Effect of interleukin 1 polymorphisms on gastric mucosal interleukin 1beta production in Helicobacter pylori infection

BACKGROUND & AIMS: Although epidemiological studies suggest that interleukin (IL)-1 genetic polymorphisms are involved in Helicobacter pylori-related gastric carcinogenesis, the data are conflicting regarding the effects of these polymorphisms on IL-1beta production. METHODS: IL-1B-511 polymorphism was genotyped by polymerase chain reaction (PCR)-restriction fragment length polymorphism, and IL-1RN variable number of tandem repeats was determined by PCR. Mucosal IL-1beta levels were measured by enzyme-linked immunosorbent assay. To determine which factors influence mucosal IL-1beta levels, gastric inflammation, and atrophy, multiple regression analyses were performed. RESULTS: We studied 117 H. pylori-infected Japanese patients. Carriers of the IL-1B-511T/T genotype or IL-1RN*2 allele had higher mucosal IL-1beta levels than noncarriers (partial regression coefficient [PRC] +/- SE), TT versus CC: 37.6 +/- 6 [antrum] and 32.1 +/- 6 [corpus] pg/mg protein (P < 0.001 for each), *1/*2 versus *1/*1: 24 +/- 8 [antrum] (P <0.01) and 36.5 +/- 7 [corpus] (P <0.001). Simultaneous carriers of IL-1B-511T/T genotype and IL-1RN*2 allele had the highest IL-1beta levels (82.9 +/- 12 [antrum] and 87.2 +/- 11 [corpus]) and showed a synergistic effect between 2 loci. The *1/*2 carriers were closely related to atrophy (PRC +/- SE; 0.87 +/- 0.4 [antrum] and 0.93 +/- 0.4 [corpus], P < 0.05), whereas being a carrier of the -511T/T genotype was related to severe gastric inflammation. CONCLUSIONS: IL-1 genetic polymorphisms influenced H. pylori-related gastric mucosal IL-1beta levels and were related to gastric inflammation and atrophy, factors thought to be important in gastric carcinogenesis.     

Practical recommendations for the use of ACE inhibitors, beta-blockers, aldosterone antagonists and angiotensin receptor blockers in heart failure: putting guidelines into practice

Surveys of prescribing patterns in both hospitals and primary care have usually shown delays in translating the evidence from clinical trials of pharmacological agents into clinical practice, thereby denying patients with heart failure (HF) the benefits of drug treatments proven to improve well-being and prolong life. This may be due to unfamiliarity with the evidence-base for these therapies, the clinical guidelines recommending the use of these treatments or both, as well as concerns regarding adverse events. ACE inhibitors have long been the cornerstone of therapy for systolic HF irrespective of aetiology. Recent trials have now shown that treatment with beta-blockers, aldosterone antagonists and angiotensin receptor blockers also leads to substantial improvements in outcome. In order to accelerate the safe uptake of these treatments and to ensure that all eligible patients receive the most appropriate medications, a clear and concise set of clinical recommendations has been prepared by a group of clinicians with practical expertise in the management of HF. The objective of these recommendations is to provide practical guidance for non-specialists, in order to increase the use of evidenced based therapy for HF. These practical recommendations are meant to serve as a supplement to, rather than replacement of, existing HF guidelines.     

A combination of human leukocyte antigen DQB1*02 and the tumor necrosis factor alpha promoter G308A polymorphism predisposes to an insulin-deficient phenotype in patients with type 2 diabetes

