Gyrification,cortical and subcortical morphometry in neurofibromatosis type 1: an uneven profile of developmental abnormalities

Background

Neurofibromatosis type 1 (NF1) is a monogenic disorder associated with cognitive impairments. In order to understand how mutations in the NF1 gene impact brain structure it is essential to characterize in detail the brain structural abnormalities in patients with NF1. Previous studies have reported contradictory findings and have focused only on volumetric measurements. Here, we investigated the volumes of subcortical structures and the composite dimensions of the cortex through analysis of cortical volume, cortical thickness, cortical surface area and gyrification.

Methods

We studied 14 children with NF1 and 14 typically developing children matched for age, gender, IQ and right/left-handedness. Regional subcortical volumes and cortical gyral measurements were obtained using the FreeSurfer software. Between-group differences were evaluated while controlling for the increase in total intracranial volume observed in NF1.

Results

Subcortical analysis revealed disproportionately larger thalami, right caudate and middle corpus callosum in patients with NF1. Cortical analyses on volume, thickness and surface area were however not indicative of significant alterations in patients. Interestingly, patients with NF1 had significantly lower gyrification indices than typically developing children primarily in the frontal and temporal lobes, but also affecting the insula, cingulate cortex, parietal and occipital regions.

Conclusions

The neuroanatomic abnormalities observed were localized to specific brain regions, indicating that particular areas might constitute selective targets for NF1 gene mutations. Furthermore, the lower gyrification indices were accompanied by a disproportionate increase in brain size without the corresponding increase in folding in patients with NF1. Taken together these findings suggest that specific neurodevelopmental processes, such as gyrification, are more vulnerable to NF1 dysfunction than others. The identified changes in brain organization are consistent with the patterns of cognitive dysfunction in the NF1 phenotype.     

Parallel group ICA+ICA: Joint estimation of linked functional network variability and structural covariation with application to schizophrenia

There is growing evidence that rather than using a single brain imaging modality to study its association with physiological or symptomatic features, the field is paying more attention to fusion of multimodal information. However, most current multimodal fusion approaches that incorporate functional magnetic resonance imaging (fMRI) are restricted to second‐level 3D features, rather than the original 4D fMRI data. This trade‐off is that the valuable temporal information is not utilized during the fusion step. Here we are motivated to propose a novel approach called “parallel group ICA+ICA” that incorporates temporal fMRI information from group independent component analysis (GICA) into a parallel independent component analysis (ICA) framework, aiming to enable direct fusion of first‐level fMRI features with other modalities (e.g., structural MRI), which thus can detect linked functional network variability and structural covariations. Simulation results show that the proposed method yields accurate intermodality linkage detection regardless of whether it is strong or weak. When applied to real data, we identified one pair of significantly associated fMRI‐sMRI components that show group difference between schizophrenia and controls in both modalities, and this linkage can be replicated in an independent cohort. Finally, multiple cognitive domain scores can be predicted by the features identified in the linked component pair by our proposed method. We also show these multimodal brain features can predict multiple cognitive scores in an independent cohort. Overall, results demonstrate the ability of parallel GICA+ICA to estimate joint information from 4D and 3D data without discarding much of the available information up front, and the potential for using this approach to identify imaging biomarkers to study brain disorders.     

Effects of low-fat milk enriched with phytosterols on plasma cholesterol concentrations and hemorheological parameters of Wistar rats

Clinical and experimental studies have shown that the use of phytosterol esters as a food ingredient reduces the plasma concentrations of cholesterol and LDL cholesterol, not affecting the HDL cholesterol levels. Based on the use of phytosterols as a food ingredient, we have conducted a 30-day feeding study with Wistar rats, drinking low-fat milk containing phytosterols, in order to evaluate the plasma cholesterol concentrations and the hemorheological parameters. Throughout the study, clinical observations, body weights and food and milk consumption were measured and at the end of the feeding period, blood samples were collected for biochemical and hemorheological determinations. There were no clinical changes, alterations in growth, food or milk consumption. In the plasma cholesterol and HDL concentrations there were no significant differences, but LDL levels decreased about 70%. In the hemorheological parameters, significant changes were observed in plasma viscosity and in membrane fluidity in all experimental groups. The blood viscosity and the erythrocyte deformability show significant improvements with the ingestion of the phytosterols enriched milk. With these results we conclude that phytosterols maintain their cholesterol lowering properties when incorporated in milk and can be considered a hypolipemic food component.     

Sepsis of a prosthetic joint and biological therapies

SIR, We read with interest the article of Ledingham and Deighton[1] updating the guidelines for prescribing TNF- blockers inadults with rheumatoid arthritis. The guidelines establish thatthe sepsis of a prosthetic joint that remains in situ is animportant exclusion criterion for     

Vanadium-doped phosphomolybdic acids as catalysts for geraniol oxidation with hydrogen peroxide

