Establishing the precise evolutionary history of a gene improves prediction of disease-causing missense mutations

PURPOSE: Predicting the phenotypic effects of mutations has become an important application in clinical genetic diagnostics. Computational tools evaluate the behavior of the variant over evolutionary time and assume that variations seen during the course of evolution are probably benign in humans. However, current tools do not take into account orthologous/paralogous relationships. Paralogs have dramatically different roles in Mendelian diseases. For example, whereas inactivating mutations in the NPC1 gene cause the neurodegenerative disorder Niemann-Pick C, inactivating mutations in its paralog NPC1L1 are not disease-causing and, moreover, are implicated in protection from coronary heart disease. METHODS: We identified major events in NPC1 evolution and revealed and compared orthologs and paralogs of the human NPC1 gene through phylogenetic and protein sequence analyses. We predicted whether an amino acid substitution affects protein function by reducing the organism’s fitness. RESULTS: Removing the paralogs and distant homologs improved the overall performance of categorizing disease-causing and benign amino acid substitutions. CONCLUSION: The results show that a thorough evolutionary analysis followed by identification of orthologs improves the accuracy in predicting disease-causing missense mutations. We anticipate that this approach will be used as a reference in the interpretation of variants in other genetic diseases as well. Genet Med 18 10, 1029–1036

Correlates of the Ultrasonographic and Elastosonographic Parameters of the Plantar Fascia in Patients with Type 2 Diabetes

Background. Prevalence of plantar fasciitis is increased in type 2 diabetes. This study was aimed at assessing the correlates of ultrasonographic and elastosonographic parameters in plantar fascia (PF) individuals with type 2 diabetes encompassing vari-ous degrees of complications.Methods. This cross-sectional study included 98 patients with type 2 diabetes. Thick-ness of PF was assessed by ultrasonography, whereas elasticity of hard tissue (Elx-Hrd) at PF insertion and course and the subcutaneous-to-insertional strain ratio (Elx 2/1) were determined by elastosonography.Results. No significant differences were detected according to age category, sex, phys-ical activity, and presence of complications, except for higher Elx-Hrd insertion and Elx 1/2 in participants with cardiac autonomic neuropathy (CAN). Thickness of PF, Elx-Hrd insertion and Elx 1/2 correlated significantly with BMI, waist circumference, fat-free mass, and parameters of peripheral neuropathy and CAN; BMI, waist circum-ference, fat mass, fat-free mass, and CAN were independently associated with PF thickness, Elx-Hrd insertion, and Elx 1/2.Conclusions. Adiposity, body composition and presence of CAN are the main correlates of PF ultrasonographic and elastosonographic parameters, suggesting that body weight reduction, maintenance of muscle mass, and prevention of neuropathic complications may result in a decreased incidence of plantar fasciitis in individuals with type 2 diabetes.Study registration. Study registered with ClinicalTrial.gov, NCT01600924 at https:// clinicaltrials.gov/ct2/show/NCT01600924

Cardiovascular Events in Patients Received Combined Fibrate/Statin Treatment versus Statin Monotherapy: Acute Coronary Syndrome Israeli Surveys Data

The effect of combination of fibrate with statin on major adverse cardiovascular events (MACE) following acute coronary syndrome (ACS) hospitalization is unclear. The main aim of this study was to investigate the 30-day rate of MACE in patients who participated in the nationwide ACS Israeli Surveys (ACSIS) and were treated on discharge with a fibrate (mainly bezafibrate) and statin combination vs. statin alone.The study population comprised 8,982 patients from the ACSIS 2000, 2002, 2004, 2006, 2008 and 2010 enrollment waves who were alive on discharge and received statin. Of these, 8,545 (95%) received statin alone and 437 (5%) received fibrate/statin combination. MACE was defined as a composite measure of death, recurrent MI, recurrent ischemia, stent thrombosis, ischemic stroke and urgent revascularization.Patients from the combination group were younger (58.1±11.9 vs. 62.9±12.6 years). However, they had significantly more co-morbidities (hypertension, diabetes), current smokers and unfavorable cardio-metabolic profiles (with respect to glucose, total cholesterol, triglyceride and HDL-cholesterol). Development of MACE was recorded in 513 (6.0%) patients from the statin monotherapy group vs. 13 (3.2%) from the combination group, p = 0.01. 30-day re-hospitalization rate was significantly lower in the combination group: 68 (15.6%) vs. 1691 (19.8%) of patients, respectively; p = 0.03. Multivariable analysis identified the fibrate/statin combination as an independent predictor of reduced risk of MACE with odds ratio of 0.54, 95% confidence interval 0.32–0.94.A significantly lower risk of 30-day MACE rate was observed in patients receiving combined fibrate/statin treatment following ACS compared with statin monotherapy. However, caution should be exercised in interpreting these findings taking into consideration baseline differences between our observational study groups

Metabolic Control in Type 1 Diabetes: Is Adjunctive Therapy the Way Forward?

