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   

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.     

Increased fracture rates in Turner's syndrome: a nationwide questionnaire survey

BACKGROUND AND OBJECTIVES: Reduced bone mineral content (BMC) and bone mineral density (BMD) have previously been reported in Turner's syndrome, although appropriate GH treatment and early induction of puberty seem to permit normal bone mass accumulation. Furthermore, an increased risk of fractures and osteoporosis have been reported in a registry study. The aim of the present study was to further characterize the risk of fractures in TS and to explore risk factors, in a historical follow-up survey based on a self-administered questionnaire. STUDY GROUPS: The questionnaire was issued to all females with TS (n = 632) in Denmark and to 1888 randomly selected controls (C) matched for age and geographical region. A total of 322 patients (51%) and 1169 controls (62%) returned the questionnaire. RESULTS: TS women were younger than C (30 years, range: 1-73 years vs. 34 years, range 2-82 years, P < 0.0005), smoked less often (17%vs. 27%, P < 0.0005), and had less frequent spontaneous menstruation (18%vs. 86%, P < 0.0005). In contrast, they used hormonal replacement therapy (HRT) more often (71%vs. 7%, P < 0.0005). The median age at start of HRT was 16 years (range 8-59 years) in TS vs. 42 years (range 12-53 years) in C (P < 0.0005). Above the age of 15 years, 83% of TS and 8% of C used HRT. GH had been used by 37% of TS but only 0.2% of C. Both type 1 and 2 diabetes were increased sevenfold among TS. Altogether, 77 individuals with TS had 109 fractures. The fracture risk was increased in TS [hazard ratio (HR, status) 1.35, confidence interval (CI) 1.04-1.75, P = 0.025]. Time to first fracture was reduced in TS (53 +/- 2 vs. 63 +/- 1; log-rank P = 0.03). Spontaneous menstruation was protective in females above 13 years of age (HR: 0.70, CI 0.54-0.93, P = 0.012). A history of parental fractures increased the risk (HR 1.92, CI 1.62-2.27, P < 0.001). Fractures of the forearm was more frequent among TS (P = 0.02). CONCLUSION: The present nationwide survey, based on questionnaires, confirms an increased risk of early fractures in TS, especially in those without ovarian function and with a positive family history of fracture and osteoporosis. It thereby emphasizes the need for being vigilant with respect to BMD measurements in these patients.     

Age-related changes in cortical bone content of insulin-like growth factor binding protein (IGFBP)-3, IGFBP-5, osteoprotegerin,and calcium in postmenopausal osteoporosis: a cross-sectional study

Serum GH and IGF-I levels decline with increasing age, whereas osteoprotegerin (OPG) increases. IGFs as well as OPG are present in bone matrix and mediate the effects of many upstream hormones (e.g. estrogen). To evaluate whether changes in these proteins may to some extent explain the decrease in bone mass in postmenopausal or senile osteoporosis, we measured bone contents of IGF-I, IGF-II, IGF binding protein (IGFBP)-3, IGFBP-5, and OPG in combined extracts obtained after EDTA and guanidine hydrochloride extraction in 60 postmenopausal women aged 47-74 (mean, 63) yr with a previous distal forearm fracture and a hip or spine Z-score less than 0. We found age-related increases in IGFBP-3 (r = 0.35; P < 0.01), IGFBP-5 (r = 0.59; P < 0.001), and OPG (r = 0.36; P < 0.01) in cortical bone, significantly inversely correlated with femoral neck and lumbar spine BMD. A correlation between age and OPG was also detected in trabecular bone (r = 0.27; P < 0.05). A pronounced age-related decrease in cortical calcium contents (r = -0.60; P < 0.001), positively correlated with femoral neck and lumbar spine BMD, was also found. No age-related changes were detected for IGF-I or IGF-II. The present study demonstrates age-related changes in cortical bone contents of IGFBPs, calcium, and OPG, possibly related to the pathophysiology of postmenopausal osteoporosis. As for OPG, our findings probably represent compensatory responses to increased osteoclastic resorption.     

A fourth dose of DTPa-IPV vaccine given to 4-6 year old children in Italy and Sweden following primary vaccination at 3, 5 and 11-12 months of age

Healthy 4-6 y old children from Italy and Sweden immunized with DTPa and inactivated or oral polio vaccines at 3, 5 and 11-12 months of age, received 1 dose of combined DTPa-IPV (n = 211) or DTPa + IPV as separate doses (n = 205) in a randomized trial. The pre-booster seroprotection rates were similar in each group and were above 60% against all antigens except diphtheria (31.3% and 37.0%) and PT (21.5% and 25.9%) in the DTPa-IPV and DTPa + IPV groups, respectively. At least 99.5% of subjects had seroprotective antibody levels against diphtheria, tetanus and polioviruses and > or = 96% showed a vaccine response to each pertussis antigen after vaccination. Post-booster antibody levels increased at least 51-fold for anti-diphtheria and anti-tetanus, at least 18-fold for anti-pertussis antibodies and at least 32-fold for antibodies against all 3 poliovirus types, compared to prior levels. DTPa-IPV was comparable to DTPa + IPV in terms of seroprotection rates and mean antibody levels against each vaccine antigen. Similar reactogenicity profiles were observed between groups including swelling > 50 mm [13% (9.1, 18.7) vs 17% (12.4, 23.4)] or involving an adjacent joint [0% (-,-) vs 1.5% (0.3, 4.3)] and were consistent with previous reports. The combined DTPa-IPV vaccine could be used to add DTP valences to the IPV vaccine currently given to children in Scandinavia and Italy at 4-6 y of age and reinforce protection against 4 diseases.