Evaluation of the inner choroid using OCT angiography

The advent of optical coherence tomography angiography (OCTA) has allowed a qualitative and quantitative analysis of the retinal vasculature and the choriocapillaris. With the use of OCTA, several studies evaluated the changes in the choriocapillaris showing how this vascular structure plays a significant role in the pathogenesis of different conditions. This article reviews the current methods of analysis of the choriocapillaris and the relevant findings in different chorioretinal diseases.Subject terms: Eye diseases, Pathogenesis     

Discovery of Aminopyrazole Derivatives as Potent Inhibitors of Wild-Type and Gatekeeper Mutant FGFR2 and 3

Fibroblast growth factor receptors (FGFR) 2 and 3 have been established as drivers of numerous types of cancer with multiple drugs approved or entering late stage clinical trials. A limitation of current inhibitors is vulnerability to gatekeeper resistance mutations. Using a combination of targeted high-throughput screening and structure-based drug design, we have developed a series of aminopyrazole based FGFR inhibitors that covalently target a cysteine residue on the P-loop of the kinase. The inhibitors show excellent activity against the wild-type and gatekeeper mutant versions of the enzymes. Further optimization using SAR analysis and structure-based drug design led to analogues with improved potency and drug metabolism and pharmacokinetics properties.     

The role of advanced oxidation protein products in intensive care unit patients with acute kidney injury

IntroductionOxidative stress (OS) is an imbalance between the production of oxidizing chemical species and the antioxidant defense. It is known that OS increases in critically ill patients with acute kidney injury (AKI). Measurement of advanced oxidation protein products (AOPPs) has been found to be a simple tool for monitoring OS.AimsThe aims of this study were to evaluate OS in intensive care unit (ICU) patients by AOPP levels and compare its levels between patients with and without AKI; we also wanted to assess the ability of AOPP to predict the development of AKI in this population.Patients, Material, and MethodsWe performed a prospective cohort study to compare AOPP levels between critically ill AKI (as defined by Risk-Injury-Failure-Loss-End Stage Renal Disease [RIFLE] criteria) and non-AKI patients.Blood samples were collected from all consecutively admitted patients upon arrival to ICU and daily for up to 4 days. We collected 234 blood samples from 86 adult medical and surgical ICU patients. The levels of AOPP were determined in the plasma and measured by spectrophotometry at 340 nm and compared between non-AKI (n = 71) and AKI patients (n = 15). We further subdivided the AKI patients according to severity of AKI (worst RIFLE class attained in ICU).ResultsAmong the 86 patients, 15 (17.44%) developed AKI during their stay in ICU, whereas 71 patients (82.56%) did not. Among the AKI patients, 5 had AKI on ICU admission, whereas 10 developed it later.The levels of AOPP were significantly higher among AKI patients compared with non-AKI patients (153.8 ± 117.8 versus 129.0 ± 114.9 μmol/L, respectively; P = .034). Patients with the most severe AKI (RIFLE class Failure) had markedly elevated AOPP levels compared with RIFLE class Risk and Injury patients (P = .012).Area under the curve of receiver operating characteristic for prediction of AKI within 48 hours after first blood sample collection was 0.5835 (P = not significant).ConclusionsThis is the first study to explore the relationship between severity of AKI and AOPP.In our adult ICU population, AOPP levels were higher in AKI compared with non-AKI critically ill patients. On the other hand, AOPP levels were not found to be a useful biomarker for AKI, as it was unable to identify patients who developed AKI within 24, 48, 76, and 96 hours.     

Applicability of Neural Networks to Suicidological Research: A Pilot Study

Suicide is a leading cause of death internationally. Prediction of the phenomenon has proved to be extremely difficult and results in this area have been modest. The objective of this pilot study was to assess the applicability of the Neural Network statistical procedure to suicidal data. The predictive ability of three statistical techniques (Logistic Regression, Discriminatory Analysis and Neural Networks) were compared in the ability to distinguish between suicides and attempts on the basis of a variety of variables. Although the Neural Network model expresses its full potential with large numbers, it has proved to be effective even in our limited sample. This suggests that neural networks may exhibit superior predictive capacity when the data set is enlarged. This technique may prove to be a useful additional tool in the field of suicide prediction and prevention.     

