GSTA1, GSTM1, GSTP1, and GSTT1 polymorphisms and susceptibility to smoking-related bladder cancer: A case-control study

ObjectivesGlutathione S-transferases (GSTs) are a family of enzymes involved in detoxification. Genes encoding for GSTA1, GSTM1, GSTP1, and GSTT1 proteins are polymorphic, which can result in complete or partial loss of enzyme activity. Previous studies have associated polymorphisms of GSTA1, GSTM1, and GSTP1 genes with a higher risk of bladder cancer, but this is still controversial. Potential role of GSTA1 polymorphism in susceptibility to bladder cancer in Whites is lacking. We examined association between GSTA1, GSTM1, GSTP1, and GSTT1 gene variants and bladder cancer risk and evaluated whether they were modified by smoking.Materials and methodsA hospital-based case-control study recruited 201 incidence cases and 122 age-matched controls. Deletion polymorphism of GSTM1 and GSTT1 was identified by polymerase chain reaction method. Single nucleotide polymorphism of GSTA1 and GSTP1 was identified by restriction fragment length polymorphism method. Uniconditional multivariate logistic regression was applied to model association between genetic polymorphisms and bladder cancer risk, as well as effect modification by smoking.ResultsNo significant difference was observed in the distributions of GSTM1, GSTT1, GSTA1, and GSTP1 gene variants between patients and controls. None of the examined polymorphisms was significantly associated with bladder cancer risk independently. The results of gene–smoking interaction analyses indicated a significant combined effect of smoking and all common GST polymorphisms tested (P for trend = 0.001). However, the most significant effect on bladder cancer risk was observed in smokers carrying lower activity GSTA1-AB/BB and GSTM-null genotype (OR = 3.5, P < 0.05) compared with GSTA1-AA and GSTM1-active non-smokers. Overall, the risk observed did not significantly differ with respect to quantity of cigarettes smoked. However, heavy smokers with GSTM1-null genotype had 2 times higher risk of bladder cancer than GSTM1-null light smokers (OR = 4.8 vs. OR = 2.0) when GSTM1-active non-smokers served as reference group. Smokers carrying both GSTM1-null and GSTA1-AB + BB genotypes exhibited the highest risk of bladder cancer (OR = 2.00, P = 0.123).ConclusionsNull or low-activity genotypes of the GSTA1, GSTM1, GSTT1, and GSTP1 did not contribute independently towards the risk of bladder cancer in our patients. However, in association with smoking, both low activity GSTA1 and GSTM1-null genotype increase individual susceptibility to bladder cancer.     

Population pharmacokinetic of antiepileptic drugs in different populations

This article reviews a population pharmacokinetics studies conducted during the past few years in Serbia. Studies have included three the most frequently used antiepileptic drugs (valproate, carbamazepine and lamotrigine) and different populations of epileptic patients: children, adults and heterogeneous population composed of both children and adults. The review compares obtained values of population pharmacokinetic models of clearance of these drugs, and factors that are significantly determined, making brief comments on the results of other authors on the same topic. Individualization of drug dosage is the basis of rational therapy, and factors of variability will always be subject of scientific research.     

Serum gamma glutamyl-transferase is a sensitive but unspecific marker of metastatic renal cell carcinoma

OBJECTIVE: To address the role of serum gamma-glutamyl transferase (GGT) as a marker of metastases in patients with renal cell carcinoma. METHODS: Serum alkaline phosphatase and GGT were determined in 156 patients with localized renal cell carcinoma and 60 patients with metastases as proven by echosonography, computerized tomography and bone scan. The control group consisted of 50 healthy subjects matched for sex and age. Sensitivity and specificity of both enzymes as markers of metastatic disease were compared. In metastatic patients, enzyme activities were analyzed according to the site of metastases. RESULTS: Both alkaline phosphatase and GGT activities were normal in majority of patients with localized renal cell carcinoma and increased in most of the patients with metastatic disease (80% and 70%, respectively). GGT did not significantly differ from alkaline phosphatase in terms of sensitivity (70% vs 80%) and specificity (89% vs 92%). Concerning the site of metastases, high frequencies of increased GGT and alkaline phosphatase were found in patients with liver-only metastases (80% and 90%, respectively). All of the patients with both liver and bone metastases exhibited increased activity of both enzymes. Despite the fact that bone cells do not express GGT, increased activity was found in patients with bone metastases-only (45%), suggesting that enzymes might be released from tumor cells. CONCLUSIONS: Our data provided evidence that GGT is a sensitive marker of metastatic renal cell carcinoma. However, findings of abnormal GGT activity cannot specify the site of involvement.     

