<Emphasis Type="Italic">FAM13A</Emphasis> and <Emphasis Type="Italic">POM121C</Emphasis> are candidate genes for fasting insulin: functional follow-up analysis of a genome-wide association study

Aims/hypothesis

By genome-wide association meta-analysis, 17 genetic loci associated with fasting serum insulin (FSI), a marker of systemic insulin resistance, have been identified. To define potential culprit genes in these loci, in a cross-sectional study we analysed white adipose tissue (WAT) expression of 120 genes in these loci in relation to systemic and adipose tissue variables, and functionally evaluated genes demonstrating genotype-specific expression in WAT (eQTLs).

Methods

Abdominal subcutaneous adipose tissue biopsies were obtained from 114 women. Basal lipolytic activity was measured as glycerol release from adipose tissue explants. Adipocytes were isolated and insulin-stimulated incorporation of radiolabelled glucose into lipids was used to quantify adipocyte insulin sensitivity. Small interfering RNA-mediated knockout in human mesenchymal stem cells was used for functional evaluation of genes.

Results

Adipose expression of 48 of the studied candidate genes associated significantly with FSI, whereas expression of 24, 17 and 2 genes, respectively, associated with adipocyte insulin sensitivity, lipolysis and/or WAT morphology (i.e. fat cell size relative to total body fat mass). Four genetic loci contained eQTLs. In one chromosome 4 locus (rs3822072), the FSI-increasing allele associated with lower FAM13A expression and FAM13A expression associated with a beneficial metabolic profile including decreased WAT lipolysis (regression coefficient, R?=??0.50, p?=?5.6?×?10^?7). Knockdown of FAM13A increased lipolysis by ~1.5-fold and the expression of LIPE (encoding hormone-sensitive lipase, a rate-limiting enzyme in lipolysis). At the chromosome 7 locus (rs1167800), the FSI-increasing allele associated with lower POM121C expression. Consistent with an insulin-sensitising function, POM121C expression associated with systemic insulin sensitivity (R?=??0.22, p?=?2.0?×?10^?2), adipocyte insulin sensitivity (R?=?0.28, p?=?3.4?×?10^?3) and adipose hyperplasia (R?=??0.29, p?=?2.6?×?10^?2). POM121C knockdown decreased expression of all adipocyte-specific markers by 25–50%, suggesting that POM121C is necessary for adipogenesis.

Conclusions/interpretation

Gene expression and adipocyte functional studies support the notion that FAM13A and POM121C control adipocyte lipolysis and adipogenesis, respectively, and might thereby be involved in genetic control of systemic insulin sensitivity.

     

Organisation of asthma care in primary health care in Mid-Sweden.

AIM: To investigate the organisation of asthma care in 240 primary health care centres (PHCCs) in Mid-Sweden. METHODS: A cross-sectional study. Main outcomes were occurrence and structure of nurse-based asthma clinics according to nationally recommended criteria, and access and use of spirometers. RESULTS: 238 PHCCs (99%) responded. 16% reported a complete, and 37% an incomplete, asthma clinic. 47% of PHCCs had no asthma clinic. The incomplete asthma clinics usually lacked sufficient asthma nurse time, a scheduled nurse surgery and a responsible GP. 77% of the PHCCs had access to a spirometer and on average 19 spirometries/1000 inhabitants/year were performed. There was a large variation in the use of spirometers. CONCLUSION: Half of the PHCCs had an asthma clinic and a majority had access to a spirometer. More frequent use of spirometry and increased time provision for the asthma nurse would be likely to produce a substantial improvement in the standard of asthma care in primary health care.     

Tachykinins Influence Interdigestive Rhythm and Contractile Strength of Human Small Intestine

The effect of the putative entericneurotransmitters neurokinin A and substance P wereinvestigated on human small intestinal motility. Eitherneurokinin A, at doses of 6-25 pmol/kg/min, or substanceP at doses of 1- 6 pmol/kg/min were administeredintravenously to healthy volunteers over 4 hr.Neurokinin A dose-dependently increased the fraction ofphase II of the migrating motor complex, contraction frequency, motility index, and amplitude ofcontractions. At the highest dose, neurokinin A induceda phase II-like pattern, disrupting the migratingmyoelectric complex. Substance P dose-dependentlyincreased phase II of the migrating motor complex. Thecontraction frequency increased slightly at the highestdose, but neither motility index nor contractionamplitude changed. It is concluded that neurokinin A and substance P stimulate small intestinalmotility in man, and it can be speculated that they playa role in the control of human small intestinalmotility.     

Regression of a large malignant gastrinoma on treatment with Sandostatin LAR: a case report

Gastrinomas may occur in the pancreas, duodenum or peripancreatic lymph nodes. The gastrin overproduction leads to the Zollinger-Ellison syndrome with multiple gastric and duodenal ulcers and diarrhea. About two thirds of gastrinomas are malignant. Diagnosis is made by clinical history, gastroscopy, and measurement of serum gastrin, gastric juice pH, CT scan, endoscopic ultrasonography and somatostatin receptor scintigraphy. Surgery should always be considered if the liver is not involved. Proton pump inhibitors offer symptomatic relief. Medical therapy for tumor control includes biotherapy with alpha-interferon and somatostatin analogs yielding a response rate of about 10-15%, chemotherapy or targeted radiotherapy. We describe a patient with almost complete response on treatment with Sandostatin LAR, a long-acting somatostatin analog. In patients with metastatic gastrinomas not suitable for chemotherapy, interferon or targeted radiotherapy, single therapy with somatostatin analogs may be an alternative.     

