MTHFR, TS and XRCC1 genetic variants may affect survival in patients with myelodysplastic syndromes treated with supportive care or azacitidine.

We evaluated the impact of genomic polymorphisms in folate-metabolizing, DNA synthesis and DNA repair enzymes on the clinical outcome of 108 patients with myelodysplastic syndromes (MDS) receiving best supportive care (BSC) or azacitidine. A statistically significant association between methylenetetrahydrofolate reductase (MTHFR) 677T/T, thymidylate synthase (TS) 5'-untranslated region (UTR) 3RG, TS 3'-UTR -6 bp/-6 bp, XRCC1 399G/G genotypes and short survival was found in patients receiving BSC by multivariate analysis (P<0.001; P=0.026; P=0.058; P=0.024). MTHFR 677T/T, TS 3'-UTR -6 bp/-6 bp and XRCC1 399G/G genotypes were associated with short survival in patients receiving azacitidine by multivariate analysis (P<0.001; P=0.004; P=0.002). We then performed an exploratory analysis to evaluate the effect of the simultaneous presence of multiple adverse variant genotypes. Interestingly, patients with ⩾1 adverse genetic variants had a short survival, independently from their International Prognostic Scoring System (IPSS) and therapy received. To our knowledge, this is the first study showing that polymorphisms in folate-metabolizing pathway, DNA synthesis and DNA repair genes could influence survival of MDS patients.

Metagenomics analysis reveals universal signatures of the intestinal microbiota in colorectal cancer, regardless of regional differences.

The human gut microbiota is a complex and dynamic community of microorganisms living in our intestines and has emerged as an important factor for colorectal adenocarcinoma (CRC). The purpose of our study was to investigate the microbiota composition in Brazilian CRC patients compared with a local control population (CTL) to find out which changes could be considered universal or regional features in CRC microbiota. Fecal samples were obtained from 28 CRC and 23 CTL individuals. The 16S rRNA gene was used for metagenomic analysis. In addition to the anthropometric variables, the clinical stage (TNM 2018) was considered. Patients with CRC had a significant increase in alpha diversity and a higher percentage of genus Prevotella and a decreased proportion of Megamonas and Ruminococcus. Additionally, the proportion of Faecalibacterium prausnitzii was associated with a better prognosis in the first stages of CRC, and Fusobacterium nucleatum proved to be an important marker of colorectal carcinogenesis and tumor aggressiveness. Although regional differences influence the composition of the microbiota, in the case of CRC, the microhabitat created by the tumor seems to be a major factor. Our results contribute to a better understanding of the carcinogenic process, and even in different environments, some factors appear to be characteristic of the microbiota of patients with CRC.

Characterization of a recurrent translocation t(2;3)(p15-22;q26) occurring in acute myeloid leukaemia.

Six patients with de novo acute myeloid leukemia (AML) and a t(2;3)(p15-21;q26-27) were identified among approximately 1000 cases enrolled in the GIMEMA trial. The t(2;3) was the sole anomaly in three patients, whereas in three cases monosomy 7, trisomy 15 and 22, and trisomy 14 represented additional aberrations. No cryptic chromosome deletions at 5q, 7q, 12p, and 20q were observed. One patient carried a FLT3 D835 mutation; FLT3 internal tandem duplication (ITD) was not detected in three patients tested. Characterization of the translocation breakpoints using a 3q26 BAC contig specific for the PRDM3 locus showed that the breakpoints were located 5' to EVIl as follows: within myelodysplatic syndrome (MDS) intron 1 (# 3), between MDS1 exons 2 and 3 in three patients (# 1, 2, 4) with a 170bp cryptic deletion distal to the breakpoint in one (# 2), and in a more centromeric position spanning from intron 2 to the 5' region of EVI1 (# 6, 5). A set of 2p16-21 BAC probes showed that the breakpoints on chromosome 2p were located within BCL11A in two separate regions (# 1, 4 and # 2-5), within the thyroid adenoma-associated (THADA) gene (# 6) or distal to the ZFP36L2 locus (# 3). Regulatory elements were present in proximity of these breakpoints. RACE PCR studies revealed a chimeric transcript in 1/6 patient analyzed, but no fusion protein. Quantitative PCR showed a 21-58-fold over-expression of the EVIl gene in all cases analyzed. The patients showed dysplasia of at least two myeloid cell lineages in all cases; they had a low-to-normal platelet count and displayed an immature CD34+ CD117+ immunophenotype. Despite intensive chemotherapy and a median age of 43 years (range 36-59), only two patients attained a short-lived response; one patient is alive with active disease at 12 months, five died at 4-14 months. We arrived at the following conclusions: (a) the t(2;3) is a recurrent translocation having an approximate 0.5% incidence in adult AML; (b) breakpoints involve the 5' region of EVIl at 3q26, and the BCL11A, the THADA gene or other regions at 2p16.1-21; (c) cryptic deletions distal to the 3q26 breakpoint may occur in some cases; (d) the juxtaposition of the 5' region of EVIl with regulatory elements normally located on chromosome 2 brings about EVI1 overexpression; (e) clinical outcome in these cases is severe.

