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Type 2 diabetes (T2D) is a complex metabolic disease associated with obesity, insulin resistance and hypoinsulinemia due to pancreatic β-cell dysfunction. Reduced mitochondrial function is thought to be central to β-cell dysfunction. Mitochondrial dysfunction and reduced insulin secretion are also observed in β-cells of humans with the most common human genetic disorder, Down syndrome (DS, Trisomy 21). To identify regions of chromosome 21 that may be associated with perturbed glucose homeostasis we profiled the glycaemic status of different DS mouse models. The Ts65Dn and Dp16 DS mouse lines were hyperglycemic, while Tc1 and Ts1Rhr mice were not, providing us with a region of chromosome 21 containing genes that cause hyperglycemia. We then examined whether any of these genes were upregulated in a set of ~5,000 gene expression changes we had identified in a large gene expression analysis of human T2D β-cells. This approach produced a single gene, RCAN1, as a candidate gene linking hyperglycemia and functional changes in T2D β-cells. Further investigations demonstrated that RCAN1 methylation is reduced in human T2D islets at multiple sites, correlating with increased expression. RCAN1 protein expression was also increased in db/db mouse islets and in human and mouse islets exposed to high glucose. Mice overexpressing RCAN1 had reduced in vivo glucose-stimulated insulin secretion and their β-cells displayed mitochondrial dysfunction including hyperpolarised membrane potential, reduced oxidative phosphorylation and low ATP production. This lack of β-cell ATP had functional consequences by negatively affecting both glucose-stimulated membrane depolarisation and ATP-dependent insulin granule exocytosis. Thus, from amongst the myriad of gene expression changes occurring in T2D β-cells where we had little knowledge of which changes cause β-cell dysfunction, we applied a trisomy 21 screening approach which linked RCAN1 to β-cell mitochondrial dysfunction in T2D.

Abstract:Poroid hidradenoma is a rare cutaneous neoplasm, most frequently situated on head and neck. It presents architectural features of hidradenoma, with solid and cystic areas and tumor cells restricted to the dermis, and cytological features of poroid neoplasm such as poroid and cuticular cells. This neoplasm is a new entity which is closely related to proma family. Similar to most of other adnexal tumors, treatment is based on surgical resection in order to prevent a possible recurrence or malignant transformation. To date, very few cases of this entity have been reported in the literature. We present a case of poroid hidradenoma in a 61-year-old woman with a soft-tissue lesion on her neck.

Background: Cardiac involvement is a major contributor of morbidity and mortality in Fabry disease (FD). Early detection and accurate evaluation of the disease progression is important in management.Cardiovascular magnetic resonance (CMR) derived feature fracking (FT) is a validated quantitative method of assessing myocardial deformation which may reflect early changes of myocardial function and track disease severity. We sought to evaluate the utility of CMR-FT as a measure of myocardial dysfunction in FD.Methods: Twenty FD patients (12 males, 40.8±14.9 years) and 20 age and sex matched healthy controls (10 males, 40.5±7.2 years) were prospectively enrolled. Subjects underwent CMR including cine, pre-/postcontrast T1 mapping and late gadolinium enhancement (LGE). FD patients were divided into three groups; group 1: patients without left ventricular hypertrophy (LVH) and LGE negative; group 2: patients with LVH positive, LGE either positive or negative; group 3: patients with LGE positive, LV wall thinning and heart failure. FT derived strain indices were measured and its associations with other processes were investigated. Results:In FD patients, 14 (70%) had LVH and 4 (20%) had LGE. Compared with normal controls, LV global longitudinal strain (GLS) were reduced significantly in all three Fabry groups (all P<0.05), global circumferential strain (GCS) were reduced only in group 2 and group 3 (P<0.05). Among three FD groups, there were significant differences of LV GLS, GCS, native T1 value and extracellular volume fraction (ECV) (all P<0.01), group 1 had mild LV strain indices impairment, group 3 had the most severe LV strain indices.When compared between FD subgroups, GLS and GCS showed significant difference between each two groups (all P<0.05). There were weak correlations between the LV functional parameters (ejection fraction, LV mass index), maximal wall thickness, T1 mapping indices (native T1, ECV) and LV strain indices. The strongest relation was between global longitudinal early diastolic strain rate and native T1 value (r=0.783, P<0.01).Conclusions: CMR strain imaging identifies myocardial deformation in FD in different stages. Strain imaging can track disease severity and may be an alternative method for follow-up of FD patients.

Fabry disease (FD) results from a deficiency in the exoglycohydrolase, α-galactosidase A (AGA), an enzyme required for the sequential degradation of glycosphingolipids, which consequently accumulate in the lysosomes of affected cells. An X-linked inherited metabolic disorder, FD has a high incidence of a later onset phenotype that is under-diagnosed and under-recognised in adulthood despite the availability of specific treatment. As the first presenting feature in adults is often left ventricular hypertrophy (LVH), we hypothesized that testing patients with an attenuated echocardiographic phenotype of unexplained hypertrophic cardiomyopathy, might identify cases of undiagnosed FD. We employed a simple screening test by measuring AGA activity in dried blood spots collected from a finger-prick of blood in a cohort of 511 individuals aged between 18 and 75 with LVH between 1.2 and 1.5 cm. Two males were identified with AGA activity below the reference interval and subsequent molecular testing confirmed the commonly reported genetic variants, p.Ala143Thr in one individual and p.Asn215Ser, in the other. Additional biochemical measurement of plasma, lyso-Gb1 was normal in both patients. Of the 179 females screened, one individual returned AGA activity slightly below the reference interval but was lost to further follow-up. This pilot study suggests that screening patients with mild-to-moderate LVH of unknown aetiology does indeed identify undiagnosed cases of FD.

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