Tumor necrosis-like weak inducer of apoptosis as a proinflammatory cytokine in human adipocyte cells: up-regulation in severe obesity is mediated by inflammation but not hypoxia.

CONTEXT Adipose tissue hypoxia and endoplasmic reticulum (ER) stress may link the presence of chronic inflammation and macrophage infiltration in severely obese subjects. We previously reported the up-regulation of TNF-like weak inducer of apoptosis (TWEAK)/fibroblast growth factor-inducible 14 (Fn14) axis in adipose tissue of severely obese type 2 diabetic subjects. OBJECTIVES The objective of the study was to examine TWEAK and Fn14 adipose tissue expression in obesity, severe obesity, and type 2 diabetes in relation to hypoxia and ER stress. DESIGN In the obesity study, 19 lean, 28 overweight, and 15 obese nondiabetic subjects were studied. In the severe obesity study, 23 severely obese and 35 control subjects were studied. In the type 2 diabetes study, 11 type 2 diabetic and 36 control subjects were studied. The expression levels of the following genes were analyzed in paired samples of sc and visceral adipose tissue: Fn14, TWEAK, VISFATIN, HYOU1, FIAF, HIF-1a, VEGF, GLUT-1, GRP78, and XBP-1. The effect of hypoxia, inflammation, and ER stress on the expression of TWEAK and Fn14 was examined in human adipocyte and macrophage cell lines. RESULTS Up-regulation of TWEAK/Fn14 and hypoxia and ER stress surrogate gene expression was observed in sc and visceral adipose tissue only in our severely obese cohort. Hypoxia modulates TWEAK or Fn14 expression in neither adipocytes nor macrophages. On the contrary, inflammation up-regulated TWEAK in macrophages and Fn14 expression in adipocytes. Moreover, TWEAK had a proinflammatory effect in adipocytes mediated by the nuclear factor-kappaB and ERK but not JNK signaling pathways. CONCLUSIONS Our data suggest that TWEAK acts as a pro-inflammatory cytokine in the adipose tissue and that inflammation, but not hypoxia, may be behind its up-regulation in severe obesity.

Real-time molecular epidemiology of tuberculosis by direct genotyping of smear-positive clinical specimens.

We applied MIRU-VNTR (mycobacterial interspersed repetitive-unit-variable-number tandem-repeat typing) to directly analyze the bacilli present in 61 stain-positive specimens from tuberculosis patients. A complete MIRU type (24 loci) was obtained for all but one (no amplification in one locus) of the specimens (98.4%), and the allelic values fully correlated with those obtained from the corresponding cultures. Our study is the first to demonstrate that real-time genotyping of Mycobacterium tuberculosis can be achieved, fully transforming the way in which molecular epidemiology techniques can be integrated into control programs.

Tetania secundaria a raquitismo carencial.

Hypocalcemia is an uncommon illness in children. In developed countries the incidence of rickets has decreased significantly, although last years this pathology is increasing at the expense of immigration. Its etiology is due to different factors such as low sun exposure, inadequate clothing and bad feeding and excessive contributions in phytates, exclusive breastfeeding and genetic factors. We report a case of a teenager 13 year old from Pakistan, who consulted for myoclonus, paresthesias, hand midwife and asymmetry walking. The laboratory emphasizes hypocalcemia deficit of 25 (OH) D and increased parathyroid hormone. Administration of calcium and vitamin D along with changes in his diet normalized clinical and laboratory parameters. Due to increased migration, the lack of sun exposure and inadequate supply this disease which was almost forgotten will appear another time.

Insulin receptor substrate-1 expression is increased in circulating leukocytes of patients with acute coronary syndrome.

The mechanisms underlying the increased risk of cardiovascular disease associated with diabetes mellitus (DM) are not fully defined. Insulin resistance in human metabolic syndrome patients is associated with decreased expression of the insulin receptor substrate-2- (Irs2-) AKT2 axis in mononuclear leukocytes (MLs). Moreover, acute coronary syndrome (ACS) has been linked through genome-wide association studies to the 2q36-q37.3 locus, which contains the Irs1 gene. Here, we investigated the expression of insulin-signaling pathway genes in MLs from patients with DM, ACS, and ACS plus DM. Quantitative real-time PCR expression studies showed no differences in the mRNA levels of Irs2, Akt2, and Akt1 among all patients. However, Irs1 mRNA expression was significantly increased in patients with ACS-diabetics and nondiabetics-compared with diabetic patients without ACS (P < .02 and P < .005, resp.). The present study reveals for the first time an association between increased Irs1 mRNA levels in MLs of patients with ACS which is not related to DM.

