Visfatin, glucose metabolism and vascular disease: a review of evidence

The adipose tissue is an endocrine organ producing substances called adipocytokines that have different effects on lipid metabolism, metabolic syndrome, and cardiovascular risk. Visfatin was recently described as an adipocytokine with potentially important effects on glucose metabolism and atherosclerosis. Visfatin has been linked to several inflammatory conditions, beta cell function, and cardiovascular disease. The growing number of publications on the subject shall bring further evidence about this adipocytokine. Its findings may contribute in the identification of higher risk individuals for diabetes and cardiovascular disease with a better comprehension about the complex intercorrelation between adiposity, glucose metabolism and vascular disease

Integrating the concept of field cancerization in the classification and risk assessment of cutaneous squamous cell carcinoma: proposal for a new classification and terminology of keratinocyte skin cancer.

The term keratinocyte skin cancer (KC) stands as an umbrella for different stages within the progression of cutaneous squamous cell carcinoma (cSCC). 1\u20102 Its earliest form is named actinic keratosis (AK), while for the in\u2010situ form different synonyms, namely intraepidermal carcinoma (IEC), Bowen's Diseases (BD) and cutaneous squamous cell carcinoma in situ [cSCC(Tis)] or intraepithelial squamous cell carcinoma (iSCC) are used.3 Instead, cSCC is histopathologically classified into well, moderately and poorly differentiated subtypes

HNF1A gene polymorphisms and cardiovascular risk factors in individuals with late-onset autosomal dominant diabetes: a cross-sectional study

<p>Abstract</p> <p>Background</p> <p>Type 2 diabetes mellitus (T2DM) is a genetically heterogeneous disease, hepatocyte nuclear factor-1 homeobox A (<it>HNF1A</it>) single-nucleotide polymorphisms (SNPs) playing a minor role in its pathogenesis. <it>HNF1A </it>is a frequent cause of monogenic diabetes, albeit with early-onset. Some uncommon subgroups like late-onset autosomal dominant diabetes mellitus (LOADDM) may present peculiar inheritance patterns with a stronger familial component. This study aims to investigate the relationship of <it>HNF1A </it>SNPs with cardiovascular risk factors in this group, as well as to characterize them in contrast with classical T2DM (CT2DM).</p> <p>Methods</p> <p>eighteen LOADDM (age at onset > 40 y.o.; diabetes in 3 contiguous generations, uniparental lineage) along with 48 CT2DM patients and 42 normoglycemic controls (N group) have been evaluated for cardiovascular risk factors and SNPs of <it>HNF1A</it>.</p> <p>Results</p> <p>LOADDM showed significantly higher frequencies of SNPs A98V (22.2% vs 2.1%, p = 0.02) and S487N (72.2% vs 43.8%, p = 0.049) of <it>HNF1A </it>compared to CT2DM. I27L did not show significant difference (66.7% vs 45.8%), but associated with lower risk of hypertriglyceridemia (OR 0.16, 95% CI 0.04–0.65, p = 0.01). "Protective effect" was independent from other well-known predictive risk factors for hypertriglyceridemia, such as waist circumference (OR 1.09 per 1 cm increase, p = 0.01) and HDL (OR 0.01 per 1 mmol/l, p = 0.005), after logistic regression.</p> <p>Conclusion</p> <p>Late onset autosomal dominant diabetes mellitus is clinically indistinguishable from classical type 2 diabetes individuals. However, LOADDM group is enriched for common <it>HNF1A </it>polymorphisms A98V and S487N. I27L showed "protective effect" upon hypertriglyceridemia in this sample of individuals, suggesting a role for <it>HNF1A </it>on diabetic individuals' lipid profile. These data contribute to the understanding of the complex interactions between genes, hyperglycemia and cardiovascular risk factors development in type 2 diabetes mellitus.</p

Investigating halo substructures with annual modulation signature

Galaxy hierarchical formation theories, numerical simulations, the discovery of the Sagittarius Dwarf Elliptical Galaxy (SagDEG) in 1994 and more recent investigations suggest that the dark halo of the Milky Way can have a rich phenomenology containing non thermalized substructures. In the present preliminary study, we investigate the case of the SagDEG (the best known satellite galaxy in the Milky Way crossing the solar neighbourhood) analyzing the consequences of its dark matter stream contribution to the galactic halo on the basis of the DAMA/NaI annual modulation data. The present analysis is restricted to some WIMP candidates and to some of the astrophysical, nuclear and particle Physics scenarios. Other candidates such as e.g. the light bosonic ones, we discussed elsewhere, and other non thermalized substructures are not yet addressed here.Comment: 17 pages, 10 figures, to appear in Eur. Phys. J.