Macrophage mannose receptor on lymphatics controls cell trafficking

Macrophage mannose receptor (MR) participates in pathogen recognition, clearance of endogenous serum glycoproteins, and antigen presentation. MR is also present on lymphatic vessels, where its function is unknown. Here we show that migration of lymphocytes from the skin into the draining lymph nodes through the afferent lymphatics is reduced in MR-deficient mice, while the structure of lymphatic vasculature remains normal in these animals. Moreover, in a tumor model the primary tumors grow significantly bigger in MR^–/– mice than in the wild-type (WT) controls, whereas the regional lymph node metastases are markedly smaller. Adhesion of both normal lymphocytes and tumor cells to lymphatic vessels is significantly decreased in MR-deficient mice. The ability of macrophages to present tumor antigens is indistinguishable between the 2 genotypes. Thus, MR on lymphatic endothelial cells is involved in leukocyte trafficking and contributes to the metastatic behavior of cancer cells. Blocking of MR may provide a new approach to controlling inflammation and cancer metastasis by targeting the lymphatic vasculature.     

Comparison of treatment and outcomes for patients with acute myocardial infarction in Minneapolis/St. Paul, Minnesota, and Göteborg, Sweden

Background

Treatment of acute myocardial infarction (AMI) is changing, and differences in medical practice are observed within and between countries on the basis of local practice patterns and available technology. These differing approaches provide an opportunity to evaluate medical practice and outcomes at the population level. The primary aim of this study was to compare medical care in patients hospitalized with AMI in 2 large cities in Sweden and the United States. A secondary aim was to compare medical outcomes.

Methods

All resident patients (age range, 30-74 years) hospitalized with AMI in Göteborg, Sweden (1995-1996), and a representative population-based sample of all patients with AMI in Minneapolis/St. Paul, Minn (1995).

Results

Patients with AMI in Göteborg (GB) were older than patients in Minneapolis/St. Paul (MSP), but fewer patients in GB had a prior history of cardiovascular disease. During the AMI admission, coronary angiography, percutaneous coronary angioplasty (PTCA), and coronary artery bypass grafting (CABG) were performed twice as frequently in MSP than in GB. Echocardiogram and exercise testing were more frequently performed in GB. During hospitalization, β-blockers were more frequently prescribed in GB, whereas calcium channel blockers, long- and short-acting nitrates, intravenous nitroglycerine, digitalis, aspirin, oral anticoagulants, heparin, and lidocaine were significantly more common in MSP. Thrombolysis, acute PTCA, ACE inhibitors, and diuretics were similar. Reinfarction was higher in men in GB (4% vs 1%, P <.009) and women in GB (3% vs 1%, P = not significant). On discharge, β-blockers and diuretics were prescribed significantly more often in GB, whereas calcium channel blockers, nitrates, and digitalis were prescribed more often in MSP. Aspirin and ACE inhibitors had similar usage rates. Despite these diagnostic and treatment contrasts, there were no differences in mortality rate at 30 days or after 3 years of follow-up after risk-adjusting for patient baseline differences.

Conclusion

Comparing patients hospitalized with AMI in MSP and GB, we found marked differences in medical care, with invasive strategies more likely to be used in MSP. This may be the result of historical practice patterns, the healthcare system, and healthcare financing differences. Despite these differences, short- or long-term mortality rates were identical.     

Effect of intervention on decision making of treatment for disease progression,prostate‐specific antigen biochemical failure and prostate cancer death

Background

Patient preference for the choice of treatment modality for prostate cancer has increasingly gained attention.

Objective

To assess the impact of client‐oriented decision on long‐term mortality, disease progression and biochemical failure compared with standard treatment protocol (TP).

Methods

With data from a Finnish multicentre, randomized controlled trial with two arms [104 in the enhanced patient participation (EPP) arm and 106 in the TP arm], disease‐specific and disease‐free survival, biochemical failure with elevated prostate‐specific antigen (PSA) level and disease progression were compared between the two arms using Wilcoxon test and also Cox proportional hazards regression model.

Results

Patients in the EPP arm had a higher risk of death by 37% [HR, 1.37 (0.87–2.17)] compared with those in the TP arm. Patients in the EPP arm were at increased risk of having biochemical failure by 14% [HR, 1.14 (0.72–1.79)] and for having disease progression by 2% [HR, 1.02 (0.61–1.70)] compared with those in the TP arm. All the differences were non‐significant.

Conclusions

Patients actively involved in the choice of treatment had higher risk of prostate cancer death but only slightly increased risk of biochemical failure and clinical disease progression. These findings would provide a good reference when patient autonomy for the choice of treatment modality is addressed.