Association of polymorphisms in CYP19A1 and CYP3A4 genes with lower urinary tract symptoms, prostate volume, uroflow and PSA in a population-based sample

PURPOSE: The known importance of testosterone for the development of benign prostatic hyperplasia (BPH) prompted us to test the hypothesis whether polymorphisms of two genes (CYP19A1 and CYP3A4) involved in testosterone metabolism are associated with clinical BPH-parameters. METHODS: A random sample of the population-based Herne lower urinary tract symptoms cohort was analysed. All these men underwent a detailed urological work-up. Two polymorphisms in the CYP19A1 gene [rs700518 in exon 4 (A57G); rs10046 at the 3'UTR(C268T)] and one in the 3'UTR of CYP3A4 [rs2740574 (A392G)] were determined by TaqMan assay from genomic DNA of peripheral blood. These polymorphisms were correlated to clinical and laboratory BPH-parameters. RESULTS: A total of 392 men (65.4 +/- 7.0 years; 52-79 years) were analysed. Mean International Prostate Symptom Score (IPSS; 7.5), Q (max) (15.4 ml/s), prostate volume (31 ml) and prostate specific antigen (PSA) (1.8 ng/ml) indicated a typical elderly population. Both polymorphisms in the CYP19A1 gene were not correlated to age, IPSS, Q (max), prostate volume and post-void residual volume. Serum PSA was higher in men carrying the heterozygous rs10046 genotype (2.0 +/- 0.1 ng/ml) than in those with the CC-genotype (1.7 +/- 0.2 ng/ml, P = 0.012). Men carrying one a mutated allele of the CYP3A4 gene had smaller prostates (27.0 +/- 2.0 vs. 32 +/- 0.8 ml, P = 0.02) and lower PSA levels (1.6 +/- 0.3 vs. 1.9 +/- 0.1 ng/ml). CONCLUSIONS: The inconsistent associations observed herein and for other gene polymorphisms warrant further studies. In general, the data regarding the association of gene polymorphism to BPH-parameters suggest that this disease is caused by multiple rather than a single genetic variant. A rigorous patient selection based on anatomo-pathological and hormonal profile may possible reduce the number of confounders for future studies thus enabling a more detailed assessment of the association between genetic factors and BPH-parameter

Association of microsomal epoxide hydrolase polymorphisms and lung cancer risk

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Key inflammatory pathways underlying vascular remodeling in pulmonary hypertension

Independent of the underlying cause, pulmonary hypertension (PH) remains adevastating condition that is characterized by limited survival. Cumulating evidence indicates that in addition to adysbalance of mediators regulating vascular tone and growth factors promoting vascular remodeling, failure to resolve inflammation and altered immune processes play apivotal role in the development and progression of PH. Here, we highlight the role of key inflammatory pathways in the pathobiology of vascular remodeling and PH, and discuss potential therapeutic interventions that may halt disease progression or even reverse pulmonary vascular remodeling. Perivascular inflammation is present in all forms of PH, and inflammatory pathways involve numerous mediators and cell types including macrophages, neutrophils, Tcells, dendritic cells, and mast cells. Dysfunctional bone morphogenic protein receptor2 (BMPR2) signaling and dysregulated immunity enable the accumulation of macrophages and other inflammatory cells in obliterative vascular lesions. Regulatory Tcells (Tregs) were shown to be of particular relevance in the control of inflammatory responses. Key cytokines/chemokines include interleukin-6, functioning via classic or trans-signaling, macrophage migratory inhibitory factor (MIF), but also other mediators such as neutrophil-derived myeloperoxidase. The expanding knowledge on this topic has resulted in multiple opportunities for sophisticated therapeutic interventions

Antibiotic Susceptibility of Periodontal Enterococcus faecalis

<p>Background: Enterococcus faecalis may contribute to periodontal breakdown in heavily infected subgingival sites, particularly in patients responding poorly to mechanical forms of periodontal therapy. Because only limited data are available on the antimicrobial sensitivity of enterococci of subgingival origin, this study evaluates the in vitro antibiotic susceptibility of E. faecalis isolated from periodontitis patients in the United States.</p><p>Methods: Pure cultures of 47 subgingival E. faecalis clinical isolates were each inoculated onto specially prepared broth microdilution susceptibility panels containing vancomycin, teicoplanin, and six oral antibiotics of potential use in periodontal therapy. After incubation in ambient air for 18 to 20 hours, minimal inhibitory drug concentrations were determined using applicable Clinical and Laboratory Standards Institute criteria and interpretative guidelines. The organisms were additionally evaluated for in vitro resistance to metronidazole at 4 mg/mL.</p><p>Results: Periodontal E. faecalis exhibited substantial in vitro resistance to tetracycline (53.2% resistant), erythromycin (80.8% resistant or intermediate resistant), clindamycin (100% resistant to 2 mg/mL), and metronidazole (100% resistant to 4 mg/mL). In comparison, the clinical isolates were generally sensitive to ciprofloxacin (89.4% susceptible; 10.6% intermediate resistant) and 100% susceptible in vitro to ampicillin, amoxicillin/clavulanate, vancomycin, and teicoplanin.</p><p>Conclusions: Tetracycline, erythromycin, clindamycin, and metronidazole revealed poor in vitro activity against human subgingival E. faecalis clinical isolates, and would likely be ineffective therapeutic agents against these species in periodontal pockets. Among orally administered antibiotics, ampicillin, amoxicillin/clavulanate, and ciprofloxacin exhibited marked in vitro inhibitory activity against periodontal E. faecalis, and may be clinically useful in treatment of periodontal infections involving enterococci.</p>