Diesel exhaust inhalation and assessment of peripheral blood mononuclear cell gene transcription effects: an exploratory study of healthy human volunteers

Ambient fine particulate matter has been associated with cardiovascular and other diseases in epidemiological studies, and diesel exhaust (DE) is a major source of urban fine particulate matter. Air pollution's cardiovascular effects have been attributed to oxidative stress and systemic inflammation, with resulting perturbation of vascular homeostasis. Peripheral leukocytes are involved in both inflammation and control of vascular homeostasis. We conducted a pilot study using microarray techniques to analyze whether global gene expression profiles in peripheral blood mononuclear cells (PBMCs) can elucidate effects of DE inhalation, for further investigation of mechanisms underlying vascular effects. In a double-blind, crossover, controlled exposure study, healthy adult volunteers were exposed in randomized order to filtered air (FA) and diluted DE in 2-h sessions. We isolated RNA (Trizol/Qiagen method) from PBMCs before and two times after each exposure. RNA samples were arrayed using the Affymetrix U133 Plus 2.0 arrays. Microarray analyses were conducted on five subjects with available RNA samples from exposures to FA and to the highest DE inhalation (200 microg/m(3) of fine particulate matter). Following data normalization and statistical analysis, a total of 1290 out of 54,675 probe sets evidenced differential expression (more than 1.5-fold up- or downregulated with p < .05) between FA and DE exposure. These genes demonstrated a clear distinction between the FA and DE groups and an indication of a time-dependent effect on biological processes such as inflammation and oxidative stress. This study addresses the value of using PBMC gene expression to assess pathways relevant to cardiovascular effect in healthy individuals.     

Comparative in vivo bioequivalence and in vitro dissolution of two cyclosporin A soft gelatin capsule formulations

OBJECTIVE: A study was conducted to establish the bioequivalence between a newly developed cyclosporin A (CsA) oral formulation, Deximune soft-gelatin capsules (Dexcel Ltd.) and Sandimmune Neoral (Novartis Inc.). MATERIALS AND METHODS: The clinical investigation was designed as a randomized, open-labeled, two-period, two-treatment crossover study, in 24 healthy fasted male volunteers. The subjects were administered a single 200 mg CsA dose of either formulation. Serial venous blood samples were obtained over 24 hours after each administration to measure CsA in whole blood by a specific TDx-immunoassay. In addition, the comparative drug release rate was assessed using a dissolution apparatus test according to the USP-24 method. RESULTS: For both treatments, a mean maximum blood concentration (Cmax) of approximately 1,200 ng/ml was obtained at about 1.6 hours (tmax) after administration and the geometric mean of the area under the blood concentration-time curve (AUC) both for test and reference was approximately 4,900 ng x h/ml. Bioequivalence was conclusively demonstrated for both rate (Cmax and tmax) and extent (AUC) of CsA absorption, between the two treatments. Moreover, the CsA blood concentration measurement at 2 hours after administration (C2), demonstrated equivalent results between the two products. The point estimates and their 90% confidence intervals were within the respective equivalence ranges for the pharmacokinetic parameters and were included in the range for drugs with a narrow therapeutic index. The comparative dissolution test for both formulations showed an in vitro release rate of more than 90% within 15 minutes. CONCLUSIONS: Based on the results, the two oral CsA formulations compared are bioequivalent and can be interchanged without need for dosage adjustment.     

Acne in the adult female patient: a practical approach

Acne vulgaris is a common reason why adult women present to dermatologists and can be a clinical challenge to treat. It may also be an important sign of an underlying endocrine disease such as Polycystic Ovary Syndrome (PCOS). Although standard acne therapies can be successfully used to treat acne in adult female patients, hormonal treatment is a safe and effective therapeutic option that may provide an opportunity to better target acne in this population, even when other systemic therapies have failed. In this article, a practical approach to the adult female patient with acne will be reviewed to enhance the dermatologist’s ability to use hormonal acne therapies and to better identify and evaluate patients with acne in the setting of a possible endocrine disorder.     

Helicobacter pylori and oesophageal and gastric cancers in a prospective study in China

In a cohort of 29,584 residents of Linxian, China, followed from 1985 to 2001, we conducted a case-cohort study of the magnitude of the association of Helicobacter pylori seropositivity with cancer risk in a random sample of 300 oesophageal squamous cell carcinomas, 600 gastric cardia adenocarcinomas, all 363 diagnosed gastric non-cardia adenocarcinomas, and a random sample of the entire cohort (N=1050). Baseline serum was evaluated for IgG antibodies to whole-cell and CagA H. pylori antigens by enzyme-linked immunosorbent assay. Risks of both gastric cardia and non-cardia cancers were increased in individuals exposed to H. pylori (Hazard ratios (HRs) and 95% confidence intervals=1.64; 1.26-2.14, and 1.60; 1.15-2.21, respectively), whereas risk of oesophageal squamous cell cancer was not affected (1.17; 0.88-1.57). For both cardia and non-cardia cancers, HRs were higher in younger individuals. With longer time between serum collection to cancer diagnosis, associations became stronger for cardia cancers but weaker for non-cardia cancers. CagA positivity did not modify these associations. The associations between H. pylori exposure and gastric cardia and non-cardia adenocarcinoma development were equally strong, in contrast to Western countries, perhaps due to the absence of Barrett's oesophagus and oesophageal adenocarcinomas in Linxian, making all cardia tumours of gastric origin, rather than a mixture of gastric and oesophageal malignancies.     

Tooth loss is associated with increased risk of gastric non-cardia adenocarcinoma in a cohort of Finnish smokers

OBJECTIVE: Tooth loss has been associated with upper gastrointestinal cancer in several studies, but only one previous study used prospectively collected data. The importance of confounding by Helicobacter pylori has not previously been addressed. The objective was to determine the association between tooth loss and upper gastrointestinal cancer in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study cohort and to determine the importance of potentially confounding dietary factors or H. pylori seropositivity. MATERIAL AND METHODS: A prospective cohort study with 29,124 subjects included 49 esophageal squamous cell carcinomas, 66 esophageal/gastric cardia adenocarcinomas, and 179 gastric non-cardia adenocarcinomas occurring between 1985 and 1999. Cox proportional hazards models adjusted for age and education were used to estimate hazard ratios (HRs) and 95% CIs. Odds ratios and 95% CIs were calculated with and without adjustment for H. pylori seropositivity in a nested case-control group to determine whether H. pylori confounded the association between tooth loss and gastric cancer. RESULTS: Tooth loss significantly increased the hazard ratio for gastric non-cardia cancer, the HR (95% CI) for edentulous subjects versus those with < 10 teeth lost was 1.65 (1.09, 2.49, respectively). No statistically significant associations were found between tooth loss and esophageal squamous cell carcinoma or esophageal/gastric cardia adenocarcinoma. Confounding by dietary factors, tobacco smoking, or H. pylori did not explain these results. CONCLUSIONS: Tooth loss was associated with increased risk of gastric non-cardia cancer, but not esophageal squamous cell carcinoma or esophageal/gastric cardia adenocarcinoma in this Finnish cohort.