In this work, vanadium-doped phosphomolybdic acids were evaluated as catalysts in green oxidation routes of terpene alcohols with hydrogen peroxide. A series of phosphomolybdic acids containing a variable load of vanadium cations (i.e., V⁵⁺ ions) were synthesized, and tested as catalysts in geraniol oxidation, the model molecule selected. All the catalysts were characterized by powder X-ray diffraction, attenuated diffuse reflectance infrared spectroscopy, UV-Vis spectroscopy, thermogravimetric analysis, N₂ adsorption–desorption isotherms, scanning electronic microscopy, X-ray dispersive spectroscopy, and n-butylamine potentiometric titration. Various catalysts were evaluated; phosphomolybdic acids with general formulae H_3+nPMo_12−nV_nO₄₀ (n = 0, 1, 2 and 3), and common Brønsted acids (i.e., H₂SO₄, H₃PO₄, and p-toluene sulfonic acid). Among them, vanadium monosubstituted phosphomolybdic acid was the most active catalyst and selective toward epoxide. The effect of main reaction variables, such as temperature, load catalyst, and reactant stoichiometry was assessed. Evaluating the effect of substrate, it was verified that only allylic alcohols such as geraniol and nerol were successfully epoxidized, demonstrating that this is a hydroxy group-assisted reaction. The effect of vanadium doping on the physicochemical properties of the phosphomolybdic acid catalysts was evaluated and used to explain their catalytic performance.

The vanadium-doped phosphomolybdic acid (H₄PMo₁₁VO₄₀) was the most active and selective heteropoly catalyst in one-pot oxidative esterification of benzaldehyde with hydrogen peroxide.     

Long non‐coding RNAs: biomarkers for acute leukaemia subtypes

Accurate diagnosis of rare inherited anaemias is challenging, requiring a series of complex and expensive laboratory tests. Targeted next‐generation‐sequencing (NGS) has been used to investigate these disorders, but the selection of genes on individual panels has been narrow and the validation strategies used have fallen short of the standards required for clinical use. Clinical‐grade validation of negative results requires the test to distinguish between lack of adequate sequencing reads at the locations of known mutations and a real absence of mutations. To achieve a clinically‐reliable diagnostic test and minimize false‐negative results we developed an open‐source tool (CoverMi) to accurately determine base‐coverage and the ‘discoverability’ of known mutations for every sample. We validated our 33‐gene panel using Sanger sequencing and microarray. Our panel demonstrated 100% specificity and 99·7% sensitivity. We then analysed 57 clinical samples: molecular diagnoses were made in 22/57 (38·6%), corresponding to 32 mutations of which 16 were new. In all cases, accurate molecular diagnosis had a positive impact on clinical management. Using a validated NGS‐based platform for routine molecular diagnosis of previously undiagnosed congenital anaemias is feasible in a clinical diagnostic setting, improves precise diagnosis and enhances management and counselling of the patient and their family.     

GBT440 increases haemoglobin oxygen affinity,reduces sickling and prolongs RBC half‐life in a murine model of sickle cell disease

A major driver of the pathophysiology of sickle cell disease (SCD) is polymerization of deoxygenated haemoglobin S (HbS), which leads to sickling and destruction of red blood cells (RBCs) and end‐organ damage. Pharmacologically increasing the proportion of oxygenated HbS in RBCs may inhibit polymerization, prevent sickling and provide long term disease modification. We report that GBT440, a small molecule which binds to the N‐terminal α chain of Hb, increases HbS affinity for oxygen, delays in vitro HbS polymerization and prevents sickling of RBCs. Moreover, in a murine model of SCD, GBT440 extends the half‐life of RBCs, reduces reticulocyte counts and prevents ex vivo RBC sickling. Importantly, oral dosing of GBT440 in animals demonstrates suitability for once daily dosing in humans and a highly selective partitioning into RBCs, which is a key therapeutic safety attribute. Thus, GBT440 has the potential for clinical use as a disease‐modifying agent in sickle cell patients.     

Comprehensive Evaluation of the Effects of Enalapril on Matrix Metalloproteinases Levels in Hypertension

Purpose

Angiotensin-converting enzyme inhibitors (ACEi) may downregulate matrix metalloproteinases (MMPs). We examined whether enalapril affects MMP-2, MMP-8, and MMP-9 levels and activity, and their endogenous inhibitors (tissue inhibitors of MMPs, TIMP-1 and TIMP-2) levels in hypertensive patients. Moreover, we assessed the effects of enalaprilat on MMP-9 and TIMP-1 secretion by human endothelial cells (HUVECs).

Methods

Thirty-eight hypertensive patients received enalapril for 8 weeks and were compared with thirty-eight normotensive controls. Blood samples were collected at baseline and after treatment. Plasma ACE activity was determined by a fluorimetric assay. Plasma MMP-2, MMP-8, MMP-9, TIMP-1, and TIMP-2 were measured by ELISA and gelatin zymography. A fluorogenic peptide cleavage assay was used to measure MMP activity. HUVECs cells were stimulated by phorbol-12-myristate-13-acetate (PMA) and the effects of enalaprilat (10^?10 to 10^?6?M) on MMP-9 and TIMP-1 levels were determined.

Results

Enalapril decreased blood pressure and ACE activity in hypertensive patients (P?<?0.05), but had no effects on plasma MMP-2, MMP-8, MMP-9, TIMP-1, and TIMP-2 levels, or MMP activity. Enalaprilat had no effects on PMA-induced increases in MMP-9 and TIMP-1 secretion by HUVECs or on MMP activity.

Conclusions

We show consistent evidence, both in vivo and in vitro, that enalapril does not affect MMPs and TIMPs levels in hypertensive patients.