Autoantibodies against 21-hydroxylase and side-chain cleavage enzyme in autoimmune Addison's disease are mainly immunoglobulin G1

OBJECTIVE: Immunoglobulin G (IgG) antibodies to the steroidogenic enzymes 21-hydroxylase (21OH) and side-chain cleavage enzyme (SCC) are important diagnostic markers for autoimmune Addison's disease and autoimmune polyendocrine syndromes (APS) types I and II. The characterization of autoantibody (IgG) subclasses may reveal information on how tIssue destruction takes place; therefore, IgG subtypes of anti-21OH and anti-SCC antibodies from sera of patients with Addison's disease, APS I and APS II were determined using recombinant 21OH and SCC. METHODS: SCC(51-521) and his-SCC(51-521) were expressed by pET-scc in the Escherichia coli strain BL21 Star (DE3) and inclusion bodies were purified. Full-length, human 21OH fused to an N-terminal 6x histidine affinity tag was expressed in insect cells by using the baculovirus expression system bac-to-bac. Western blots were used to investigate the IgG subtype(s) of the autoantibodies against 21OH and SCC in patients and healthy blood donors. RESULTS: All anti-SCC positive sera (n=10) contained autoantibodies of the IgG1 subclass, while four out of ten also contained IgG3. All anti-21OH positive sera (n=16) had autoantibodies exclusively against IgG1. Sera from 20 healthy subjects did not show any reactivity against 21OH or SCC. CONCLUSIONS: The finding of a predominating IgG1 response against 21OH and SCC may suggest that T helper (Th) cells of the Th1 subclass are involved in destruction of the adrenal cortex in patients with autoimmune Addison's disease.     

Functional and Physiologic Assessment of the Colonic Reservoir or Side-to-End Anastomosis After Low Anterior Resection for Rectal Cancer: A Two-Year Follow-Up

PURPOSE Functional disturbances are common after anterior resection for rectal cancer. This study was designed to compare functional and physiologic outcome after low anterior resection and total mesorectal excision with a colonic J-pouch or a side-to-end anastomosis.METHODS Functional and physiologic variables were analyzed in patients randomized to a J-pouch (n = 36) or side-to-end anastomosis (n = 35). Postoperative functional outcome was investigated with questionnaires. Anorectal manometry was performed preoperatively and at six months, one year, and two years postoperatively.RESULTS There was no statistical difference in functional outcome between groups at two years. Maximum neorectal volume increased in both groups but was approximately 40 percent greater at two years in pouches compared with the side-to-end anastomosis. Anal sphincter pressures volumes were halved postoperatively and did not recover during follow-up of two years. Male gender, low anastomotic level, pelvic sepsis, and the postoperative decrease of sphincter pressures were independent factors for more incontinence symptoms.CONCLUSIONS Colonic J-pouch and side-to-end anastomosis gives comparable functional results two years after low anterior resection. Neorectal volume had no detectable influence on function. There was a pronounced and sustained postoperative decrease in sphincter pressures.Supported by the Stockholm County Council, Public Health and Medical Services Committee and the Swedish Research Council, grant #09101.Reprints are not available.     

Job strain, job demands and adrenergic beta1-receptor-polymorphism: a possible interaction affecting blood pressure in men

