Glucokinase (GCK) Mutations and Their Characterization in MODY2 Children of Southern Italy

Type 2 Maturity Onset Diabetes of the Young (MODY2) is a monogenic autosomal disease characterized by a primary defect in insulin secretion and hyperglycemia. It results from GCK gene mutations that impair enzyme activity. Between 2006 and 2010, we investigated GCK mutations in 66 diabetic children from southern Italy with suspected MODY2. Denaturing High Performance Liquid Chromatography (DHPLC) and sequence analysis revealed 19 GCK mutations in 28 children, six of which were novel: p.Glu40Asp, p.Val154Leu, p.Arg447Glyfs, p.Lys458_Cys461del, p.Glu395_Arg397del and c.580-2A>T. We evaluated the effect of these 19 mutations using bioinformatic tools such as Polymorphism Phenotyping (Polyphen), Sorting Intolerant From Tolerant (SIFT) and in silico modelling. We also conducted a functional study to evaluate the pathogenic significance of seven mutations that are among the most severe mutations found in our population, and have never been characterized: p.Glu70Asp, p.His137Asp, p.Phe150Tyr, p.Val154Leu, p.Gly162Asp, p.Arg303Trp and p.Arg392Ser. These seven mutations, by altering one or more kinetic parameters, reduced enzyme catalytic activity by >40%. All mutations except p.Glu70Asp displayed thermal-instability, indeed >50% of enzyme activity was lost at 50°C/30 min. Thus, these seven mutations play a pathogenic role in MODY2 insurgence. In conclusion, this report revealed six novel GCK mutations and sheds some light on the structure-function relationship of human GCK mutations and MODY2

Internal and external forcing of multidecadal Atlantic climate variability over the past 1,200 years

The North Atlantic experiences climate variability on multidecadal scales, which is sometimes referred to as Atlantic multidecadal variability. However, the relative contributions of external forcing such as changes in solar irradiance or volcanic activity and internal dynamics to these variations are unclear. Here we provide evidence for persistent summer Atlantic multidecadal variability from AD 800 to 2010 using a network of annually resolved terrestrial proxy records from the circum-North Atlantic region. We find that large volcanic eruptions and solar irradiance minima induce cool phases of Atlantic multidecadal variability and collectively explain about 30% of the variance in the reconstruction on timescales greater than 30 years. We are then able to isolate the internally generated component of Atlantic multidecadal variability, which we define as the Atlantic multidecadal oscillation. We find that the Atlantic multidecadal oscillation is the largest contributor to Atlantic multidecadal variability over the past 1,200 years. We also identify coherence between the Atlantic multidecadal oscillation and Northern Hemisphere temperature variations, leading us to conclude that the apparent link between Atlantic multidecadal variability and regional to hemispheric climate does not arise solely from a common response to external drivers, and may instead reflect dynamic processes

Biplane opening wedge high tibial osteotomy with a distal tuberosity osteotomy, radiological and clinical analysis with minimum follow-up of 2 Years

Background: High tibial osteotomy is an established and helpful treatment for unicompatimental osteoarthritis associated with varus deformity. However, asupratubercle high tibial osteotomy leads to a decrease in patellar height making the technique not suitable in case of concomitant patella baja. Moreover, this kind of osteotomy can change in situ forces at patellofemoral joint and the lateral patellar tilt. With the aim to widen the indication of high tibial osteotomy was proposed a biplane opening wedge high tibial osteotomy with a distal tuberosity osteotomy (B-OWHTO). This technique provide that the tibial tuberosity remains joined to the tibial metaphysis so as not to theoretically alter the patellar height. However, some Authors claim that BOWHTO could lead to an increase in tibial slope. The purpose of the present study was to assess the tibial slope, patella-femoral changes and axial correction as well as functional outcomes following a B-OWHTO. Methods: Patients operated on with a B-OWHTO and a minimum 24 months of follow-up were included. The mechanical alignment of the lower limb, patellar height, lateral patellar tilt and posterior tibial slope were calculated preoperatively, immediately after surgery and at the 24-month follow-up. The clinical results were evaluated using the Lysholm, Kujala and Hospital for Special Surgery knee scores. The possible postoperative development of patellofemoral pain or radiologic patellofemoral alteration was also evaluated. Results: Twenty-three patients were included with a mean follow-up of 33 months (range 27-41). The mechanical alignment of the lower limb shifted from a mean 9.3º ± 2.5 varus preoperatively to a mean 0.2º ± 2.2 valgus postoperatively. No changes in patellar height, lateral patellar tilt or in the posterior tibial slope were observed. The mean Lysholm and HSS scores improved from 68.3 ± 9.1 and 64.2 ± 5.2 preoperatively to 93.2 ± 2.1 and 94.1 ± 3.6 at final follow-up (p < 0.01). The mean Kujala score improved from 67.3 ± 9.8 to 86.4 ± 7.6 at final follow up (p < 0.01). No patients developed both radiological or clinical symptoms at patellofemoral joint. Conclusions: Open wedge high tibial osteotomy with a dihedral L-cut distal and posterior to the tibial tubercle accurately corrected axial malalignment without any change at patella-femoral joint or any modification to the posterior tibial slope while providing improved knee function at short-term follow-up. The radiographic as well as the clinical results support the use of this technique to treat medial compartment knee osteoarthritis and varus malalignment in young and middle-aged patients with a normal-to-low patellar height

AKAPs integrate genetic findings for autism spectrum disorders

Contains fulltext : 115371.pdf (publisher's version ) (Open Access)Autism spectrum disorders (ASDs) are highly heritable, and six genome-wide association studies (GWASs) of ASDs have been published to date. In this study, we have integrated the findings from these GWASs with other genetic data to identify enriched genetic networks that are associated with ASDs. We conducted bioinformatics and systematic literature analyses of 200 top-ranked ASD candidate genes from five published GWASs. The sixth GWAS was used for replication and validation of our findings. Further corroborating evidence was obtained through rare genetic variant studies, that is, exome sequencing and copy number variation (CNV) studies, and/or other genetic evidence, including candidate gene association, microRNA and gene expression, gene function and genetic animal studies. We found three signaling networks regulating steroidogenesis, neurite outgrowth and (glutamatergic) synaptic function to be enriched in the data. Most genes from the five GWASs were also implicated-independent of gene size-in ASDs by at least one other line of genomic evidence. Importantly, A-kinase anchor proteins (AKAPs) functionally integrate signaling cascades within and between these networks. The three identified protein networks provide an important contribution to increasing our understanding of the molecular basis of ASDs. In addition, our results point towards the AKAPs as promising targets for developing novel ASD treatments