PNPLA3 genetic variation in alcoholic steatosis and liver disease progression

Alcoholic liver disease (ALD) accounts for the majority of chronic liver diseases in Western countries, and alcoholic cirrhosis is among the premier causes of liver failure, hepatocellular carcinoma (HCC) and liver-related mortality causes. Studies in different genders and ethnic groups, as well as in twins provide strong evidence for a significant contribution of host genetic factors to liver disease development in drinkers. The intense quest for genetic modifiers of alcohol-induced fibrosis progression have identified and repeatedly confirmed a genetic polymorphism in the gene coding for patatin-like phospholipase domain-containing 3 (PNPLA3; adiponutrin; rs738409 C/G, M148I) as a risk factor for alcoholic cirrhosis and its related complication, HCC, in different populations. Although carriership of one or both mutated PNPLA3 alleles does not explain the entire liver phenotypic variability in drinkers, it clearly represents one of the strongest single genetic modulators in a complex trait such as ALD. As more genetic data supporting its important role aggregates, novel insight as to PNPLA3’s function and that of its genetic variation in liver injury is unveiled pointing to an important novel pathway in alcohol-mediated hepatic lipid turnover with strong implications on inflammation, extra cellular matrix remodelling, and hepatocarcinogenesis. Future study shall decipher whether the gathered knowledge can be translated into therapeutic benefits of patients.     

Heat shock protein 90alpha-dependent translocation of annexin II to the surface of endothelial cells modulates plasmin activity in the diabetic rat aorta

The goals of this article were (1) to identify cell surface proteins whose expression was regulated by diabetes and (2) to assess their contribution to diabetic complications. We purified heat shock protein 90alpha (Hsp90alpha) from the membrane fraction of high glucose-treated endothelial cells (ECs) as a binding partner for a diabetes-specific phage. Further investigation revealed that high glucose elevated cell surface Hsp90alpha in cultured cells, and that diabetes increased the amount of Hsp90alpha on the luminal surface of the aorta. We also found that high glucose or diabetes promoted the association of Hsp90alpha with annexin II and increased the expression of annexin II on the surface of aortic ECs. Finally, plasmin activity was increased by high glucose or diabetes, and this change was partially reversed with an annexin II antibody. These findings reveal a novel glucose-regulated interaction between Hsp90alpha and annexin II, and raise the possibility that increased expression of annexin II, which promotes the generation of plasmin, is linked to clotting abnormalities associated with the diabetic state.     

The G972R variant of the Insulin Receptor Substrate-1 (IRS-1) gene, body fat distribution and insulin-resistance

Aims/hypothesis. Insulin resistance is recognised as the core factor in the pathogenesis of Type II (non-insulin-dependent) diabetes mellitus, hypertension and atherosclerosis. Several studies indicate the possible role of mutations of the insulin receptor substrate-1 (IRS-1) gene in the pathogenesis of insulin-resistance and suggest a possible interaction between the IRS-1 gene and obesity, either by an effect on the development of obesity or by causing or aggravating the obesity-associated insulin resistance. Therefore, the prevalence of the G972R mutation of the IRS-1 gene was compared in 157 non-diabetic obese subjects (BMI > 30 m/kg²) and in 157 lean subjects (BMI < 28 m/kg²). By investigating the relation between this IRS-1 mutation, measures of obesity and metabolic parameters, we explored the possible influence of this mutation on body fat distribution and insulin resistance. Methods. The G972R mutation was detected by PCR amplification and BstN-1 restriction enzyme digestion. Data were analysed by univariate and multivariate analysis. Results. The G972R allele was significantly more frequent in obese subjects than in lean subjects (p < 0.002); however, no difference was found between centrally and peripherally obese subjects. Obese G972R carriers had significantly higher BMI (p < 0.001), fasting insulin (p < 0.01), triglycerides (p < 0.03) and HOMA_IR (p < 0.001) than obese non-carriers. No differences were observed between G972R carriers and non-carriers among control subjects. Multivariate analysis confirmed that the IRS-1 G972R mutation was significantly and independently associated with reduced insulin sensitivity (p < 0.009) in the obese group. Conclusion/interpretation. The G972R mutation of the IRS-1 gene associates with obesity, but not with fat distribution, in this Italian cohort, and within the obese subjects this IRS-1 variant strongly associates with metabolic parameters suggesting greater insulin-resistance. These findings indicate a possible interaction between the IRS-1 variant and obesity in worsening insulin sensitivity. [Diabetologia (2001) 44: 367–372] Received: 11 August 2000 and in revised form: 25 October 2000     

MTHFR C677T polymorphism,folate status and colon cancer risk in acromegalic patients

Background

Acromegalic patients have a higher risk of developing colorectal tumours (CRT). The common C677T polymorphism in methylenetetrahydrofolate reductase (MTHFR) gene is a well-documented CRT risk factor in the general population, but its role in acromegaly has never been examined.