Neural cell adhesion molecule expression on renal interstitial cells.

BACKGROUND: At early stages of kidney development, the neural cell adhesion molecule (NCAM) is highly expressed on cells of the metanephrogenic mesenchyme. During maturation of the fetal kidney, NCAM gradually disappears. So far, it has been widely accepted that NCAM in the adult kidney is only expressed by nerves, and not by other cell types. METHODS: NCAM expression was analysed in human adult healthy and diseased kidneys by immunohistochemistry and western blot analysis. NCAM+ renal interstitial cells were further characterized by double immunofluorescent staining using antibodies against neurofilaments, alpha smooth muscle actin, vimentin, alpha5beta1 integrin, CD68, CD11c, HLA-DR and the potential progenitor cell markers CD34, CD117, CD133, CD24, nestin and cadherin-11. RESULTS: In adult human kidneys, NCAM expression is restricted to rare interstitial cells with dendritic morphology, which are neurofilament-negative and predominantly localized on the corticomedullary junction. They are also negative for fibroblast cell markers, but co-express the haematopoietic stem cell markers CD34 and CD133. The number of NCAM+ interstitial cells increased in the initial phases of interstitial fibrosis. Western blot analysis of renal tissues with incipient interstitial fibrosis tissues showed the expression of the 140 kDa NCAM isoform. CONCLUSIONS: These data indicate that a rare subpopulation of NCAM+ interstitial cells could represent renal progenitors, and that NCAM+ interstitial cells can participate in the initial phase of interstitial fibrosis.     

Bactericidal activity of oral beta-lactam antibiotics in plasma and urine versus isogenic Escherichia coli strains producing broad- and extended-spectrum beta-lactamases

Bacteria harbouring extended-spectrum β-lactamases (ESBLs), derived by mutation from TEM-1, TEM-2 or SHV-1 β-lactamases, have been described world-wide. The in vitro activities of these enzymes against β-lactam antibiotics, including oral cephalosporins, are well recognised. The aim of this investigation was to assess the bactericidal activity of oral β-lactam antibiotics available in Croatia (amoxicillin/clavulanate, cephalexin, cefuroxime, cefadroxil and ceftibuten), in biological fluids against isogenic Escherichia coli strains producing broad-spectrum (TEM-1, TEM-2 and SHV-1) and extended-spectrum β-lactamases (SHV-2, SHV-3, SHV-4, SHV-5, SHV-12). Bactericidal activity of oral β-lactams in plasma and urine was tested in time-kill experiments and by determining bactericidal titres at different time intervals post-dose. The killing rate of antibiotics in urine was slower than in plasma, but faster than in Mueller–Hinton broth. High bactericidal titres in urine were only maintained throughout the whole dosing interval by ceftibuten against strains producing broad-, SHV-2 and SHV-3 β-lactamases. The older generation cephalosporins can be considered for the therapy of urinary tract infections caused by E. coli harbouring TEM-1, TEM-2 and SHV-1 β-lactamases but a shorter dosing interval is needed. Ceftibuten can be recommended with caution in ESBL producing E. coli except those producing SHV-4, SHV-5 and SHV-12 that confer resistance to it. If these enzymes are produced, fluoroquinolones or carbapenems could be considered.     

