D-homoannulation of 17alpha,21-dihydroxy-20-keto steroids (corticosteroids)

Synthetic corticosteroids are widely used as anti-inflammatory agents. Mechanisms of their degradation continue to be studied. D-ring homoannulation is a well-known metabolic pathway for steroids in vivo. The rearrangement with aluminium trichloride of the commercial anti-inflammatory drugs hydrocortisone, cortisone and dexamethasone is here presented. The structures of the corresponding 17a-keto-17-hydroxy-D-homosteroids are established by mono- and two-dimensional NMR analysis. Inversion of the alpha-configuration of C-16 is observed in the Lewis acid assisted D-homoannulation of dexamethasone.     

DNA POLYMERASE ACTIVITY FROM THE BRAIN OF OCTOPUS VULGARIS LAM

Abstract— The DNA polymerase of the optic lobes of Octopus vulgaris Lam has been solubilized and some of its properties have been investigated. The enzyme catalyses the incorporation of [³H]thymidine triphosphate into a DNase-sensitive, acid-insoluble product in the presence of DNA, the four deoxynucleoside triphosphates and Mg²⁺. The pH optimum is between pH 9.2 and 9.6, the optimal concentration of Mg²⁺ is between 10 and 30 mM and the optimal temperature is in the range 27°-30°C. The content of enzyme per mg protein is highest in the vertical and optic lobes and lowest in the suboesophageal lobe.     

Challenging popular tools for the annotation of genetic variations with a real case,pathogenic mutations of lysosomal alpha-galactosidase

Background

Severity gradation of missense mutations is a big challenge for exome annotation. Predictors of deleteriousness that are most frequently used to filter variants found by next generation sequencing, produce qualitative predictions, but also numerical scores. It has never been tested if these scores correlate with disease severity.

Results

wANNOVAR, a popular tool that can generate several different types of deleteriousness-prediction scores, was tested on Fabry disease. This pathology, which is caused by a deficit of lysosomal alpha-galactosidase, has a very large genotypic and phenotypic spectrum and offers the possibility of associating a quantitative measure of the damage caused by mutations to the functioning of the enzyme in the cells. Some predictors, and in particular VEST3 and PolyPhen2 provide scores that correlate with the severity of lysosomal alpha-galactosidase mutations in a statistically significant way.

Conclusions

Sorting disease mutations by severity is possible and offers advantages over binary classification. Dataset for testing and training in silico predictors can be obtained by transient transfection and evaluation of residual activity of mutants in cell extracts. This approach consents to quantitative data for severe, mild and non pathological variants.

     

Unimlecular Depurination of Substituted Deoxyadenosines by Fast Atom Bombardment Mass Spectrometry/Mass Spectrometry

Abstract

The effect of benzoyl substitution on the unimolecular depurination of deoxyadenosine, in the gas-phase, has been evaluated. The glycosidic bond dissociation of the conjugated acids and bases of the isomeric species occurs remote fran the charge sites.     

Different entities of proximal spinal muscular atrophy within one family

 The molecular analysis of the survival motor neuron (SMN) gene and several closely flanking polymorphic markers in an atypical pedigree with four patients suffering from spinal muscular atrophy (SMA) over two generations has raised new aspects concerning the etiology and the molecular spectrum of autosomal recessive SMA. Three patients in two generations show homozygous deletions of exons 7 and 8 of the telomeric copy of SMN (telSMN), thus confirming the presence of autosomal recessive SMA, with localisation on chromosome 5q12. The fourth SMA patient with mild neurogenic atrophy (confirmed by muscle biopsy and electromyography) shows no homozygous deletion of telSMN but carries a heterozygous deletion of telSMN, as can be deduced from her two affected homozygously deleted children. No intragenic mutation has been identified in the remaining telSMN. In addition, she shares only one SMA chromosome with her affected brother, is haploidentical with two healthy brothers, and has a 31-year-old healthy son, who has inherited an SMN-deleted paternal chromosome and the SMN non-deleted maternal chromosome. These results suggest that this patient either has a neurogenic atrophy of a different origin or exhibits an unusual heterozygous manifestation of SMA 5q12. Interestingly, the two haploidentical telSMN-deleted affected sibs in the second generation show a strikingly discordant clinical picture indicating that, in addition to telSMN mutations, other factors influence the phenotype of SMA in the reported pedigree. Received: 20 March 1997 / Accepted: 4 June 1997     

Effect of stress and ACTH on dopamine metabolism in the nucleus accumbens and frontal cortex

The effect of ACTH and electric foot shock stress on DOPAC content were determined in the frontal cortex and nucleus accumbens. Twenty min of stress enhanced DOPAC levels in the frontal cortex and in the nucleus accumbens by about 80% and 35%, respectively. On the other hand, a single dose of ACTH failed to change DOPAC concentration in the above brain areas. The present results show that the activation of mesolimbic and mesocortical dopaminergic systems is not mediated by ACTH secretion.     

Remission in psoriatic arthritis: is it possible and how can it be predicted?

Introduction

Since remission is now possible in psoriatic arthritis (PsA) we wished to examine remission rates in PsA patients following anti tumour necrosis factor alpha (TNFα) therapy and to examine possible predictors of response.

Methods

Analysis of a prospective patient cohort attending a biologic clinic, between November 2004 and March 2008, was performed prior to commencing therapy and at regular intervals. Baseline clinical characteristics including demographics, previous disease-modifying antirheumatic drug (DMARD) response, tender and swollen joint counts, early morning stiffness, pain visual analogue score, patient global assessment, C reactive protein (CRP) and health assessment questionnaire (HAQ) were collected.

Results

A total of 473 patients (152 PsA; 321 rheumatoid arthritis (RA)) were analyzed. At 12 months remission, defined according to the disease activity score using 28 joint count and CRP (DAS28-CRP), was achieved in 58% of PsA patients compared to 44% of RA patients, significant improvement in outcome measures were noted in both groups (P < 0.05). Analysis of a subgroup of PsA and RA patients matched for DAS28-CRP at baseline also showed higher numbers of PsA patients achieving remission. Linear regression analysis identified the HAQ at baseline as the best predictor of remission in PsA patients (P < 0.001).

Conclusions

DAS28 remission is possible in PsA patients at one year following anti-TNF therapy, at higher rates than in RA patients and is predicted by baseline HAQ.