BACKGROUND: Job strain and the Arg389Gly polymorphism in the adrenergic beta1-receptor gene have been linked to hypertension. We aimed to study whether there is an interaction between the Arg389Gly polymorphism and job strain and its components (job demand and decision latitude) in relation to blood pressure. METHODS: From the Malm? Diet and Cancer population cohort, 6095 individuals were randomly selected to be followed regarding cardiovascular risk factors. From this group, employed individuals with baseline data regarding work characteristics were included (1338 men and 1707 women). Determination of adrenergic beta1-receptor Arg389Gly polymorphism was possible in 1271 men and 1601 women, and these individuals formed the study group. RESULTS: Men with the combination of Arg389Arg and job strain were more often on antihypertensive medication (P = 0.04), whereas blood pressure was not significantly higher, in comparison with those without both of these two factors. The interaction term genotype x job strain was borderline significant for systolic blood pressure (P = 0.07) after adjustments for age, country of birth, and job status. The demand score showed significant interaction in men with genotype (P = 0.01 for systolic blood pressure and P = 0.009 for diastolic blood pressure) after adjustments for age, country of birth, job status, antihypertensive treatment, and BMI. Men with the Gly389 allele had lower blood pressure with increasing demand score (P = 0.001), whereas men homozygous for the Arg389 allele had lower blood pressure with increasing latitude score (P = 0.03). In women, those with job strain tended to have higher blood pressure than those without job strain, among carriers of Arg389Arg and Arg389Gly genotype. CONCLUSION: Men with job strain and the Arg389Arg polymorphism were more often on antihypertensive treatment than other men. Significant interactions between the Arg389Gly polymorphism and aspects of job stress are described, but the absolute blood pressure differences are small. Considering the commonness of the polymorphism, stress, and hypertension further studies are indicated.     

Association between a variant in the 11 beta-hydroxysteroid dehydrogenase type 2 gene and primary hypertension

The enzyme 11 beta-hydroxysteroid dehydrogenase type 2 (11BHSD2) converts cortisol to cortisone in the kidney, thereby protecting the mineralocorticoid receptor from the mineralocorticoid actions of cortisol. The syndrome of Apparent Mineralocorticoid Excess (AME), a rare monogenic form of early onset hypertension with autosomal recessive inheritance, is caused by homozygous or compound heterozygous loss of function mutations in the 11BHSD2 gene. Association has been reported between a microsatellite marker flanking the 11BHSD2 gene (D16S496) and primary hypertension. The aim of this study was to identify variants in the 11BHSD2 gene and to test if such variants or the D16S496 are associated with primary hypertension, in Swedes. To address this, the coding sequences of the 11BHSD2 gene was screened for mutations in 20 patients with primary hypertension with single strand conformation polymorphism and direct DNA sequencing techniques. A polymorphism was identified in exon 3; G534A (Glu178Glu). This polymorphism and the D16S496 microsatellite were tested for association with primary hypertension in a population consisting of 292 patients with primary hypertension and 263 normotensive control subjects. The frequency of G534G homozygotes was higher in patients with primary hypertension than in normotensive control subjects (92.8% vs 87.8%; P < 0.05). The allele frequencies of the D16S496 microsatellite did not differ between the two groups (chi(2) = 11.0, df = 10; P = 0.36). In conclusion, over-representation of individuals homozygous for the G534 allele in hypertensive patients compared with control subjects suggests that a mutation in linkage disequilibrium with the G534A polymorphism could increase susceptibility to primary hypertension. Journal of Human Hypertension (2000) 14, 819-823     

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.     

Norethisterone Treatment, a Major Risk-Factor for Veno-Occlusive Disease in the Liver After Allogeneic Bone Marrow Transplantation

In this single-center study, we retrospectively analyzed incidenceand risk factors for hepatic veno-occlusive disease (VOD) in 249 consecutive patients who underwent allogeneic hematopoietic stem celltransplantation between January 1990 and June 1995. Twenty-four of the249 transplanted patients developed VOD. The probabilities ofdeveloping VOD were 17% among women and 7% in men (P = .01). In women treated with norethisterone, the incidence was 27%compared with 3% in women without this treatment (P = .007).One-year survival rates were 17% and 73% in patients with (n = 24)or without VOD (n = 225), respectively. The use of heparin prophylaxis (100 IE/kg/24 hours for 1 month) did not alter the incidence or 1-year mortality of VOD. In multivariate analysis, thefollowing risk factors were significant: norethisterone treatment (P < .001), bilirubin >26 µmol/L before bone marrowtransplantation (BMT) (P = .002), one HLA-antigen mismatch(P = .003), previous abdominal irradiation (P = .02), and conditioning with busulphan (P = .02). Ourconclusion is that norethisterone treatment should not be used inpatients undergoing BMT and heparin prophylaxis did not affect theincidence or mortality of VOD.