Review of Community Pharmacy Staff Educational Needs for Supporting Mental Health Consumers and Carers

Development of a mental health education package for community pharmacy staff should be informed by mental health consumers/carers’ needs, expectations and experiences, and staff knowledge, skills and attitudes. This review (1) explored research on community pharmacy practice and service provision for mental health consumers/carers, and (2) identified validated methods for assessing staff knowledge, skills and attitudes about mental illness to inform the development of a training questionnaire. A literature scan using key words knowledge, skills, attitudes, and beliefs combined with community pharmacy, pharmacist, and pharmacy support staff, and mental illness, depression, anxiety was conducted. A small number of studies were found that used reliable methods to assess pharmacists’ training needs regarding mental illness and treatment options. There was little published specifically in relation to depression and anxiety in community pharmacy practice. No studies assessed the training needs of pharmacy support staff. A systematic analysis of pharmacy staff learning needs is warranted.     

Embryogenesis and ossification of Emydura subglobosa (Testudines,Pleurodira, Chelidae) and patterns of turtle development

Using the Standard Event System (SES) to study patterns of vertebrate development, we describe a series of 17 embryos of the pleurodire turtle Emydura subglobosa. Based on a sequence heterochrony analysis including 23 tetrapod taxa, we identified autapomorphic developmental shifts that characterise Testudines, Cryptodira, and Pleurodira. The main results are that Testudines are characterised by an autapomorphic late neck development, whereas pleurodires and cryptodires show a different developmental timing of the mandibular process. Additionally, we described the ossification pattern of E. subglobosa and compared the data to those of five other turtles. Pleurodires show the epiplastron to ossify before or simultaneously with maxilla and dentary. In contrast, cryptodires show a later ossification of this bone. Because evolutionary developmental studies on turtles have previously focused only on “model organisms” that all belong to Cryptodira, we underline the necessity to include a pleurodire taxon for a more comprehensive, phylogenetically more informative approach. Developmental Dynamics 238:2770–2786, 2009. © 2009 Wiley‐Liss, Inc.     

Evaluation of the genetic basis of phenotypic heterogeneity in north Indian patients with Thalassemia major

Objectives: To assess the molecular basis of phenotypic heterogeneity in north Indian patients with thalassemia major (TM). Methods: To determine the clinical severity, 130 patients of TM were studied for the age of first presentation and frequency of blood transfusion. The type of beta mutations, Xmn–1 ^G γ polymorphism and G6PD Mediterranean mutation was characterized. Analysis of the phenotypic presentation and the genotype was performed. Results: Majority (83.8%) presented before 1 year of age (mean 8.8 months). The caste distribution showed 41.6% were Aroras and 32.3% were migrants from Pakistan. IVS1‐5(G→C) was commonest (32.7%) and the common five Indian mutations comprised of 88.4% of alleles. The mean age of presentation with IVS1‐5(G→C), Fr 8/9, (+G) 619‐bp del and IVS1‐1(G→T) homozygosity was 4.3, 6, 3.4 and 9.1 months respectively. Xmn–1^Gγ status showed ?/? in 66.9%, +/? in 26.1% and +/+ in 6.9% patients. Xmn–1^Gγ?/? presented before 1 year of age. The mean age of presentation with +/+ was 18.3 months. Six hemizygous boys and one heterozygous girl with G6PD Mediterranean were found (prevalence 5.3%). Eight patients could be reclassified as thalassemia intermedia on follow up. Conclusions: This study showed that majority of TM in north India present before 1 year of age and homozygous 619‐bp deletion presents the earliest. The presence of Xmn‐1^Gγ polymorphism delays the presentation, is associated with the IVS 1‐1 (G→T) and shows variable improvement with hydroxyurea therapy. Based on the results of genotyping, reevaluation of patients can improve the outcome in a few patients.     

Periocular rejuvenation using a unique non-ablative long-pulse 2940 nm Er:YAG laser

Lasers in Medical Science - The periocular region is challenging for cosmetic laser surgeons. Surgery and laser resurfacing have traditionally been used to correct periorbital lines and wrinkles....