Haemodynamic effects of acute intravenous metoprolol in apical ballooning syndrome with dynamic left ventricular outflow tract obstruction

Takotsubo syndrome, also called apical ballooning syndrome, is a clinical entity characterized by transient hypokinesis, akinesis, or dyskinesis of the left ventricular mid‐segments with or without apical involvement, and without obstructive coronary lesions. The contemporary presence of left ventricular outflow tract obstruction (LVOTO), systolic anterior motion of the anterior mitral leaflet, and acute mitral regurgitation might explain the worsening of the heart failure or the occurrence of cardiogenic shock in some patients with apical ballooning syndrome. The use of β‐blockers should improve the LVOTO gradient by reducing basal hypercontractility, increasing left ventricular filling and size, and reducing heart rate. However, clear evidence of the direct haemodynamic effects of β‐blockers is still lacking. We present a case of apical ballooning syndrome complicated by dynamic LVOTO, treated with metoprolol.     

Lowering homocysteine levels with folic acid and B-vitamins do not reduce early atherosclerosis, but could interfere with cognitive decline and Alzheimer’s disease

Inheired or acquired hyperhomocysteinemia (HHcy) is associated with several impairments, as certain tumors, deep venous thrombosis, tube neural defects, osteoporosis, early atherosclerosis and vascular acute events (IMA, stroke, PVD), mild cognitive impairments till Alzheimer’s disease (AD). But, vascular and neuronal derangements are the most frequent HHcy-manifestations. As far as early atherosclerosis, some clinical trials demonstrated that folates and B_6–12 vitamins supplementation is unable to reduce atherosclerotic lesions and cardiovascular events, even if it lowers HHcy levels. Thus, for atherosclerosis and its acute events (IMA, stroke, PVD) HHcy acts as a powerful biomarker rather than a risk factor. For that, the supplementation with folates and B vitamins to lower atherosclerotic lesions-events in hyperhomocysteinemic patients is not recommended. On the contrary, several clinical investigations demonstrated that folates and vitamins administration is able to reduce Hcy serum levels and antagonize some mechanisms favouring neurodegenerative impairments, as mild cognitive impairment, AD and dementia. Thus, contrarily to the atherosclerotic manifestations in hyperhomocysteinemic patients, preventive treatment with folates and B_6–12 vitamins reduces Hcy concentration and could prevent or delay cognitive decline and AD.     

Could thiazolidinediones increase the risk of heart failure in Friedreich's ataxia patients?

Clinical evidence and the recent decisions of the European Medicines Agency and the Food and Drug Administration challenge the safety of thiazolidinediones treatment. Recently, this treatment has been suggested for Friedreich's ataxia because thiazolidinediones improve neurological symptoms. Hypertrophic cardiomyopathy is the most prevalent cardiac feature and the cause of premature death in Friedreich's ataxia patients. We recommend that therapy with peroxisome proliferator‐activated receptor‐gamma agonists like thiazolidinediones be taken with caution, as they cause a decrease in the number of fast fibers and an increase in mitochondrial biogenesis in cardiac muscle because of the induction of peroxisome proliferator‐activated receptor‐gamma coactivator‐1α. Furthermore, the incidence of heart failure may increase when thiazolidinediones are combined with insulin, and moreover, they produce cyclooxygenase 2 inhibition, inducing a thrombotic response. Thus, patients are predisposed to adverse cardiovascular outcomes. In our opinion, the possible fatal consequences must be taken into account when peroxisome proliferator‐activated receptor‐gamma agonist drugs are considered as possible therapeutic agents for Friedreich's ataxia patients. © 2011 Movement Disorder Society