Our previous results have suggested that genes outside the human leukocyte antigen (HLA) class II locus may affect the phenotype of type 2 diabetic patients from families with both type 1 and type 2 diabetes (mixed type 1/2). To study whether the TNF alpha gene could be such a modifying gene, we studied TNF alpha promoter polymorphisms (G-->A substitution at positions -308 and -238) in relation to HLA-DQB1 genotypes in type 2 patients from mixed type 1/2 families or common type 2 diabetes families as well as in patients with adult-onset type 1 diabetes and control subjects. The TNF alpha(308) AA/AG genotype frequency was increased in adult onset type 1 patients (55%, 69 of 126), but it was similar in type 2 patients from type 1/2 families (35%, 33/93) or common type 2 families (31%, 122 of 395), compared with controls (33%, 95/284; P < 0.0001 vs. type 1). The TNF alpha(308) A and DQB1*02 alleles were in linkage disequilibrium in type 1 patients (Ds = 0.81; P < 0.001 vs. Ds = 0.25 in controls) and type 2 patients from type 1/2 families (Ds = 0.59, P < 0.05 vs. controls) but not in common type 2 patients (Ds = 0.39). The polymorphism was associated with an insulin-deficient phenotype in the type 2 patients from type 1/2 families only together with DQB*02, whereas the common type 2 patients with AA/AG had lower waist to hip ratio [0.92 (0.12) vs. 0.94 (0.11), P = 0.008] and lower fasting C-peptide concentration [0.48 (0.47) vs. 0.62 (0.46) nmol/liter, P = 0.020] than those with GG, independently of the presence of DQB1*02. In conclusion, TNF alpha is unlikely to be the second gene in the HLA area responsible for our previous findings in type 1/2 patients. However, we could show an association between TNF alpha(308) polymorphism and the phenotype of common type 2 diabetes.     

Histological patterns of gastritis in H. pylori-infected individuals with a family history of gastric cancer

OBJECTIVE: Different types of chronic gastritis, including antral predominant, corpus predominant, and multifocal pangastritis, are associated with Helicobacter pylori infection. Specific patterns of H. pylori gastritis that might characterize individuals with family histories of noncardia gastric cancer (GC) were investigated. METHODS: Histopathological changes associated with H. pylori gastritis were assessed in 111 individuals with family histories of GC and in 77 without from a region with high prevalence of H. pylori infection and GC. Gastric biopsies were taken from 12 sites (antrum, five; corpus, six; and cardia, one). RESULTS: Individuals (age < 36 yr) with family histories of GC developed pangastritis and had higher H. pylori bacterial scores (p < 0.05) in the gastric corpus, whereas those without family histories of GC typically had antral predominant gastritis. The correlation between density of polymorphonuclear leukocytes and density of H. pylori at each biopsy site was statistically significant (p < 0.01). Pangastritis was associated with a higher density of lymphoid aggregates and follicles (p < 0.05) in the corpus of younger individuals (age < 36) and in the antrum of older individuals (age > or = 48) with positive family histories of GC. CONCLUSIONS: Pangastritis and high lymphoid follicle density associated with H. pylori infection were found in patients with family histories of GC. Because a family history of gastric carcinoma is associated with increased risk of gastric cancer development, characterization of histological patterns of gastritis may be applicable to gastric cancer screening and surveillance, especially in relatively young at-risk populations.     

Simian AIDS-related lymphoma growth in severe combined immunodeficiency mice is independent of karyotypic abnormalities or Bcl-6 mutations

Simian AIDS-related lymphomas (sARL) of cynomolgus monkeys infected with a simian immunodeficiency virus (SIVsm) were studied in relation to growth in severe combined immunodeficient (SCID) mice, karyotype abnormalities, and DNA sequence of the first noncoding region of the Bcl-6 gene. The tumors were diffuse large B cell lymphomas and expressed a simian homolog to Epstein-Barr virus (HVMF-1) in 12 of 13 primary tumors and corresponding cell lines. A tested cell line was tumorigenic in SCID mice. Tumors in the SCID mice showed cell growth features similar to those in the original lymphoma, suggesting that no subpopulation with growth advantage was selected for in the mice. Spectral karyotype analysis of sARL cell lines showed normal cytogenetic features except for a trisomy of monkey chromosome 2 (corresponding to human chromosomes 7 and 21) in two of five sARL lines, which was not recovered in SCID tumors established from the same cell line. Sequence analysis of a Bcl-6 gene fragment showed sequence variations indicative of population polymorphism(s) in 10 of 13 sARLs, and no evidence of Bcl-6 mutations. Thus Bcl-6 mutations in the first noncoding region are irrelevant for sARL development in cynomolgus monkeys and for tumorigenicity of sARL cell lines. We also demonstrate that no cytogenetic alterations are needed for the development of highly aggressive lymphomas in the SIV-immunosuppressed host.     

