The central fibroblast growth factor receptor/beta klotho system: Comprehensive mapping in Mus musculus and comparisons to nonhuman primate and human samples using an automated in situ hybridization platform

Central activation of fibroblast growth factor (FGF) receptors regulates peripheral glucose homeostasis and reduces food intake in preclinical models of obesity and diabetes. The current work was undertaken to advance our understanding of the receptor expression, as sites of ligand action by FGF19, FGF21, and FGF1 in the mammalian brain remains unresolved. Recent advances in automated RNAscope in situ hybridization and droplet digital PCR (ddPCR) technology allowed us to interrogate central FGFR/beta klotho (Klb) system at the cellular level in the mouse, with relevant comparisons to nonhuman primate and human brain. FGFR1-3 gene expression was broadly distributed throughout the CNS in Mus musculus, with FGFR1 exhibiting the greatest heterogeneity. FGFR4 expression localized only in the medial habenula and subcommissural organ of mice. Likewise, Klb mRNA was restricted to the suprachiasmatic nucleus (SCh) and select midbrain and hindbrain nuclei. ddPCR in the rodent hypothalamus confirmed that, although expression levels are indeed low for Klb, there is nonetheless a bonafide subpopulation of Klb+ cells in the hypothalamus. In NHP and human midbrain and hindbrain, Klb + cells are quite rare, as is expression of FGFR4. Collectively, these data provide the most robust central map of the FGFR/Klb system to date and highlight central regions that may be of critical importance to assess central ligand effects with pharmacological dosing, such as the putative interactions between the endocrine FGFs and FGFR1/Klb, or FGF19 with FGFR4.     

Direction and magnitude of nicotine effects on the fMRI BOLD response are related to nicotine effects on behavioral performance

Considerable variability across individuals has been reported in both the behavioral and fMRI blood oxygen level-dependent (BOLD) response to nicotine. We aimed to investigate (1) whether there is a heterogeneous effect of nicotine on behavioral and BOLD responses across participants and (2) if heterogeneous BOLD responses are associated with behavioral performance measures. In this double-blind, placebo-controlled, cross-over study, 41 healthy participants (19 smokers)—drawn from a larger population-based sample—performed a visual oddball task after acute challenge with 1 mg nasal nicotine. fMRI data and reaction time were recorded during performance of the task. Across the entire group of subjects, we found increased activation in the anterior cingulate cortex, middle frontal gyrus, superior temporal gyrus, post-central gyrus, planum temporal and frontal pole in the nicotine condition compared with the placebo condition. However, follow-up analyses of this difference in activation between the placebo and nicotine conditions revealed that some participants showed an increase in activation while others showed a decrease in BOLD activation from the placebo to the nicotine condition. A reduction of BOLD activation from placebo to nicotine was associated with a decrease in reaction time and reaction time variability and vice versa, suggesting that it is the direction of BOLD response to nicotine which is related to task performance. We conclude that the BOLD response to nicotine is heterogeneous and that the direction of response to nicotine should be taken into account in future pharmaco-fMRI research on the central action of nicotine.     

Jakinibs: a new class of kinase inhibitors in cancer and autoimmune disease

Cytokines are critical for normal cell growth and immunoregulation but also contribute to growth of malignant cells and drive immune-mediated disease. A large subset of immunoregulatory cytokines uses the type I and type II cytokine receptors and pharmacological targeting of these cytokines/cytokines receptors has proven to be efficacious in treating immune and inflammatory diseases. These receptors rely on Janus family of kinases (Jaks) for signal transduction. Recently the first Jak inhibitor (jakinib) has been approved by the FDA and a second has been recommended for approval. Many other Jakinibs are likely to follow and in this brief review, we will discuss the state-of-the art of this new class of pharmacological agents.     

Reproducibility of hepatic fat fraction measurement by magnetic resonance imaging

Purpose:

To evaluate the reproducibility of magnetic resonance imaging (MRI)‐determined hepatic fat fraction (%) across imaging sites with different magnet types and field strength. Reproducibility among MRI platforms is unclear, even though evaluating hepatic fat fractions (FFs) using MRI‐based methods is accurate against MR spectroscopy.

