Amylin exerts osteogenic actions with different efficacy depending on the diabetic status

Amylin displays osteogenic features, but its role in diabetic osteopenia is unclear. We examined the possible osteogenic action of amylin infusion for 3 days into fructose-induced insulin-resistant (IR) and streptozotocin-induced type 2 diabetic (T2D) and normal (N) rats. Amylin failed to affect glycaemia or parathyroid hormone levels in any group, but reduced hyperinsulinemia in IR rats. In N rats, amylin increased bone formation rate and reduced osteoclast surface and erosive surface in the femoral metaphysis, and increased osteoprotegerin (OPG)/receptor activator of NFκB ligand (RANKL) mRNA ratio in the tibia. In T2D rats, amylin normalized trabecular structure parameters and increased osteoblast number and osteocalcin (OC) expression in long bones. In contrast, in IR rats, no apparent osteogenic effect of amylin in the femur was observed, although both OC and OPG/RANKL ratio were increased in the tibia. Our findings demonstrate a different osteogenic efficacy of amylin in two diabetic settings.     

Analysis of incidence,risk factors and clinical outcome of thromboembolic and bleeding events in 431 allogeneic hematopoietic stem cell transplantation recipients

Allogeneic hematopoietic stem cell transplantation recipients have an increasing risk of both hemorrhagic and thrombotic complications. However, the competing risks of two of these life-threatening complications in these complex patients have still not been well defined. We retrospectively analyzed data from 431 allogeneic transplantation recipients to identify the incidence, risk factors and mortality due to thrombosis and bleeding. Significant clinical bleeding was more frequent than symptomatic thrombosis. The cumulative incidence of a bleeding episode was 30.2% at 14 years. The cumulative incidence of a venous or arterial thrombosis at 14 years was 11.8% and 4.1%, respectively. The analysis of competing factors for venous thrombosis revealed extensive chronic graft-versus-host disease to be the only independent prognostic risk factor. By contrast, six factors were associated with an increased risk of bleeding; advanced disease, ablative conditioning regimen, umbilical cord blood transplantation, anticoagulation, acute III-IV graft-versus-host disease, and transplant-associated microangiopathy. The development of thrombosis did not significantly affect overall survival (P=0.856). However, significant clinical bleeding was associated with inferior survival (P<0.001). In allogeneic hematopoietic stem cell transplantation, significant clinical bleeding is more common than thrombotic complications and affects survival.     

Safety and efficacy of liraglutide in patients with type 2 diabetes with elevated liver enzymes: individual patient data meta-analysis of the LEAD programme

BackgroundFatty liver disease has reached epidemic proportions in type 2 diabetes. Glucagon-like peptide-1 (GLP-1) analogues are licensed for treatment of type 2 diabetes, yet little data exist on efficacy and safety in liver injury. We aimed to assess the safety and efficacy of 26 weeks' liraglutide on liver function compared with an active placebo.MethodsIndividual patient data meta-analysis was done with patient level data combined from six 26-week, phase 3, double-blind randomised controlled trials on type 2 diabetes, which comprise the Liraglutide Effect and Action in Diabetes (LEAD) programme. In addition, the LEAD-2 sub-study was analysed to assess the effect on CT-measured hepatic steatosis.FindingsOf 4442 patients analysed, 2241 (50·8%) had an abnormal alanine aminotransferase (ALT) at baseline (mean 33·8 IU/L [SD 14·9] in female participants; 47·3 [18·3] in male participants). Liraglutide 1·8 mg reduced ALT in these patients compared with placebo (?8·20 vs ?5·01 IU/L, p=0·003), and was dose dependent (no significant differences vs placebo with liraglutide 0·6 or 1·2 mg). This effect was lost after adjustment for liraglutide's effect on reduction of weight (corrected mean ALT difference vs placebo ?1·41 IU/L, p=0·21) and HbA1c (corrected mean ALT difference vs placebo 0·57 IU/L, p=0·63). Adverse effects with 1·8 mg liraglutide were similar between patients with and without baseline abnormal ALT. In the LEAD-2 sub-study, liraglutide 1·8 mg (26 weeks) improved hepatic steatosis (CT-measured liver:spleen attenuation ratio) from baseline (0·10, p=0·001) and showed a trend towards improvement compared with placebo (0.10 vs 0·00, p=0·07).Interpretation26 weeks of liraglutide (1·8 mg) is safe, well tolerated, and improves liver enzymes compared with placebo in patients with type 2 diabetes.FundingWellcome Trust.     