Purpose

We investigated the influence of MTHFR C677T polymorphism, folate status and other lifestyle, nutritional and disease-specific variables on CRT risk in acromegaly.

Methods

Clinical data were collected from 115 acromegalic patients (25 with active disease) who underwent a complete colonoscopy. C677T MTHFR genotype, homocysteine, vitamin B₁₂, insulin growth factor and insulin levels, as well as metabolic variables were evaluated.

Results

Colorectal tumours were identified in 51 patients (3 adenocarcinomas). MTHFR C677T distribution was in the Hardy–Weinberg equilibrium and similar in patients with or without CRT. There was a correlation between patients with TT genotype and CRT occurrence (Spearman’s test: P = 0.03), with an Odds Ratio (OR) of 1.32 (95 % CI 0.522–3.362, P NS). A folate–MTHFR genotype interaction on CRT risk was found (P = 0.037): in the lower folate subgroup, TT patients showed a 2.4 higher OR for CRT (95 % CI 0.484–11.891; P NS) than C-allele carriers. Smoking (P = 0.007), increased HbA_1c levels (P = 0.021), dyslipidaemia (P = 0.049), acromegaly control (P = 0.057), and folate–MTHFR genotype interaction (P = 0.088) were associated with CRT at multivariate analysis.

Conclusions

In this cohort of acromegalic patients, CRT risk is increased in 677TT MTHFR patients with low plasma folate levels. Smoking, high HbA_1c levels, dyslipidaemia and disease activity were also associated with increased CRT risk.     

Conservative approach in Peutz-Jeghers syndrome: Single-balloon enteroscopy and small bowel polypectomy

AIM: To assess the usefulness of the balloon assisted enteroscopy in preventing surgical intervention in pa-tients with Peutz-Jeghers syndrome (PJS) having a small bowel large polyps. METHODS: Seven consecutive asymptomatic pts(age 15-38 years) with PJS have been collected; six under-went polypectomy using single balloon enteroscopy(Olympus SIF Q180) with antegrade approach using push and pull technique. SBE system consists of the SIF-Q180 enteroscope, an overtube balloon control unit(OBCU Olympus Balloon Control Unit) and a dispos-able silicone splinting tube with balloon(ST-SB1). All procedures were performed under general anesthesia. Previously all pts received wireless capsule endos-copy(WCE). Prophylactic polypectomy was reservedmainly in pts who had polyps 15 mm in diameter. The balloon is inflated and deflated by a balloon control unit with a safety pressure setting range from-6.0 kPa to +5.4 kPa. Informed consent has been obtained from pts or parents for each procedure.RESULTS: Six pts underwent polypectomy of small bowel polyps; in 5 pts a large polyp 15 mm(range 20-50 mm in diameter) was resected; in 1 patient with WCE negative, SBE was performed for previous surgi-cal resection of gastrointestinal stromal tumors. In 2 pts endoscopic clips were placed due to a polypectomy. No surgical complication have been reported. SBE with resection of small bowel large polyps in PJS pts was useful to avoid gastrointestinal bleeding and emergency laparotomy due to intestinal intussuscep-tions. No gastrointestinal tumors were found in sub-sequent enteroscopic surveillance in all seven pts. In order surveillance, all pts received WCE, upper en-doscopy, ileocolonoscopy every 2 years. No pts had extraintestinal malignant lesions. SBE was performed when WCE was positive for significant polyps( 15 mm).CONCLUSION: The effective of prophylactic polyp-ectomy of small bowel large polyps( 15 mm) could be the first line treatment for conservative approach in management of PJS patients.     

Current status of ambulatory blood pressure monitoring in Asian countries: A report from the HOPE Asia Network

Ambulatory blood pressure monitoring (ABPM) can measure 24‐hour blood pressure (BP), including nocturnal BP and diurnal variations. This feature of ABPM could be of value in Asian populations for preventing cardiovascular events. However, no study has yet investigated regarding the use of ABPM in actual clinical settings in Asian countries/regions. In this study, 11 experts from 11 countries/regions were asked to answer questionnaires regarding the use of ABPM. We found that its use was very limited in primary care settings and almost exclusively available in referral settings. The indications of ABPM in actual clinical settings were largely similar to those of home BP monitoring (HBPM), that is, diagnosis of white‐coat or masked hypertension and more accurate BP measurement for borderline clinic BP. Other interesting indications, such as nighttime BP patterns, including non‐dipper BP, morning BP surge, and BP variability, were hardly adopted in daily clinical practice. The use of ABPM as treatment guidance for detecting treated but uncontrolled hypertension in the Asian countries/regions didn't seem to be common. The barrier to the use of ABPM was primarily its availability; in referral centers, patient reluctance owing to discomfort or sleep disturbance was the most frequent barrier. ABPM use was significantly more economical when it was reimbursed by public insurance. To facilitate ABPM use, more simplified indications and protocols to minimize discomfort should be sought. For the time being, HBPM could be a reasonable alternative.     