Análisis de las principales variables determinantes de la evolución de la mortalidad por demencias en Andalucía.

BACKGROUND The dementias are a cause of mortality have increased over the last years. Therefore is important to analyze the variables more related to its development in Andalusia between 1999 and 2010. METHODS With the deaths of 60 and over by dementia from Andalusia Statistical Institute and the populations from corresponding years, are estimated crude mortality rates, standardized and age-specific; by joinpoint regression was calculated percentages annual change; and also, with the population estimates by marital status and deaths was calculated crude rates and standardized for age, sex and marital status. RESULTS The standardized mortality rates increased from 124.8 to 161.0 deaths per 100,000 in women and 110.3 to 147.7 in men, the annual increase was 4.2% and 3.8% in women and men. The women died more than men with a standardized rate ratio between 1.08 and 1.29. Age was the variable that determined mortality. CONCLUSIONS Mortality from dementia in Andalusia has increased over the past 12 years and will continue to increase with the consequent social and health impacts posed by these diseases, configured as a major health problem.

Sources of pre-analytical variations in yield of DNA extracted from blood samples: analysis of 50,000 DNA samples in EPIC.

The European Prospective Investigation into Cancer and nutrition (EPIC) is a long-term, multi-centric prospective study in Europe investigating the relationships between cancer and nutrition. This study has served as a basis for a number of Genome-Wide Association Studies (GWAS) and other types of genetic analyses. Over a period of 5 years, 52,256 EPIC DNA samples have been extracted using an automated DNA extraction platform. Here we have evaluated the pre-analytical factors affecting DNA yield, including anthropometric, epidemiological and technical factors such as center of subject recruitment, age, gender, body-mass index, disease case or control status, tobacco consumption, number of aliquots of buffy coat used for DNA extraction, extraction machine or procedure, DNA quantification method, degree of haemolysis and variations in the timing of sample processing. We show that the largest significant variations in DNA yield were observed with degree of haemolysis and with center of subject recruitment. Age, gender, body-mass index, cancer case or control status and tobacco consumption also significantly impacted DNA yield. Feedback from laboratories which have analyzed DNA with different SNP genotyping technologies demonstrate that the vast majority of samples (approximately 88%) performed adequately in different types of assays. To our knowledge this study is the largest to date to evaluate the sources of pre-analytical variations in DNA extracted from peripheral leucocytes. The results provide a strong evidence-based rationale for standardized recommendations on blood collection and processing protocols for large-scale genetic studies.

Cancer genes hypermethylated in human embryonic stem cells.

Developmental genes are silenced in embryonic stem cells by a bivalent histone-based chromatin mark. It has been proposed that this mark also confers a predisposition to aberrant DNA promoter hypermethylation of tumor suppressor genes (TSGs) in cancer. We report here that silencing of a significant proportion of these TSGs in human embryonic and adult stem cells is associated with promoter DNA hypermethylation. Our results indicate a role for DNA methylation in the control of gene expression in human stem cells and suggest that, for genes repressed by promoter hypermethylation in stem cells in vivo, the aberrant process in cancer could be understood as a defect in establishing an unmethylated promoter during differentiation, rather than as an anomalous process of de novo hypermethylation.

Mitochondrial haplogroups and polymorphisms reveal no association with sporadic prostate cancer in a southern European population.

BACKGROUND It is known that mitochondria play an important role in certain cancers (prostate, renal, breast, or colorectal) and coronary disease. These organelles play an essential role in apoptosis and the production of reactive oxygen species; in addition, mtDNA also reveals the history of populations and ancient human migration. All these events and variations in the mitochondrial genome are thought to cause some cancers, including prostate cancer, and also help us to group individuals into common origin groups. The aim of the present study is to analyze the different haplogroups and variations in the sequence in the mitochondrial genome of a southern European population consisting of subjects affected (n = 239) and non-affected (n = 150) by sporadic prostate cancer. METHODOLOGY AND PRINCIPAL FINDINGS Using primer extension analysis and DNA sequencing, we identified the nine major European haplogroups and CR polymorphisms. The frequencies of the haplogroups did not differ between patients and control cohorts, whereas the CR polymorphism T16356C was significantly higher in patients with PC compared to the controls (p = 0.029). PSA, staging, and Gleason score were associated with none of the nine major European haplogroups. The CR polymorphisms G16129A (p = 0.007) and T16224C (p = 0.022) were significantly associated with Gleason score, whereas T16311C (p = 0.046) was linked with T-stage. CONCLUSIONS AND SIGNIFICANCE Our results do not suggest that mtDNA haplogroups could be involved in sporadic prostate cancer etiology and pathogenesis as previous studies performed in middle Europe population. Although some significant associations have been obtained in studying CR polymorphisms, further studies should be performed to validate these results.