Peroxisome proliferator-activated receptor-gammaPro12Ala polymorphism and the association with blood pressure in type 2 diabetes: skaraborg hypertension and diabetes project

OBJECTIVE: This study explored whether the Pro12Ala polymorphism in the peroxisome proliferator-activated receptor-gamma (PPARgamma) is associated with blood pressure in subjects with type 2 diabetes. DESIGN: A community-based, cross-sectional observation study. SETTING: Primary care. PATIENTS: One hundred and ninety-two men and 192 women with type 2 diabetes who consecutively underwent annual follow-up. MAIN OUTCOME MEASURE: The PPARgammaPro12Ala genotype was determined by polymerase chain reaction-based techniques. Associations between genotype and blood pressure were analysed by linear regression and expressed as differences in blood pressure (delta) with 95% confidence interval (CI). RESULTS: The mean systolic blood pressure and the diastolic blood pressure were 160 mmHg (standard deviation = 22.8) and 84 mmHg (standard deviation = 9.6), respectively. Subjects with Pro/Ala (24%) or Ala/Ala (2%) had lower diastolic blood pressure (delta = 2.8; 95% CI, 0.6-5.0) when adjusted for age and gender compared with Pro/Pro subjects (74%). This association was restricted to men (delta = 4.4; 95% CI, 1.3-7.4), who also had a borderline significant difference in systolic blood pressure (delta = 6.9; 95% CI, -0.8 to 13.8). In men the difference in diastolic blood pressure remained after adjustment for age, body mass index, serum triglycerides, serum insulin and haemoglobin A(1c) (delta = 4.6; 95% CI, 1.1-8.1). A subanalysis of normotensive men (n = 100) confirmed the difference associated with the Pro12Ala polymorphism in diastolic blood pressure (delta = 5.2; 95% CI, 0.6-10.0). CONCLUSIONS: The common Pro12Ala polymorphism in PPARgamma is associated with lower diastolic blood pressure in male subjects with type 2 diabetes.     

Atrial fibrillation signal organization predicts sinus rhythm maintenance in patients undergoing cardioversion of atrial fibrillation.

AIMS: Electrical remodelling is believed to influence the outcome following cardioversion of patients with persistent atrial fibrillation (AF). However, the results in clinical studies are conflicting. We assessed the hypothesis that non-invasively obtained atrial fibrillatory organization can be used as a predictor of sinus rhythm (SR) maintenance. METHODS AND RESULTS: Fifty-four patients (37 men, age 67+/-11) with persistent AF (median duration 3 months, 1 day to 18 months), without anti-arrhythmic drug treatment, referred for cardioversion were studied. Assessment of the atrial harmonic decay was made by time-frequency analysis of the ECG. At 1-month follow-up, 30 patients had relapsed into AF. The mean harmonic decay at inclusion of those relapsing into AF was 1.5+/-0.3 compared with 1.1+/-0.3 among those maintaining SR (P=0.0004). Using a cut-off value of harmonic decay 相似文献   

Low-dose antacids versus 400 mg cimetidine twice daily for reflux oesophagitis. A comparative, placebo-controlled, multicentre study

Ninety-one patients with reflux oesophagitis were randomly allocated to treatment with one chewable antacid tablet (acid-neutralizing capacity, 30 mmol) four times daily, 400 mg cimetidine twice daily, or placebo. The study was double-blind, with a double-dummy technique. Endoscopy was performed before inclusion and after 8 weeks' treatment. Symptoms were recorded on diary cards and on visual analogue scales. Statistically significant healing of oesophagitis was achieved in all three treatment groups, but none of the active regimens were significantly superior to placebo. Symptoms were significantly reduced with both cimetidine and antacids compared with placebo. Patients taking antacids consumed significantly less extra antacids for pain relief and had significantly better global assessment score than patients taking cimetidine during the first and second half of the study, respectively. In conclusion, neither cimetidine nor antacids were significantly superior to placebo in healing of reflux oesophagitis. Both the active regimens were superior to placebo for symptomatic relief.     