A Serological Biomarker of Laminin Gamma 1 Chain Degradation Reflects Altered Basement Membrane Remodeling in Crohn’s Disease and DSS Colitis

Background: The laminin gamma 1 chain (LMγ1) is abundant along the crypt-villus axis in the intestinal basement membrane. / Aims: We investigated whether a serological biomarker of laminin degradation was associated with disease activity in patients with Crohn’s disease (CD) and in rats with dextran sulfate sodium (DSS)-induced colitis. / Methods: Serum samples from CD patients (n = 43), healthy subjects (n = 19), and Sprague Dawley rats receiving 5–6% DSS water for five days and regular drinking water for 11 days were included in this study. The LG1M biomarker, a neo-epitope degradation fragment of the LMγ1 chain generated by matrix metalloproteinases-9 (MMP-9), was measured in serum to estimate the level of laminin degradation. / Results: Serum LG1M was elevated in CD patients with active and inactive disease compared to healthy subjects (p < 0.0001). LG1M distinguished CD patients from healthy subjects, with an area under the curve (AUC) of 0.81 (p < 0.0001). Serum LG1M was decreased in DSS rats compared to controls 2 days after DSS withdrawal, and increased upon reversal of the disease. / Conclusions: Increased serum LG1M in active and inactive CD patients supports the evidence of altered LM expression in both inflamed and non-inflamed tissue. Moreover, lower LG1M levels in the early healing phase of DSS-induced colitis may reflect ongoing mucosal repair

Elevated ectodomain of type 23 collagen is a novel biomarker of the intestinal epithelium to monitor disease activity in ulcerative colitis and Crohn's disease

BACKGROUND: Impaired intestinal epithelial barrier is highly affected in inflammatory bowel disease. Transmembrane collagens connecting the epithelial cells to the extracellular matrix have an important role in epithelial cell homeostasis. Thus, we sought to determine whether the transmembrane type 23 collagen could serve as a surrogate marker for disease activity in patients with Crohn's disease and ulcerative colitis. METHODS: We developed an enzyme-linked immunosorbent assay to detect the ectodomain of type 23 collagen (PRO-C23) in serum, followed by evaluation of its levels in both acute and chronic dextran sulfate sodium colitis models in rats and human inflammatory bowel disease cohorts. Serum from 44 Crohn's disease and 29 ulcerative colitis patients with active and inactive disease was included. RESULTS: In the acute and chronic dextran sulfate sodium-induced rat colitis model, the PRO-C23 serum levels were significantly increased after colitis and returned to normal levels after disease remission. Serum levels of PRO-C23 were elevated in Crohn's disease (p < 0.05) and ulcerative colitis (p < 0.001) patients with active disease compared to healthy donors. PRO-C23 differentiated healthy donors from ulcerative colitis (area under the curve: 0.81, p = 0.0009) and Crohn's disease (area under the curve: 0.70, p = 0.0124). PRO-C23 differentiated ulcerative colitis patients with active disease from those in remission (Area under the curve: 0.75, p = 0.0219) and Crohn's disease patients with active disease from those in remission (area under the curve: 0.68, p = 0.05). CONCLUSION: PRO-C23 was elevated in rats with active colitis, and inflammatory bowel disease patients with active disease. Therefore, PRO-C23 may be used as a surrogate marker for monitoring disease activity in ulcerative colitis and Crohn's disease

Common and low frequency variants in MERTK are independently associated with multiple sclerosis susceptibility with discordant association dependent upon HLA-DRB1*15:01 status

Multiple Sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system. The risk of developing MS is strongly influenced by genetic predisposition, and over 100 loci have been established as associated with susceptibility. However, the biologically relevant variants underlying disease risk have not been defined for the vast majority of these loci, limiting the power of these genetic studies to define new avenues of research for the development of MS therapeutics. It is therefore crucial that candidate MS susceptibility loci are carefully investigated to identify the biological mechanism linking genetic polymorphism at a given gene to the increased chance of developing MS. MERTK has been established as an MS susceptibility gene and is part of a family of receptor tyrosine kinases known to be involved in the pathogenesis of demyelinating disease. In this study we have refined the association of MERTK with MS risk to independent signals from both common and low frequency variants. One of the associated variants was also found to be linked with increased expression of MERTK in monocytes and higher expression of MERTK was associated with either increased or decreased risk of developing MS, dependent upon HLA-DRB1*15:01 status. This discordant association potentially extended beyond MS susceptibility to alterations in disease course in established MS. This study provides clear evidence that distinct polymorphisms within MERTK are associated with MS susceptibility, one of which has the potential to alter MERTK transcription, which in turn can alter both susceptibility and disease course in MS patients