Metagenomics analysis reveals universal signatures of the intestinal microbiota in colorectal cancer, regardless of regional differences

The human gut microbiota is a complex and dynamic community of microorganisms living in our intestines and has emerged as an important factor for colorectal adenocarcinoma (CRC). The purpose of our study was to investigate the microbiota composition in Brazilian CRC patients compared with a local control population (CTL) to find out which changes could be considered universal or regional features in CRC microbiota. Fecal samples were obtained from 28 CRC and 23 CTL individuals. The 16S rRNA gene was used for metagenomic analysis. In addition to the anthropometric variables, the clinical stage (TNM 2018) was considered. Patients with CRC had a significant increase in alpha diversity and a higher percentage of genus Prevotella and a decreased proportion of Megamonas and Ruminococcus. Additionally, the proportion of Faecalibacterium prausnitzii was associated with a better prognosis in the first stages of CRC, and Fusobacterium nucleatum proved to be an important marker of colorectal carcinogenesis and tumor aggressiveness. Although regional differences influence the composition of the microbiota, in the case of CRC, the microhabitat created by the tumor seems to be a major factor. Our results contribute to a better understanding of the carcinogenic process, and even in different environments, some factors appear to be characteristic of the microbiota of patients with CRC.

Severe obstructive disease: similarities and differences between smoker and non-smoker patients with COPD and/or bronchiectasis.

INTRODUCTION: Poorly reversible airflow obstruction may or may not be related to smoking. OBJECTIVES: To describe patients with severe obstructive lung disease including etiology, imaging, functional aspects, systemic manifestations, and the pattern of bronchodilator response. METHODS: Sixty-eight patients (age 55.9±13.7 years, FEV(1) [forced expiratory volume in one second] 31.9±10.2% predicted) underwent spirometry, evaluation of body mass composition, 6-minute walk test, X-ray, thorax high-resolution CT scanning, and clinical evaluation. RESULTS: Of 68 patients enrolled, 37 had chronic obstructive pulmonary disease (COPD) and 31, extensive bronchiectasis. Among COPD patients the CT scans showed emphysema in 78.4%, and bronchiectasis in 48.6%. There were no significant differences between smokers and non-smokers, except for vital capacity, significantly smaller in non-smokers (p<0.001). We found 29 and 20 volume responders (VR) according to Paré et al. (FEV(1)/FVC>1=flow responder or <1=VR) and ATS/ERS criteria, respectively. According to Paré et al. criteria, there were 18 patients with FEV(1)<30% predicted among 29 VR, and 12 with FEV(1)<30% predicted among 39 without volume response (p=0.0101). CONCLUSIONS: In patients with severe obstruction, smoking does not appear to be relevant in determining functional or systemic differences, and Paré et al. criteria can detect more VR. Bronchiectasis is a common finding in severe COPD.

An interleukin-33/ST2 signaling deficiency reduces overt pain-like behaviors in mice.

Interleukin (IL)-33, the most recent member of the IL family of cytokines, signals through the ST2 receptor. IL-33/ST2 signaling mediates antigen challenge-induced mechanical hyperalgesia in the joints and cutaneous tissues of immunized mice. The present study asked whether IL-33/ST2 signaling is relevant to overt pain-like behaviors in mice. Acetic acid and phenyl-p-benzoquinone induced significant writhing responses in wild-type (WT) mice; this overt nociceptive behavior was reduced in ST2-deficient mice. In an antigen-challenge model, ST2-deficient immunized mice had reduced induced flinch and licking overt pain-like behaviors. In the formalin test, ST2-deficient mice also presented reduced flinch and licking responses, compared with WT mice. Naive WT and ST2-deficient mice presented similar responses in the rota-rod, hot plate, and electronic von Frey tests, indicating no impairment of motor function or alteration in basal nociceptive responses. The results demonstrate that IL-33/ST2 signaling is important in the development of overt pain-like behaviors.