Protection against liver injury by PGE1 or anti‐TNF‐α is associated with a reduction of TNF‐R1 expression in hepatocytes

Background: Tumour necrosis factor‐α (TNF‐α) has been shown to exacerbate or protect against liver injury in different experimental models. In a previous study, we observed that enhancement of TNF‐α expression in hepatocytes by prostaglandin E ₁ (PGE ₁ ) pre‐administration induced iNOS expression and cytoprotection against experimental liver injury in rats. Nevertheless, the reduction of TNF‐α bioactivity by anti‐TNF‐α antibodies also reduced liver injury by D‐GalN. The purpose of the present study was to evaluate whether protection by PGE ₁ or anti‐TNF‐α was related to a common effect on the membrane‐bound TNF‐α receptor expression. Methods: Liver injury was induced in male Wistar rats by intraperitoneal injection of D‐galactosamine (D‐GalN) (1?g/kg). PGE ₁ or anti‐TNF‐α was administered at 30 or 60?min before D‐GalN, respectively. Liver injury was evaluated by alanine aminotransferase (ALT) activity in serum and histological examination in liver sections. TNF‐αwas determined by ELISA in serum. The expression of TNF‐α receptor type 1 (TNF‐R1) and TNF‐α receptor type 2 (TNF‐R2) in hepatocytes was assessed by immunohistochemistry and immunoprecipitation?+?Western‐blot analysis. Results: PGE ₁ or anti‐TNF‐α reduced liver injury induced by D‐GalN. Although PGE ₁ enhanced and anti‐TNF‐α reduced TNF‐α concentration in serum, both protective treatments reduced the expression of TNF‐R1 in hepatocytes. TNF‐R2 was not detected in our experimental conditions. Conclusions: Our study showed that reduction of liver injury by PGE ₁ or anti‐TNF‐α antibodies was related to a reduction of TNF‐R1 expression in hepatocytes.     

Characterization of skeletal alterations in a model of prematurely aging mice

An age-related bone loss occurs, apparently associated with the concomitant increase in an oxidative stress situation. However, the underlying mechanisms of age-related osteopenia are ill defined since these studies are time consuming and require the use of many animals (mainly rodents). Here, we aimed to characterize for the first time the bone status of prematurely aging mice (PAM), which exhibit an increased oxidative stress. Tibiae from adult (6 months) PAM show an increase in bone mineral density (BMD) and bone mineral content (assessed by bone densitometry) versus those in their normal counterparts (non-prematurely aging mice, NPAM) and similarly decreased in both kinds of mouse with age. However, at this bone site, trabecular BMD (determined by μ-computerized tomography) was similar in both adult PAM and old (18 months) NPAM. Femurs from these groups of mice present an increase in oxidative stress, inflammation, osteoclastogenic, and adipogenic markers, but a decrease in the gene expression of osteoblastic differentiation markers and of the Wnt/β-catenin pathway. Our findings show that adult PAM recapitulate various age-related bone features, and thus are a suitable model for premature bone senescence studies.     

MicroRNAs as potential regulators of platelet function and bleeding diatheses

Although a growing number of studies suggest that microRNAs (miRNAs) play a relevant role in platelet biology, their implications in bleeding diatheses are starting to be investigated. Indeed, several studies have shown that alterations in the intracellular levels of highly expressed platelet miRNAs provoke a thrombotic phenotype. On the other hand, primary immune thrombocytopenia (ITP), which is considered the hallmark of acquired bleeding disorders, has been recently associated with altered levels of miRNAs in peripheral blood mononuclear cells, plasma, and platelets. In this review, we will focus on miRNAs that may affect the hemostatic and thrombotic functions of platelets, and we will discuss the different studies that have attempted to associate miRNAs with regulatory mechanisms of ITP.     

Intramedullary versus Extramedullary Tibial Cutting Guide in Severely Obese Patients Undergoing Total Knee Replacement: A Randomized Study of 70 Patients with Body Mass Index >35 kg/m<Superscript>2</Superscript>

Background  Patients with obesity have an increased risk of osteoarthritis of the knee, which can lead to the need for total knee replacement (TKR). TKR may be more complex in obese patients and the correct orientation of the implant is more difficult. We selected patients with body mass index (BMI) >35 kg/m² undergoing TKR and studied the utility of an intramedullary tibial cutting guide in facilitating the correct orientation of the tibial implant. Methods  Seventy patients with BMI >35 kg/m² were selected for a prospective, randomized study. Patients were divided into two groups: In group 1 (n = 31), the tibial component was implanted using the aid of a intramedullary tibial guide. In group 2 (n = 39), the tibial component was implanted using the aid of an extramedullary tibial cutting guide. Results  The two groups were comparable with respect to age, BMI, and degree of preoperative deformity. Mean age was 69.35 in group 1 and 70.06 in group 2. Group 1 had a mean BMI of 39.84 kg/m² and group 2 of 40.05 kg/m². Postoperative orientation of the femur and tibia and the mechanical axis were within the normal range in both groups. A statistically significant difference between the two groups was observed in tourniquet time, which was longer in group 2 than in group 1 (p = 0.038). Conclusion  Two types of guide were compared in correctly orienting the tibial component of the TKR in patients with a BMI >35 kg/m². The lesser tourniquet time in the group in which the intramedullary guide was used suggest its usefulness because the positioning and orientation of the tibial cut was carried out more rapidly and anatomical references were not needed for correct orientation, as it is guided by the anatomical axis of the tibia. The use of the intramedullary guide reduces surgical time in these patients.