Tumor necrosis factor-alpha -308 promoter polymorphism contributes independently to HLA alleles in the severity of rheumatoid arthritis in Mexicans

The aim of this study was to determine the frequency and potential relevance of the promoter polymorphisms of the tumor necrosis factor-alpha (TNF-alpha) in the severity of rheumatoid arthritis (RA) in Mexicans. HLA-DR and polymorphisms at positions -238 and -308 of TNF-alpha gene were determined in 137 Mexican RA patients (44 with severe and 93 with non-severe RA) as well as in 169 healthy controls (99 were typed for HLA-DR). We observed an increased frequency of HLA-DR4 in severe RA compared to healthy controls (pC=0.02, OR=2.33). TNF polymorphism analysis showed a significant increased frequency of TNF -238 GG genotype in the whole group of RA patients when compared to healthy controls (pC=0.007, OR=4.71). When the analyses were carried out separately in severe and non-severe RA patients, the increased frequency of -238 GG genotype only was observed in patients with non-severe forms of the disease. Analysis of -308 polymorphism showed increased frequency of -308 T2 (A) allele in severe RA when compared to non-severe disease (pC=0.011, OR=3.29) and to healthy controls (pC=0.002, OR=3.97). The data demonstrate that -308 T2 (A) allele is associated with susceptibility to develop severe RA in Mexicans. This association could be independent from HLA-DR alleles and might be used as a prognostic marker for severe RA.     

Purification and properties of poly(ADP-ribose)polymerase from Crithidia fasciculata. Automodification and poly(ADP-ribosyl)ation of DNA topoisomerase I

Poly(ADP-ribose)polymerase has been purified more than 160000-fold from Crithidia fasciculata. This is the first PARP isolated to apparent homogeneity from trypanosomatids. The purified enzyme absolutely required DNA for catalytic activity and histones enhanced it 2.5-fold, when the DNA:histone ratio was 1:1.3. The enzyme required no magnesium or any other metal ion cofactor. The apparent molecular mass of 111 kDa, determined by gel filtration would correspond to a dimer of two identical 55-kDa subunits. Activity was inhibited by nicotinamide, 3-aminobenzamide, theophylline, thymidine, xanthine and hypoxanthine but not by adenosine. The enzyme was localized to the cell nucleus. Our findings suggest that covalent poly(ADP-ribosyl)ation of PARP itself or DNA topoisomerase I resulted in the inhibition of their activities and provide an initial biochemical characterization of this covalent post-translational modification in trypanosomatids.     

Resequencing and association analysis of arylalkylamine N‐acetyltransferase (AANAT) gene and its contribution to major depression susceptibility

Abstract: Circadian rhythms disruptions, including abnormalities of circadian phase position and melatonin secretion, have been described in major depression (MD). Arylalkylamine N‐acetyltransferase (AANAT) is a key enzyme of the melatonin pathway involved in circadian oscillations of melatonin levels. We assessed the contribution of AANAT gene variability to susceptibility to MD considering common and rare genetic variations through a sequential sequencing and single nucleotide polymorphism (SNP)‐based genotyping approach in a sample of 445 unrelated patients with MD (257 unipolar MD, 188 bipolar depression) and 440 community‐based screened control subjects. We identified 17 sequence changes, thirteen of which represented novel sequence variations. We did not observe an over‐representation of patients carrying rare variants compared with the healthy controls. Common variants (MAF > 2%) were included in a case–control association analysis that showed significant association after multiple testing correction of two SNPs located in the promoter region of AANAT with MD: rs3760138 (P = 0.00006) and rs4238989 (P = 0.005). Multimarker analysis found significant associations between two three‐marker protective haplotypes and a susceptibility three‐marker haplotype containing the rare alleles of rs3760138‐rs4238989‐rs8150 and MD. We present evidence of the association of genetic variability in the AANAT gene with susceptibility to MD. Our results support the hypothesis that the melatonin‐signaling pathway and circadian clock mechanisms may contribute to the pathophysiology of MD.     

Single-nucleotide polymorphisms in the lysyl oxidase-like protein 4 and complement component 3 genes are associated with increased risk for endometriosis and endometriosis-associated infertility

This study was conducted to assess genetic associations with endometriosis in a Puerto Rican population. Statistically significant differences in the allelic frequencies and genotype distribution of genetic variants in lysyl oxidase-like protein 4 (LOXL4) and complement component 3 (C3) were documented in patients with endometriosis-associated infertility versus controls, and in patients with endometriosis versus controls, respectively. In women who have the risk genotype at both single-nucleotide polymorphisms, the estimated risk for endometriosis nearly doubled.     

Renal dysfunction after chronic blockade of nitric oxide synthesis

The effects of the chronic inhibition of nitric oxide (NO) on renal hemodynamics and tubular function were studied in rats treated for 8 weeks with the NO synthesis inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME; 40 mg/kg/day). In addition, the effect of L-NAME administration on vasoactive systems (renin-angiotensin system, aldosterone, catecholamines, endothelin, and thromboxane A(2)) was evaluated. Chronic inhibition of NO significantly elevated blood pressure, reduced glomerular filtration rate and renal blood flow, blunted the pressure-diuresis-natriuresis response, and increased protein urine excretion. All these changes were associated with blunted nitrite production in response to acetylcholine in glomeruli. No changes were observed in the plasma levels of either renin activity, aldosterone, or endothelin in L-NAME-treated rats. Similarly, no differences were observed in the urinary excretion of thromboxane B(2) between both group of animals. By contrast, plasma concentrations of both epinephrine and norepinephrine were elevated in rats treated with L-NAME. In summary, the results show that chronic blockade of NO produced not only alterations in renal function, but also renal damage, suggesting an important renoprotective role of NO. An activation of sympathoadrenal system could participate in these renal alterations.     

Movimiento de alumnos ayudantes: experiencia de una institución cubana

The teaching-support student movement arose out of the necessity to cover the lack of teachers caused by the massive exodus of professionals at the beginning of the Cuban Revolution. Five decades later it is still alive and continuously perfects and adjusts itself according to the dynamic social requirements of the country. This article intends to describe the experience acquired at the University Hospital “Arnaldo Milián Castro” based on the work of teaching-support students in the period from 2011 to 2016, emphasising its achievements and challenges in the fulfilment of its main objectives in Cuban higher medical education such as: to support the development of the instructional and educational process, to address the professional orientation towards specialities deficient in professionals and to quickly acquire skills for teaching, research, and those related to specialities.