern Italy. Illness in 344 people, 69 of whom were staff members, met the case definition. Norwalk-like virus (NLV) was found in 22 of 28 stool specimens tested. The source of illness was likely contaminated drinking water, as environmental inspection identified a breakdown in the resort water system and tap water samples were contaminated with fecal bacteria. Attack rates were increased (51.4%) in staff members involved in water sports. Relative risks were significant only for exposure to beach showers and consuming drinks with ice. Although Italy has no surveillance system for nonbacterial gastroenteritis, no outbreak caused by NLV has been described previously in the country.