Vitamin D deficiency in rheumatoid arthritis: prevalence,determinants and associations with disease activity and disability

Introduction  

The aim of this study was to estimate the prevalence and determinants of vitamin D deficiency in patients with rheumatoid arthritis (RA) as compared to healthy controls and to analyze the association between 25-hydroxyvitamin D (25(OH)D) with disease activity and disability.     

Identification of a novel pyrrole derivative endowed with antimycobacterial activity and protection index comparable to that of the current antitubercular drugs streptomycin and rifampin

A hit optimization procedure based on isosteric and bioisosteric replacement of decorating groups at both the N1 and the C5 phenyl rings of 1,5-diarylpyrroles led to identification of 4-((1-(4-fluorophenyl)-2-methyl-5-(4-(methylthio)phenyl)-1H-pyrrol-3-yl)methyl)thiomorpholine that is characterized by a very high activity toward both Mycobacterium tuberculosis 103471 and H37Rv strains (MIC values of 0.125μg/mL), and a safe profile in terms of cytotoxicity (CC(50) of >128μg/mL) and protection index (>1000). Antitubercular activity and protection index of the new compound are comparable to those found for the current antitubercular drugs streptomycin and rifampin.     

Che‐1‐induced inhibition of mTOR pathway enables stress‐induced autophagy

Mammalian target of rapamycin (mTOR) is a key protein kinase that regulates cell growth, metabolism, and autophagy to maintain cellular homeostasis. Its activity is inhibited by adverse conditions, including nutrient limitation, hypoxia, and DNA damage. In this study, we demonstrate that Che‐1, a RNA polymerase II‐binding protein activated by the DNA damage response, inhibits mTOR activity in response to stress conditions. We found that, under stress, Che‐1 induces the expression of two important mTOR inhibitors, Redd1 and Deptor, and that this activity is required for sustaining stress‐induced autophagy. Strikingly, Che‐1 expression correlates with the progression of multiple myeloma and is required for cell growth and survival, a malignancy characterized by high autophagy response.     

Stable phenotypic expression by chick chondroblasts in long-term suspension cultures as determined by proteoglycan analysis

The influence of cell shape on phenotypic expression was studied in chick vertebral chondroblasts maintained for several weeks in suspension culture. To monitor phenotypic expression, synthesis of proteoglycans was studied in cultures of freshly-isolated 1-day-old chondroblasts and 1-to-6-week-old chondroblasts. The rate of proteoglycan synthesis was virtually identical in 1-week or older chondroblasts; however, this rate was 3- to 5-fold higher than in 1-day-old cells. When compared to the latter cells, the various populations of older chondroblasts synthesized monomers of the major cartilage proteoglycan (KS: CS-PG) of slightly lower molecular size and a lower level of unsubstituted N-acetylgalactosamine residues on their core protein but with similar chondroitin sulfate chains and levels of O-linked oligosaccharides. At no time of culture were changes in the proportions of the major vs the minor cartilage proteoglycans detected. The results suggest that in contrast to epithelioid chondroblasts in standard monolayer cultures studied previously, the round floating chondroblasts express very stable biosynthetic properties for a prolonged time in suspension. The distinct biosynthetic properties of 1-day-old chondroblasts are discussed in terms of an initial, transitory response to the culture condition and in relation to regulatory mechanisms for proteoglycan elaboration.     

A metabolomics-based approach for non-invasive diagnosis of chromosomal anomalies

Introduction

Chromosomal anomalies (CA) are the most frequent fetal anomalies.

Objective

To evaluate the diagnostic performance of a machine learning ensemble model based on the maternal serum metabolomic fingerprint of fetal aneuploidies during the second trimester .

Methods

This is a case-control pilot study. Metabolomic profiles have been obtained on serum of 328 mothers (220 controls and 108 cases), using gas chromatography coupled to mass spectrometry. Eight machines learning and classification models were built and optimized. An ensemble model was built using a voting scheme. All samples were randomly divided into two sets. One was used as training set, the other one for diagnostic performance assessment.

Results

Ensemble machine learning model correctly classified all cases and controls. The accuracy was the same for trisomy 21 and 18; also, the other CA were correctly detected. Elaidic, stearic, linolenic, myristic, benzoic, citric and glyceric acid, mannose, 2-hydroxy butyrate, phenylalanine, proline, alanine and 3-methyl histidine were selected as the most relevant metabolites in class separation.

Conclusion

The proposed model, based on the maternal serum metabolomic fingerprint of fetal aneuploidies during the second trimester, correctly identifies all the cases of chromosomal abnormalities. Overall, this preliminary analysis appeared suggestive of a metabolic environment conductive to increased oxidative stress and a disturbance in the fetal central nervous system development. Maternal serum metabolomics can be a promising tool in the screening of chromosomal defects. Moreover, metabolomics allows to extend our knowledge about biochemical alterations caused by aneuploidies and responsible for the observed phenotypes.