Materials and Methods:

Overweight subjects were recruited to undergo eight MRI examinations at five imaging centers with a range of magnet manufacturers and field strengths (1.5 and 3 T). FFs were estimated in liver and in fat‐emulsion phantoms using three methods: 1) dual‐echo images without correction (nominally out‐of‐phase [OP] and in‐phase [IP]); 2) dual‐dual‐echo images (two sequences) with T2* correction (nominally OP/IP and IP/IP); and 3) six‐echo images with spectral model and T2* correction, at sequential alternating OP and IP echo times (Methods 1, 2, and 3, respectively).

Results:

Ten subjects were recruited. For Methods 1, 2, and 3, respectively, hepatic FF ranged from ?2.5 to 27.0, 1.9 to 29.6, and 1.3 to 34.4%. Intraclass correlation coefficients were 0.85, 0.89, and 0.91 for each method, and within‐subject coefficients of variation were 18.5, 9.9, and 10.3%, respectively. Mean phantom FFs derived by Methods 2 and 3 were comparable to the known FF for each phantom. Method 1 underestimated phantom FF.

Conclusion:

Methods 2 and 3 accurately assess FF. Strong reproducibility across magnet type and strength render them suitable for use in multicenter trials and longitudinal assessments. J. Magn. Reson. Imaging 2013;37:1359–1370. © 2012 Wiley Periodicals, Inc.

     

Patch testing in Iranian children with allergic contact dermatitis

Background

Allergic contact dermatitis is a common disorder in adults and children alike and appears to be on the increase. The purpose of this study was to determine the sensitization trends in Iranian children with contact dermatitis.

Methods

The result of 109 patch tests performed using the 24 allergens of the European Standard Series in patients below 18 years old from September 2007 to March 2009 were recorded and analyzed. The tests were evaluated at 48 and 72 h after performing.

Results

The study population consisted of 72 (66.1 %) females and 37 (33.9 %) males. Hands were the most commonly affected anatomic site. In the final evaluation of the tests on day three, 51 (46.8 %) individuals showed a positive reaction to at least one allergen. Females were significantly more likely to show a positive response to at least one allergen (p-value?=?0.031, odds ratio: 2.46). The most common allergens were nickel sulfate, cobalt, methylisothiazolinone, and colophony with 21 (19.3 %), 11 (10.1 %), 7 (6.4 %), and 6 (5.5 %) positive reactions, respectively. Contact allergy to nickel sulfate was more common in females than males (23.6 % vs. 10.8 %). There was no statistically significant relationship between personal or family history of atopy and a positive reaction to patch testing. The clinical and practical relevance were assessed for nickel and cobalt with a clinical current relevance in 11 (52.3 %) and 4 (36.4 %), respectively.

Conclusions

Nickel sulfate, cobalt, methylisothiazolinone, and colophony are the most common allergens responsible for induction of allergic contact dermatitis in Iranian children and adolescents. Females tended to show more positive reactions to allergens.

     

Velocity encoded cardiovascular magnetic resonance to assess left atrial appendage emptying

Background

The presence of impaired left atrial appendage (LAA) function identifies patients who are prone to thrombus formation in the LAA and therefore being at high risk for subsequent cardioembolic stroke. LAA function is typically assessed by measurements of LAA emptying velocities using transesophageal echocardiography (TEE) in clinical routine. This study aimed at evaluating the feasibility of assessing LAA emptying by velocity encoded (VENC) cardiovascular magnetic resonance (CMR).

Methods

This study included 30 patients with sinus rhythm (n = 18) or atrial fibrillation (n = 12). VENC-CMR velocity measurements were performed perpendicular to the orifice of the LAA. Peak velocities were measured of passive diastolic LAA emptying (e-wave) in all patients. Peak velocities of active, late-diastolic LAA emptying (a-wave) were assessed in patients with sinus rhythm. Correlation and agreement was analyzed between VENC-CMR and TEE measurements of e- and a-wave peak velocities.