Efeito da suplementação de óleo de cártamo sobre o peso corporal, perfil lipídico, glicídico e antioxidante de ratos wistar induzidos a obesidade / Effects of safflower oil supplementation on body weight, glucose and lipid profile and antioxidant capacity in rats with diet-induced obesity

O objetivo deste estudo foi avaliar o efeito da suplementação de óleo de cártamo sobre peso corporal, perfis lipídico e glicídico e capacidade da atividade antioxidante enzimática em ratos Wistar induzidos à obesidade por dieta hiperlipídica. Utilizaram-se 28 ratos adultos, machos, distribuídos em quatro grupos experimentais: Grupo Controle e dieta normolipídica (GCN); Grupo controle e dieta hiperlipídica (GCH); Grupo Óleo de cártamo e dieta normolipídica (GNOC) e Grupo Óleo de cártamo e dieta hiperlipídica (GHOC). Durante 30 dias, observaram-se consumo alimentar e peso corporal e, ao final do experimento, glicemia, perfil lipídico, formação de Substâncias Reativas ao Ácido Tiobarbitúrico (TBARS) e atividade das enzimas antioxidantes: Catalase (CAT), Glutationa Peroxidase (GHS-Px) e Superóxido dismutase (SOD). Os resultados demonstraram que o consumo alimentar foi menor nos grupos tratados com óleo de cártamo e a média do peso corporal foi inferior no GNOC e superior no GCH. Houve aumento das concentrações de Lipoproteína de Alta Densidade (HDL-colesterol) no GNOC. Os grupos GCH e GHOC demonstraram médias de TBARS superiores a dos grupos GCN e GNOC. O GCH apresentou menor GSH-Px e o GHOC, menor atividadede CAT quando comparado aos grupos GCN e GNOC. Concluiu-se que a suplementação com óleo de cártamo reduziu consumo alimentar e o ganho de peso corporal dos animais aumentou o HDL-colesterol no grupo com dieta normolipídica, mas não foi capaz de prevenir o aumento da peroxidação lipídica induzida pela dieta hiperlipídica, embora tenha evitado a redução da atividade antioxidante enzimática representada pela GHS-Px...

The aim of this study was to assess the effects of safflower oil supplementation on body weight, glucose and lipid profiles and the antioxidant enzyme activities in Wistar rats with high-fat diet-induced obesity. The 28 adult male rats were divided into four groups: Control Group fed on Standard (low-fat) Diet (GCN); Control Group fed on High-fat Diet (GCH); Safflower Oil Group with Standard Diet (GNOC) and Safflower Oil Group with High-fat Diet (GHOC). Food intake and body weight were monitored for 30 days. At the end of the experiment, blood was collected for assays of blood glucose, lipid profile, formation of thiobarbituric acid reactive substances (TBARS) and antioxidant enzyme activities: viz. catalase (CAT), glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD). The results showed that food intake was lower in the groups treated with safflower oil and that the average body weight was lower in GNOC and higher in GCH. There were increased concentrations of high-density lipoprotein (HDL cholesterol) in GNOC. Both high-fat groups (GCH and GHOC) showed higher average TBARS than GCN and GNOC. GCH showed lower GSH-Px activity and GHOC showed lower CAT activity than GCN and GNOC. It was concluded that supplementation with safflower oil reduced the food intake and body weight of the animals, and increased the HDL-cholesterol in the normal diet group, but did not prevent the increase in lipid peroxidation induced by the high-fat diet, despite having prevented the reduction of the antioxidant enzyme activity of GSH-Px...

An interleukin-33/ST2 signaling deficiency reduces overt pain-like behaviors in mice

Interleukin (IL)-33, the most recent member of the IL family of cytokines, signals through the ST2 receptor. IL-33/ST2 signaling mediates antigen challenge-induced mechanical hyperalgesia in the joints and cutaneous tissues of immunized mice. The present study asked whether IL-33/ST2 signaling is relevant to overt pain-like behaviors in mice. Acetic acid and phenyl-p-benzoquinone induced significant writhing responses in wild-type (WT) mice; this overt nociceptive behavior was reduced in ST2-deficient mice. In an antigen-challenge model, ST2-deficient immunized mice had reduced induced flinch and licking overt pain-like behaviors. In the formalin test, ST2-deficient mice also presented reduced flinch and licking responses, compared with WT mice. Naive WT and ST2-deficient mice presented similar responses in the rota-rod, hot plate, and electronic von Frey tests, indicating no impairment of motor function or alteration in basal nociceptive responses. The results demonstrate that IL-33/ST2 signaling is important in the development of overt pain-like behaviors.