Despite advances in insulin therapies, patients with type 1 diabetes (T1DM) have a shorter life span due to hyperglycaemia-induced vascular disease and hypoglycaemic complications secondary to insulin therapy. Restricting therapy for T1DM to insulin replacement is perhaps an over-simplistic approach, and we focus in this work on reviewing the role of adjuvant therapy in this population. Current data suggest that adding metformin to insulin therapy in T1DM temporarily lowers HbA1c and reduces weight and insulin requirements, but this treatment fails to show a longer-term glycaemic benefit. Agents in the sodium glucose co-transporter-2 inhibitor (SGLT-2) class demonstrate the greatest promise in correcting hyperglycaemia, but there are safety concerns in relation to the risk of diabetic ketoacidosis. Glucagon-like peptide-1 agonists (GLP-1) show a modest effect on glycaemia, if any, but significantly reduce weight, which may make them suitable for use in overweight T1DM patients. Treatment with pramlintide is not widely available worldwide, although there is evidence to indicate that this agent reduces both HbA1c and weight in T1DM. A criticism of adjuvant studies is the heavy reliance on HbA1c as the primary endpoint while generally ignoring other glycaemic parameters. Moreover, vascular risk markers and measures of insulin resistance—important considerations in individuals with a longer T1DM duration—are yet to be fully investigated following adjuvant therapies. Finally, studies to date have made the assumption that T1DM patients are a homogeneous group of individuals who respond similarly to adjuvant therapies, which is unlikely to be the case. Future longer-term adjuvant studies investigating different glycaemic parameters, surrogate vascular markers and harder clinical outcomes will refine our understanding of the roles of such therapies in various subgroups of T1DM patients

Percutaneous coronary interventions and statin therapy

Lipid lowering therapy with statins reduces the risk of cardiovascular events in patients with coronary artery disease. Recent in vitro and in vivo studies demonstrated LDL-independent action of this class of drugs, which appears in modulating endothelial function, inflammation and thrombosis. Periprocedural myocardial infarction and contrast induced nephropathy after percutaneous coronary intervention (PCI), associated with worse outcome on short and long term follow-up, are both complications related to inflammatory pathogenetic mechanisms. Randomized studies showed a beneficial effect of short-term statin pretreatment in reducing peri-procedural cardiac markers release in patients undergoing PCI. In fact, statin therapy before elective PCI reduced periprocedural myocardial infarction in patients with stable angina. Furthermore, an acute loading with high-dose atorvastatin prevented myocardial damage in patients with acute coronary syndromes undergoing early PCI (<48 hours). In patients already on chronic statin therapy, a reload with high dose statin was associated with a significant improvement on 30-day cardiac outcome. Finally, statin therapy at the time of PCI significantly decreased the incidence of contrast-induced nephropathy. All these evidences support an "upstream administration" of short-term, high-dose statins in all patients undergoing PCI, in order to achieve pleiotropic, LDL-independent effects of these drugs

Percutaneous coronary interventions and statin therapy

Lipid lowering therapy with statins reduces the risk of cardiovascular events in patients with coronary artery disease. Recent in vitro and in vivo studies demonstrated LDL-independent action of this class of drugs, which appears in modulating endothelial function, inflammation and thrombosis. Periprocedural myocardial infarction and contrast induced nephropathy after percutaneous coronary intervention (PCI), associated with worse outcome on short and long term follow-up, are both complications related to inflammatory pathogenetic mechanisms. Randomized studies showed a beneficial effect of short-term statin pretreatment in reducing peri-procedural cardiac markers release in patients undergoing PCI. In fact, statin therapy before elective PCI reduced periprocedural myocardial infarction in patients with stable angina. Furthermore, an acute loading with high-dose atorvastatin prevented myocardial damage in patients with acute coronary syndromes undergoing early PCI (<48 hours). In patients already on chronic statin therapy, a reload with high dose statin was associated with a significant improvement on 30-day cardiac outcome. Finally, statin therapy at the time of PCI significantly decreased the incidence of contrast-induced nephropathy. All these evidences support an "upstream administration"of short-term, high-dose statins in all patients undergoing PCI, in order to achieve pleiotropic, LDL-independent effects of these drugs