Results

A significant correlation and good agreement was found between VENC-CMR and TEE measurements of maximal e-wave velocities (r = 0.61, P < 0.001; mean difference 0 ± 10 cm/s). The a-wave was detectable by VENC-CMR in all patients with sinus rhythm. Correlation was also significant for measurements of peak a-wave velocities between VENC-CMR and TEE (r = 0.71, P < 0.001). There was no significant correlation of LAA emptying velocities with clinical characteristics and only a modest negative correlation of passive LAA emptying with LA function.

Conclusions

The assessment of active and passive LAA emptying by VENC-CMR is feasible. Further evaluation is required of potential future clinical applications such as risk stratification for cardioembolic stroke.     

Tomonaga–Luttinger Spin Liquid and Kosterlitz–Thouless Transition in the Spin-1/2 Branched Chains: The Study of Topological Phase Transition

In the present work, we provide a comprehensive numerical investigation of the magnetic properties and phase spectra of three types of spin-1/2 branched chains consisting of one, two and three side spins per unit block with intra-chain interaction and a uniform inter-chain interaction in the presence of an external magnetic field. In a specific magnetic field interval, the low-temperature magnetization of these chains shows a step-like behavior with a pronounced plateau depending on the strength and the type of intra-chain interaction being ferromagnetic or antiferromagnetic. We demonstrate that when inter-chain interaction J1 is antiferromagnetic and intra-chain interaction J2 is ferromagnetic, the magnetization of the models manifests a smooth increase without a plateau, which is evidence of the existence of a Luttinger-like spin liquid phase before reaching its saturation value. On the other hand, when J1 is ferromagnetic and J2 is antiferromagnetic, the low-temperature magnetization of the chain with two branches shows an intermediate plateau at one-half of the saturation magnetization that breaks a quantum spin liquid phase into two regions. The magnetization of the chain with three branches exhibits two intermediate plateaus and two regions of a quantum spin liquid. We demonstrate that the chains with more than one side spin illustrate in their ground-state phase diagram a Kosterlitz–Thouless transition from a gapful phase to a gapless spin liquid phase.     

Pregnancy in the Sickle Cell Disease and Fetomaternal Outcomes in Different Sickle cell Genotypes: A Systematic Review and Meta-Analysis

BackgroundPregnancy is a major concern among women with the sickle cell disease (SCD), and it is associated with increased adverse outcomes. The aim of the present meta-analysis is to report the fetomaternal outcomes in different sickle cell genotypes.MethodsIn this systematic review and meta-analysis, a comprehensive search of databases and search engines such as PubMed, Scopus, Web of Science, ProQuest, Cochrane Library, Science Direct and Google Scholar were performed. Any observational studies that had compared at least one outcome such as maternal outcomes, fetal outcomes, and morbidity between two groups of pregnant women with different types of sickle cell genotypes and pregnant women without SCD were evaluated.ResultsA total number of 9,827 pregnant women with SCD were examined. The results showed that pregnancy in SCD increased the risk of adverse outcomes for the mothers (including postpartum hemorrhage, prematurity, pregnancy-induced hypertension, pre-eclampsia, eclampsia, cesarean section, lower segment cesareansection, maternal death), fetus (including live births, low birth weight, intrauterine growth restriction, APGAR score at 5 min <7, stillbirth, neonatal death, perinatal mortality, acute fetal distress, intrauterine fetal death) and morbidity among the SCD(severe anemia, urinary tract infection, blood transfusion, painful crisis, acute chest syndrome, vaso-occlusive crises).ConclusionAccording to the results of this meta-analysis, pregnancy in the SCD is associated with an increased risk of maternal outcomes, fetal outcomes, and morbidity among SCD patients with different genotypes. Pregnancy in sickle cell hemoglobinopathies needs careful multidisciplinary management and cautious caring so as to decrease maternal and fetal morbidity and mortality.