The independent effects of polycystic ovary syndrome and obesity on serum concentrations of gonadotrophins and sex steroids in premenopausal women

OBJECTIVE To investigate the basal levels of gonadotrophins and sex steroids, with special reference to the effects of obesity and body fat distribution, In premenopausal women, both those with polycystic ovary syndrome (PCOS) and those with normal ovaries and regular menstrual cycles. DESIGN Cross-sectional study. The separate effects of obesity (and body fat distribution and fasting Insulin levels) and PCOS on endocrine variables were evaluated by means of analysis of covariance. PATIENTS Sixty-seven women with anovulatory menstrual cycles and polycystic ovaries according to ultrasonography and 59 women with normal ovaries and regular cycles, both groups covering a wide range of body mass index (BMI, PCOS, 17·6-37·4, mean 25·7 kg/m²; controls, 18·8-40·9, mean 25·1 kg/m²). MEASUREMENTS Serum levels of gonadotrophins, sex steroid hormones, prolactin and GH obtained in the early follicular phase in the controls, fasting insulin levels, anthropometric measures (BMI, skinfolds, waist hip ratio). RESULTS Mean serum concentrations of LH, andro-stenedione, testosterone, the free androgen index (FAI; all P < 0·0001) and DHEAS (P < 0·01) were higher, and serum FSH (P < 0·01) and serum SHBG levels lower (P < 0·0001), in the PCOS group than in the controls. Women with PCOS had a more pronounced upper body fat distribution and higher fasting insulin levels than the controls. Independent of PCOS, BMI was positlvely associated with serum levels of FSH (P < 0·001) and negatively with levels of LH (P < 0·05), LH/FSH ratio (P < 0·0001), SHBG (P < 0·0001) and androstenedione (P < 0·01), whereas for levels of testosterone, FAI and DHEAS the impact of obesity differed significantly between the groups. Thus, in the PCOS group, testosterone levels (P < 0·05) and the FAI (P < 0·001) were positively associated with BMI, whereas they were constant throughout the entire range of BMI in the controls. DHEAS levels were positively associated with BMI in the PCOS group (P < 0·05) and negatively in the controls (P < 0·01). Measures of upper body fat were related to testosterone and FAI levels, independent of BMI. CONCLUSIONS Lower FSH levels were found in women with PCOS than during the early follicular phase of normally ovulating women, suggesting a role in anovulation in PCOS. Obesity itself exerted effects on endocrine variables, with the net result of a reduced LHIFSH ratio and lower serum levels of androstenedione and SHBG in both groups; obesity was associated with increased levels of DHEAS, testosterone and FAI exclusively in the women with PCOS. The results underline the endocrine impact of obesity and body fat distribution and the necessity of applying reference values of BMI matched subjects when establishing the endocrine profile of women with PCOS.     

The effect of hepatectomy on glucose homeostasis in pig and in man.

BACKGROUND/AIMS: The liver is regarded the most important source of glucose production and it is common practice to administer glucose during human liver transplantations to avoid hypoglycaemia. The purpose of this study was to evaluate the importance of extra-hepatic contribution (kidney, gut and muscle) to the glucose homeostasis in the anhepatic pig and in man during the anhepatic phase of human liver transplantations. METHODS: Blood glucose and lactate were monitored in the anhepatic phase in 46 patients undergoing liver transplantation. Arterial-venous differences of lactate, glucose, glycerol, alanine and free fatty acids were measured over kidney, gut and hind leg in 18 pigs made anhepatic. RESULTS: Blood glucose did not change significantly and blood lactate increased only marginally during the anhepatic phase of human orthotopic liver transplantation. In the anhepatic pig, however, blood glucose decreased with a halflife of about 26 min and blood lactate increased. Kidney gluconeogenesis was 0.116+/-0.016 mmol min(-1). Fifty percent of kidney glucose output could be accounted for by lactate- and glycerol uptake. CONCLUSIONS: The results show that in humans extra hepatic gluconeogenesis is sufficient to maintain normal blood glucose in the anhepatic phase of orthotopic liver transplantation, while in the pig this was not the case.