Aspirin-induced asthma and HLA-DRB1 and HLA-DPB1 genotypes

BACKGROUND: Aspirin-induced asthma (AIA) affects one in 10 individuals with adult-onset asthma. It is not known if aspirin sensitivity is due to immune mechanisms or to interference with biochemical pathways. OBJECTIVE: The study aimed to test for possible involvement of the genes of the Major Histocompatibility Complex (MHC) in AIA. METHODS: HLA-DPB1 and HLA-DRB1 genotyping was carried out by DNA methods in 59 patients with positive challenge tests for AIA and in 48 normal and 57 asthmatic controls. RESULTS: The DPB1*0301 frequency was increased in AIA patients when compared with normal controls (19.5% vs 5.2%, Odds Ratio = 4.4, 95% Confidence Interval (CI) 1.6-12.1, P = 0.002), and compared with asthmatic controls (4.4%, OR = 5.3, 95% CI = 1.9-14.4, P = 0.0001). The frequency of DPB1*0401 in AIA subjects was decreased when compared with normal controls (28.8% vs 49.0%, OR = 0.42, 95% CI = 0.24-0.74, P = 0.003) and asthmatic controls (45.6%, OR = 0.48, 95% CI = 0.28-0.83, P = 0.008). The results remained significant when corrected for multiple comparisons. There were no significant HLA-DRB1 associations with AIA. CONCLUSION: The presence of an HLA association suggests that immune recognition of an unknown antigen may be part of the aetiology of AIA.     

Localization and expression of the alpha1A-1, alpha1B and alpha1D-adrenoceptors in hyperplastic and non-hyperplastic human prostate

PURPOSE: To determine the expression and localization of the alpha1A-1, alpha1B and alpha1D-adrenoceptor (AR) subtypes in hyperplastic and non-hyperplastic human prostate tissue. MATERIALS AND METHODS: The expression of the alpha1-AR subtypes was examined at the mRNA level by quantitative solution hybridization, and at the protein level by immunohistochemistry using subtype selective antibodies. RESULTS: While the overall level of alpha1-AR mRNA was not significantly different between hyperplastic and non-hyperplastic tissue, there were significant differences in the ratio of the alpha1-AR subtypes expressed in the two tissue types. The most significant finding from these studies was the reduced expression of the alpha1b-AR mRNA in both glandular and stromal hyperplasia. By immunohistochemistry, the alpha1A-1-AR was detected in the stroma and not in the glandular epithelium. The alpha1B-AR was localized predominantly in the epithelium and was weakly present in the stroma. Lower levels of the alpha1B-AR were detected in the hyperplastic prostatic epithelium. The alpha1D-AR was detected in areas of stroma and was abundantly present in blood vessels. CONCLUSIONS: The alpha1A-1-, alpha1B- and alpha1D-AR subtypes are differentially localized in human prostate, and the expression levels of all three subtypes are altered in BPH. Alterations in a1-AR subtype expression (particularly the alpha1B-AR) in BPH cannot be solely attributed to changes in tissue morphometry resulting from hyperplasia and may be of significance in the pathogenesis of BPH.     

Differential expression of CYP1A1 and CYP1B1 in human breast epithelial cells and breast tumor cells

OBJECTIVES: The aim of this study was to evaluate the tolerance and outcome of elderly cervical carcinoma patients treated with radiation therapy (RT). METHODS: Three hundred ninety-eight patients with stage I-III cervical carcinoma treated with definitive RT were analyzed. Patients were divided into nonelderly (ages 35-69) (n = 338) and elderly (ages >/= 70) (n = 60) groups. A comparison of patient, tumor and treatment factors, morbidity, and outcome was performed. Median follow-up was 81 months. RESULTS: Elderly patients had a higher rate of comorbid conditions including diabetes (P = 0. 02), coronary artery disease (P = 0.003), and hypertension (P = 0. 001) than younger patients. Comorbid conditions in the elderly resulted in more frequent treatment breaks and less ability to undergo definitive treatment with intracavitary RT (ICRT). While the 5-year actuarial disease-free (DFS) and cause-specific (CSS) survival rates were comparable between the two groups, disease recurrence and death from cervical cancer were more common beyond 5 years in the elderly group. When patients not undergoing ICRT and those with treatment protraction were excluded, differences in the DFS and CSS curves were no longer evident. The frequency and severity of acute and chronic sequelae were similar. CONCLUSIONS: Elderly cervical carcinoma patients have an equivalent overall outcome following radiation therapy to younger patients when comparable treatment is delivered. Age per se is not associated with a higher rate of acute or chronic sequelae. Comorbid conditions adversely impacted on the quality and delivery of RT in the elderly group and help explain observed differences in outcome based on age.     