Efeitos do extrato de Ginkgo biloba (EGb 761) e da natação repetida sobre a memória, ansiedade e atividade motora de ratos / Effects of Ginkgo biloba extract (EGb 761) and repeated swimming on memory, anxiety and motor activity of rat

O extrato de Ginkgo biloba (EGb 761) e exercícios físicos isoladamente são capazes de modificar as funções cognitivas e aliviar os sintomas de ansiedade. Contudo, estes tratamentos em conjunto devem ser caracterizados. Em nossa pesquisa, verificamos que a administração oral repetida do extrato (40 ou 80 mg/kg/dia) e o exercício de natação ao qual os ratos eram submetidos causaram aumento de entradas destes animais nos braços fechados do labirinto em cruz elevado e diminuição da imobilidade dos mesmos no campo aberto, sugerindo um aumento de suas atividades motoras. Além disso, o exercício de natação aumentou a exploração no campo aberto e o tratamento com EGb 761 cancelou este efeito, sugerindo a interação entre EGb 761 e exercício de natação, provavelmente com um mesmo substrato neurobiológico capaz de minimizar a atividade exploratória em ratos nadadores. Análises comportamentais sobre o teste de reconhecimento de objetos mostraram que, quando submetidos a exercício de natação e/ou tratamento com EGb 761 durante testes de 24 horas, os ratos nadadores levaram mais tempo explorando os novos objetos do que os familiares. Estes resultados mostram que o EGb 761 e os exercícios, ambos isolados ou em conjunto, têm um poderoso efeito sobre a memória de longo-prazo. Entretanto, o proposto efeito ansiolítico do EGb 761 e de exercícios de natação pode ser questionado.

Either ingestion of a Ginkgo biloba proprietary extract (EGb 761) or physical exercise can enhance cognitive functioning and alleviate symptoms of anxiety; however, their combined effects have yet to be characterized. Rats subjected to repeated oral administration of the extract (40 or 80 mg/kg/day) and swimming exercise exhibited an increased number of closed-arm entries in the elevated plus-maze and decreased immobility in the open , suggesting an increase in motor activity. In addition, the exercise of swimming increased the exploration of the open and chronic treatment with EGb 761 could cancel this effect; this indicates interaction between EGb 761 and swimming exercise, which may show a common neurobiological substrate, capable of reducing exploratory activity in swimming rats. Analysis of behavior in the object-recognition test showed that rats subjected to swimming exercise and/or treatment with EGb 761, during tests of 24 hours, spent more time exploring novel objects than familiar ones. These results show that EGb 761 and/or physical exercise have powerful effects on long-term memory. However, the proposed anxiolytic characteristics of EGb 76 and swimming exercise may be questioned.

The use of methadone as a treatment tool for opiate addicts: A two-year follow-up study.

Eighty-three per cent of a sample of 116 drug addicts in a Sydney methadone treatment programme were successfully followed up. Methadone was not found to be "the quick cure" for opiate addiction. More than two-thirds were still taking methadone, only 3% had not taken any opiates for six months or longer, and a further 5% had not taken any opiates for less than six months. The remainder (22%) were using illegal opiates either regularly or intermittently, or were in gaol. However, from the employment, crime and social-emotional stability data, it may be concluded that the methadone programme, particularly if adhered to continuously, is "successful". These findings generally support the findings of overseas studies. The clients, especially those who were still adhering to the programme, felt that methadone was helpful, although there was concern about still being drug-dependent and about side effects.

Sibutramine enhances insulin sensitivity ameliorating metabolic parameters in a double-blind, randomized, placebo-controlled trial.

AIM: To assess the effect of sibutramine-assisted weight reduction program on insulin sensitivity and metabolic parameters in obese normal glucose tolerant individuals over a period of 24 weeks. RESEARCH DESIGN AND METHODS: A double-blind, placebo-controlled, parallel, prospective clinical trial was carried out at our medical centre. Forty female normal glucose tolerant patients, body mass index: 34.3 +/- 2.9 kg/m2 and age: 41.1 +/- 9.9 (range: 19-58 years), were randomized to placebo or sibutramine, 10 mg once daily. RESULTS: Seventeen patients from sibutramine group and 14 placebo had completed the study protocol. Significant weight change was seen in sibutramine (p < 0.01) (-5.6 kg or -6.1% vs. +0.9 kg or +1.1% in placebo). Insulin sensitivity enhanced in sibutramine group (Kitt: from 4.03 +/- 1.97 to 5.09 +/- 2.48%/min; p < 0.05). Homeostasis model assessment-IR (HOMA-IR) decreased from 7.8 +/- 6.9 to 5.6 +/- 4.5 (p < 0.05). HOMA-beta also decreased from 508 +/- 381 to 374 +/- 256 (p < 0.05). No changes were observed in the placebo control group regarding insulin sensitivity or secretion. Concomitant reductions were observed in the sibutramine group in lipid parameters (triglycerides and high-density lipoprotein-cholesterol), uric acid and gamma-glutamyl transferase (p < 0.05). CONCLUSIONS: Sibutramine has demonstrated efficacy in reducing weight in non-diabetic women along with amelioration in insulin sensitivity and additional improvement in metabolic parameters.