     

Triazolopyridazine LRRK2 kinase inhibitors

Leucine-rich repeat kinase 2 (LRRK2) has been implicated in the pathogenesis of Parkinson’s disease (PD). Inhibition of LRRK2 kinase activity is a therapeutic approach that may lead to new treatments for PD. Herein we report the discovery of a series of [1,2,4]triazolo[4,3-b]pyridazines that are potent against both wild-type and mutant LRRK2 kinase activity in biochemical assays and show an unprecedented selectivity towards the G2019S mutant. A structural rational for the observed selectivity is proposed.     

Genetic differences in cystic fibrosis patients with and without pancreatic insufficiency

Summary To determine the number and frequency of mutations that occur at the cystic fibrosis locus (CF), we have examined the allele and haplotype frequencies of eight polymorphic DNA markers linked to CF in 163 Italian patients who were sub-divided according to their clinical presentations. The distribution of haplotypes for the tightly linked polymorphisms KM.19 and XV-2c differ significantly between patients with and those without pancreatic insufficiency. The haplotype found most commonly in CF chromosomes occurs much more frequently in pancreatic insufficient than in pancreatic sufficient patients. Among the 19 pancreatic sufficient patients, 6 (31.6%) show at least one copy of the rare KM.19 = 1, XV-2c = 2 haplotype, as against 16 of 138 patients (11.6%) with pancreatic insufficiency. In addition, only 5 pancreatic sufficient patients (26.3%) are homozygous for the common 2,1 haplotype, as compared with 88 patients (63.8%) with pancreatic insufficiency. These findings support the hypothesis of allelic heterogeneity at a single locus in CF and suggest that different mutations underlie the presence or absence of pancreatic insufficiency in this disorders.     

Improved function of rat islets upon co-microencapsulation with Sertoli's cells in alginate/poly-L-ornithine

The purpose of this study was to assess whether Sertoli's cells would improve functional performance of homologous pancreatic islets within microcapsules. Purified rat Sertoli's cells were co-enveloped with islets in microcapsules that had been fabricated with alginic acid and poly-L-ornithine. Confocal laser microscopy was used to determine any mitogenic effects of Sertoli's cells on islets beta-cells. Insulin secretion from islets, with or without Sertoli's cells, was examined, and grafts of Sertoli's cells with islets in microcapsules into diabetic mice were carried out. Co-incubation of Sertoli's cells with islets resulted in a significant increase in the islet beta-cell mitotic rate, which was coupled with significantly higher insulin release under glucose stimulation, as compared to controls. Grafts of co-microencapsulated Sertoli's cells with islets resulted in prolongation of the achieved normoglycemia in the animals receiving Sertoli's cells with islets as compared to controls that received islets only. Sertoli's cells do promote mitogenic activities upon in vitro co-incubation with islets, whose in vitro functional and in vivo post-transplant consequences were evident. Sertoli's cells could, therefore, be co-microencapsulated with islets for transplantation in diabetic recipients.     

Thermal broadening of the Soret band in heme complexes and in heme-proteins: role of iron dynamics

We report the thermal broadening of the Soret band in heme-CO, heme-OH and protoporphyrin IX in the temperature range 300–20 K. For protoporphyrin IX the temperature dependent Gaussian line broadening follows the behavior predicted by the harmonic approximation in the entire temperature range investigated. In contrast, for heme-CO and heme-OH the harmonic behavior is obeyed only up to about 180 K and an anomalous line broadening increase is observed at higher temperatures. This effect is attributed to the onset of anharmonic motions of the iron atom with respect to the porphyrin plane. Comparison with previously reported analogous data for heme proteins enables us to suggest that the onset of substate interconversions in these latter systems can be reflected in motions of the iron atom with respect to the porphyrin plane. Correspondence to: L. Cordone     

Volatile Constituents of the Aerial Parts of Pulicaria sicula (L.) Moris Growing Wild in Sicily: Chemotaxonomic Volatile Markers of the Genus Pulicaria Gaertn.

The chemical composition of the essential oil isolated from the aerial parts of Pulicaria sicula (L.) Moris was characterized by GC‐FID and GC/MS analyses. The oil was particularly rich in oxygenated terpenoids. Among the oxygenated monoterpenes (content of 44.5%), the most abundant were borneol (23.7%), bornyl acetate (6.5%), and isothymol isobutyrate (6.2%). Caryophyllene oxide (10.2%), caryophylladienol I (4.3%), and caryophylla‐3,8(13)‐dien‐5β‐ol (4.4%) were identified as the main constituents among the oxygenated sesquiterpenes. Furthermore, a complete literature review on the composition of the essential oils of all the Pulicaria taxa studied so far was performed and a principal component analysis (PCA) was carried out.