Synthesis of 1-hydroxy and 1-acyloxypyrrolidin-2-ones

A series of 1-hydroxypyrrolidin-2-ones (v) has been prepared by reduction of gamma-nitrocarboxylic acid esters with Zn dust in the presence of ammonium chloride. Acylation of compounds (v) gave the corresponding 1-acyloxypyrrolidin-2-ones (VI). None of the synthesized compounds showed any significant antiflammatory activity.     

Susceptibility to esophageal cancer and genetic polymorphisms in glutathione S-transferases T1, P1, and M1 and cytochrome P450 2E1

Genetic polymorphisms in enzymes involved in carcinogen metabolism have been shown to influence susceptibility to cancer. Cytochrome P450 2E1 (CYP2E1) is primarily responsible for the bioactivation of many low molecular weight carcinogens, including certain nitrosamines, whereas glutathione S-transferases (GSTs) are involved in detoxifying many other carcinogenic electrophiles. Esophageal cancer, which is prevalent in China, is hypothesized to be related to environmental nitrosamine exposure. Thus, we conducted a pilot case-control study to examine the association between CYP2E1, GSTM1, GSTT1, and GSTP1 genetic polymorphisms and esophageal cancer susceptibility. DNA samples were isolated from surgically removed esophageal tissues or scraped esophageal epithelium from cases with cancer (n = 45), cases with severe epithelial hyperplasia (n = 45), and normal controls (n = 46) from a high-risk area, Linxian County, China. RFLPs in the CYP2E1 and the GSTP1 genes were determined by PCR amplification followed by digestion with RsaI or DraI and Alw26I, respectively. Deletion of the GSTM1 and GSTT1 genes was examined by a multiplex PCR. The CYP2E1 polymorphism detected by RsaI was significantly different between controls (56%) and cases with cancer (20%) or severe epithelial hyperplasia (17%; P < 0.001). Persons without the RsaI variant alleles had more than a 4-6-fold risk of developing severe epithelial hyperplasia (adjusted odds ratio, 6.0; 95% confidence interval, 2.3-16.0) and cancer (adjusted odds ratio, 4.8; 95% confidence interval, 1.8-12.4). Polymorphisms in the GSTs were not associated with increased esophageal cancer risk. These results indicate that CYP2E1 may be a genetic susceptibility factor involved in the early events leading to the development of esophageal cancer.     

HIV-1 and bleach

The high proportion of diabetic patients is partly responsible for the high frequency of chronic renal failure in Reunion. The confection and maintenance of an arterio-venous fistule is a major problem in those patients. We report herein our experience with temporary vascular access by internal jugular vein catherization with subcutaneous tunnelization using silastic catheters. The mean duration of utilisation of these accesses is 107 days for diabetic patients and 98 days for nondiabetic patients. The major complication observed is sepsis (18.36%). Diabetes mellitus which represent a traditional risk factor does not seem to be responsible here, the climatic and hygienic conditions prevailing in this part of the world could be a contributing factor. Nevertheless, we find the utilisation of these catheters a suitable solution during the waiting period because it is an easy operation, of the good quality of the material used and the comfort brought to the patient.     