Common and low Frequency variants in MERTK are independently associated with multiple sclerosis susceptibility with discordant association dependent upon HLA-DRB1*15:01 status

Multiple Sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system. The risk of developing MS is strongly influenced by genetic predisposition, and over 100 loci have been established as associated with susceptibility. However, the biologically relevant variants underlying disease risk have not been defined for the vast majority of these loci, limiting the power of these genetic studies to define new avenues of research for the development of MS therapeutics. It is therefore crucial that candidate MS susceptibility loci are carefully investigated to identify the biological mechanism linking genetic polymorphism at a given gene to the increased chance of developing MS. MERTK has been established as an MS susceptibility gene and is part of a family of receptor tyrosine kinases known to be involved in the pathogenesis of demyelinating disease. In this study we have refined the association of MERTK with MS risk to independent signals from both common and low frequency variants. One of the associated variants was also found to be linked with increased expression of MERTK in monocytes and higher expression of MERTK was associated with either increased or decreased risk of developing MS, dependent upon HLA-DRB1*15:01 status. This discordant association potentially extended beyond MS susceptibility to alterations in disease course in established MS. This study provides clear evidence that distinct polymorphisms within MERTK are associated with MS susceptibility, one of which has the potential to alter MERTK transcription, which in turn can alter both susceptibility and disease course in MS patients

Skeletal Plasmacytoma: Progression of disease and impact of local treatment; an analysis of SEER database

<p>Abstract</p> <p>Background</p> <p>Previous reports suggest an as yet unidentifiable subset of patients with plasmacytoma will progress to myeloma. The current study sought to establish the risk of developing myeloma and determine the prognostic factors affecting the progression of disease.</p> <p>Methods</p> <p>Patients with plasmacytoma diagnosed between 1973 and 2005 were identified in the SEER database(1164 patients). Patient demographics and clinical characteristics, treatment(s), cause of death, and survival were extracted. Kaplan-Meier, log-rank, and Cox regression were used to analyze prognostic factors.</p> <p>Results</p> <p>The five year survival among patients initially diagnosed with plasmacytoma that later progressed to multiple myeloma and those initially diagnosed with multiple myeloma were almost identical (25% and 23%; respectively). Five year survival for patients with plasmacytoma that did not progress to multiple myeloma was significantly better (72%). Age > 60 years was the only factor that correlated with progression of disease (p = 0.027).</p> <p>Discussion</p> <p>Plasmacytoma consists of two cohorts of patients with different overall survival; those patients that do not progress to systemic disease and those that develop myeloma. Age > 60 years is associated with disease progression. Identifying patients with systemic disease early in the treatment will permit aggressive and novel treatment strategies to be implemented.</p

Personalised profiling to identify clinically relevant changes in tremor due to multiple sclerosis

Background: There is growing interest in sensor-based assessment of upper limb tremor in multiple sclerosis and other movement disorders. However, previously such assessments have not been found to offer any improvement over conventional clinical observation in identifying clinically relevant changes in an individual's tremor symptoms, due to poor test-retest repeatability. Method: We hypothesised that this barrier could be overcome by constructing a tremor change metric that is customised to each individual's tremor characteristics, such that random variability can be distinguished from clinically relevant changes in symptoms. In a cohort of 24 people with tremor due to multiple sclerosis, the newly proposed metrics were compared against conventional clinical and sensor-based metrics. Each metric was evaluated based on Spearman rank correlation with two reference metrics extracted from the Fahn-Tolosa-Marin Tremor Rating Scale: a task-based measure of functional disability (FTMTRS B) and the subject's self-assessment of the impact of tremor on their activities of daily living (FTMTRS C). Results: Unlike the conventional sensor-based and clinical metrics, the newly proposed ’change in scale’ metrics presented statistically significant correlations with changes in self-assessed impact of tremor (max R2>0.5,p< 0.05 after correction for false discovery rate control). They also outperformed all other metrics in terms of correlations with changes in task-based functional performance (R2=0.25 vs. R2=0.15 for conventional clinical observation, both p< 0.05).Conclusions: The proposed metrics achieve an elusive goal of sensor-based tremor assessment: improving on conventional visual observation in terms of sensitivity to change. Further refinement and evaluation of the proposed techniques is required, but our core findings imply that the main barrier to translational impact for this application can be overcome. Sensor-based tremor assessments may improve personalised treatment selection and the efficiency of clinical trials for new treatments by enabling greater standardisation and sensitivity to clinically relevant changes in symptoms