A Double-Blind Randomized Controlled Trial (RCT) of Titanium-13Zirconium versus Titanium Grade IV Small-Diameter Bone Level Implants in Edentulous Mandibles - Results from a 1-Year Observation Period

Background: The use of endosseous dental implants has become common practice for the rehabilitation of edentulous patients, and a two‐implant overdenture has been recommended as the standard of care. The use of small‐diameter implants may extend treatment options and reduce the necessity for bone augmentation. However, the mechanical strength of titanium is limited, so titanium alloys with greater tensile and fatigue strength may be preferable. Purpose: This randomized, controlled, double‐blind, multicenter study investigated in a split‐mouth model whether small‐diameter implants made from Titanium‐13Zirconium alloy (TiZr, Roxolid?) perform at least as well as Titanium Grade IV implants. Methods and Materials: Patients with an edentulous mandible received one TiZr and one Ti Grade IV small‐diameter bone level implant (3.3 mm, SLActive®) in the interforaminal region. The site distribution was randomized and double‐blinded. Outcome measures included change in radiological peri‐implant bone level from surgery to 12 months post‐insertion (primary), implant survival, success, soft tissue conditions, and safety (secondary). Results: Of 91 treated patients, 87 were available for the 12‐month follow‐up. Peri‐implant bone level change (?0.3 ± 0.5 mm vs ?0.3 ± 0.6 mm), plaque, and sulcus bleeding indices were not significantly different between TiZr and Ti Grade IV implants. Implant survival rates were 98.9 percent and 97.8 percent, success rates were 96.6 percent and 94.4 percent, respectively. Nineteen minor and no serious adverse events were related to the study devices. Conclusion: This study confirms that TiZr small‐diameter bone level implants provide at least the same outcomes after 12 months as Ti Grade IV bone level implants. The improved mechanical properties of TiZr implants may extend implant therapy to more challenging clinical situations.     

Heparan sulfate mimetics can efficiently mobilize long-term hematopoietic stem cells

Background

Although mobilization of hematopoietic stem cells and hematopoietic progenitor cells can be achieved with a combination of granulocyte colony-stimulating factor and plerixafor (AMD3100), improving approaches for hematopoietic progenitor cell mobilization is clinically important.

Design and Methods

Heparan sulfate proteoglycans are ubiquitous macromolecules associated with the extracellular matrix that regulates biology of hematopoietic stem cells. We studied the effects of a new family of synthetic oligosaccharides mimicking heparan sulfate on hematopoietic stem cell mobilization. These oligosaccharides were administered intravenously alone or in combination with granulocyte colony-stimulating factor and/or AMD3100 in mice. Mobilized hematopoietic cells were counted and phenotyped at different times and the ability of mobilized hematopoietic stem cells to reconstitute long-term hematopoiesis was determined by competitive transplantation into syngenic lethally irradiated mice followed by secondary transplantation.

Results

Mimetics of heparan sulfate induced rapid mobilization of B-lymphocytes, T-lymphocytes, hematopoietic stem cells and hematopoietic progenitor cells. They increased the mobilization of hematopoietic stem cells and hematopoietic progenitor cells more than 3-fold when added to the granulocyte colony-stimulating factor/AMD3100 association. Hematopoietic stem cells mobilized by mimetics of heparan sulfate or by the granulocyte colony-stimulating factor/AMD3100/mimetics association were as effective as hematopoietic stem cells mobilized by the granulocyte colony-stimulating factor/AMD3100 association for primary and secondary hematopoietic reconstitution of lethally irradiated mice.

Conclusions

This new family of mobilizing agents could alone or in combination with granulocyte colony-stimulating factor and/or AMD3100 mobilize a high number of hematopoietic stem cells that were able to maintain long-term hematopoiesis. These results strengthen the role of heparan sulfates in the retention of hematopoietic stem cells in bone marrow and support the use of small glyco-drugs based on heparan sulfate in combination with granulocyte colony-stimulating factor and AMD3100 to improve high stem cell mobilization, particularly in a prospect of use in human therapeutics.