Rat neutrophils express alpha4 and beta1 integrins and bind to vascular cell adhesion molecule-1 (VCAM-1) and mucosal addressin cell adhesion molecule-1 (MAdCAM-1)

The alpha4 integrins, which are constitutively expressed on all human leukocyte subtypes except neutrophils, interact with vascular cell adhesion molecule-1 (VCAM-1) and mucosal addressin cell adhesion molecule (MAdCAM-1) on endothelium to mediate selective recruitment of leukocyte subpopulations, other than neutrophils, to sites of inflammation. However, here we report that a different paradigm of leukocyte recruitment may exist in the rat. Flow cytometric analysis of rat neutrophils using a panel of monoclonal antibodies which recognize rat alpha4 and beta1 integrins showed consistent, low levels of expression. Although alpha4 was expressed at lower levels on neutrophils than all other rat leukocytes, this level of expression was sufficient to mediate significant levels of alpha4- and beta1-dependent neutrophil adhesion to rat and human VCAM-1, and alpha4-dependent, but beta1-independent, adhesion to human MAdCAM-1. These data suggest that rat neutrophils, unlike other species, may use alpha4 integrins to traffic to sites of inflammation in vivo.     

Replication checkpoint enforced by kinases Cds1 and Chk1

Cdc2, the kinase that induces mitosis, is regulated by checkpoints that couple mitosis to the completion of DNA replication and repair. The repair checkpoint kinase Chk1 regulates Cdc25, a phosphatase that activates Cdc2. Effectors of the replication checkpoint evoked by hydroxyurea (HU) are unknown. Treatment of fission yeast with HU stimulated the kinase Cds1, which appears to phosphorylate the kinase Wee1, an inhibitor of Cdc2. The protein kinase Cds1 was also required for a large HU-induced increase in the amount of Mik1, a second inhibitor of Cdc2. HU-induced arrest of cell division was abolished in cds1 chk1 cells. Thus, Cds1 and Chk1 appear to jointly enforce the replication checkpoint.     

BRCA1 splice variants BRCA1a and BRCA1b associate with CBP co-activator

PURPOSE: To define the appearance of gastric stromal sarcomas at magnetic resonance (MR) imaging. MATERIALS AND METHODS: Nine patients with gastric stromal sarcoma underwent MR imaging with the following sequences: nonenhanced and gadolinium-enhanced breath-hold, T1-weighted, spoiled gradient-recalled echo (n = 9); fat-suppressed, T2-weighted, fast spin echo (n = 9); and breathing-independent, half-Fourier rapid acquisition with relaxation enhancement (n = 6). Lesion morphology, signal intensity features, and relationships to the gastric wall and surrounding organs were retrospectively evaluated. The diagnosis of gastric stromal sarcoma was histologically proved in all patients. RESULTS: The nine tumors were solitary, multilobulated, shaped irregularly, predominantly exophytic, and large (diameter range, 7-28 cm [mean, 15.8 cm]). The epicenters of all lesions were extrinsic to the stomach, and all lesions arose from the gastric cardia or body. Regions of necrosis and hemorrhage were detected in all cases. Marginal definition on MR images corresponded to histologic grade: High-grade neoplasms possessed ill-defined margins, and low-grade neoplasms demonstrated more well-defined margins. Relationships to surrounding organs depicted at MR imaging corresponded well with histopathologic findings. CONCLUSION: Gastric stromal sarcomas demonstrate characteristic MR imaging features, which correspond well with histopathologic findings. The direct multiplanar capability of MR imaging facilitates delineation of relationships of the tumors to the stomach and surrounding organs.     

Distinction of CYP1A1 and CYP1A2 activity by selective inhibition using fluvoxamine and isosafrole

A one step competitive Enzyme-Linked Immunosorbent assay (ELISA) method was developed to detect mycobacterial antigen in cerebrospinal fluid (CSF) for the diagnosis of tuberculous meningitis and compared with a standard competitive ELISA method. Indigenously prepared soluble extract of Mycobacterium tuberculosis H37 Rv was used as antigen. The study was conducted using CSF of 230 clinically diagnosed cases of tuberculous meningit is and 208 control subjects. A cutoff value of 0.57 ng/ml by the one step ELISA and 0.5 ng/ml by the standard ELISA method were determined. The specificity of both methods were 100% and positivity was 68.26% and 70.43% respectively. A follow up study was conducted in 63 cases at various interval of time after starting anti-tubercular therapy i.e. at 3 weeks (63 cases), 6 weeks (27 cases) and > or = 4-12 months (13 cases). It was observed that antigen levels decreased gradually, but were much above the cutoff range. Indigenously prepared antigen was compared with antigen prepared in other laboratories and standard molecular weight markers using SDS PAGE (Sodium Do-decyl Sulphate Polycrylamide Gel Electrophoresis).