Prevalence of diabetes in a cancer population in a Malaga hospital.

BACKGROUND There are multiple risk factors for cancer, including obesity, sedentary lifestyle, diabetes (DM). Hormon Insulin is a growth factor that promotes cellular differentiation. AIMS The aim of our study is to observe impaired glycaemia in cancer population compared with control. METHODS We studied the prevalence of diabetes (DM) and impaired fasting glycaemia (IFG) in 374 patients with different types of cancer before treatment, by medical records in a Malaga hospital (Spain). We compared the prevalence of basal hyperglycaemia in these patients with general population, within an age range and by gender. RESULTS AND DISCUSSION The prevalence of diabetes was 32.35% in our cancer patients. The comparison depends of age range, and by gender prevalence was: 45-54 years, DM: 40.91% in men cases, versus (vs.) 14.5% in men control (p = 0.005). 55-64 years, IFG: 23.08% in women cases, vs. 5.9% in women control (p = 0.001). 65-74 years, DM: 47.13% in men cases, vs. 25.4% in men control (p = 0.000), and IFG: 23.81% in women cases, vs. 9.5% in women control (p = 0.019). We found a higher prevalence of diabetes in specific types of cancer such as prostate (p < 0.005). Moreover, men had a higher prevalence of diabetes or less diabetes control than women in our cancer sample. CONCLUSIONS We recommend an OGTT (oral glucose tolerance test) for better diagnosis of possible DM in patients with cancer, and an appropriate treatment. It may be an independent risk factor for cancer to have decreased insulin activity, or DM.

Metastasis of renal cell carcinoma to the buccal mucosa 19 years after radical nephrectomy

Renal cell carcinoma (RCC) has high metastatic potential, which requires early diagnosis to optimize the chance of cure. Metastasis of RCC to the head and neck region is less common and metastasis to the buccal mucosa is extremely rare. This phenomenon occurs mostly in patients with generalized dissemination, especially with lung metastases. In this article we report a case of buccal mucosa metastasis from RCC in a 65-year-old man who presented 19 years after undergoing a left radical nephrectomy for clear cell RCC. Surgical excision of the buccal lesion was performed without evidence of recurrence or new metastatic lesions after 6 years of followup. To our knowledge, this is the first case of metastasis to the buccal mucosa from a RCC reported in the literature.

Soft tissue extramedullary plasmacytoma.

We present the uncommon case of a subcutaneous fascia-based extramedullary plasmacytoma in the leg, which was confirmed by the pathology report and followed up until its remission. We report the differential diagnosis with other more common soft tissue masses. Imaging findings are nonspecific but are important to determine the tumour extension and to plan the biopsy.

Adherence to interferon β-1b treatment in patients with multiple sclerosis in Spain

BACKGROUND Adherence to interferon β-1b (INFβ-1b) therapy is essential to maximize the beneficial effects of treatment in multiple sclerosis (MS). For that reason, the main objectives of this study are to assess adherence to INFβ-1b in patients suffering from MS in Spain, and to identify the factors responsible for adherence in routine clinical practice. METHODOLOGY/PRINCIPAL FINDINGS This was an observational, retrospective, cross-sectional study including 120 Spanish patients with MS under INFβ-1b treatment. Therapeutic adherence was assessed with Morisky-Green test and with the percentage of doses received. The proportion of adherent patients assessed by Morisky-Green test was 68.3%, being indicative of poor adherence. Nevertheless, the percentage of doses received, which was based on the number of injected medication, was 94.3%. The main reason for missing INFβ-1b injections was forgetting some of the administrations (64%). Therefore, interventions that diminish forgetfulness might have a positive effect in the proportion of adherent patients and in the percentage of doses received. In addition, age and comorbidities had a significant effect in the number of doses injected per month, and should be considered in the management of adherence in MS patients. CONCLUSION/SIGNIFICANCE Among all the available methods for assessing adherence, the overall consumption of the intended dose has to be considered when addressing adherence.

Fomentar el diagnóstico precoz de la infección por VIH

Boletín semanal para profesionales sanitarios de la Secretaría General de Salud Pública, Inclusión y Calidad de Vida de la Consejería de Salud y Bienestar Social

Obesity-associated insulin resistance is correlated to adipose tissue vascular endothelial growth factors and metalloproteinase levels.

BACKGROUND The expansion of adipose tissue is linked to the development of its vasculature, which appears to have the potential to regulate the onset of obesity. However, at present, there are no studies highlighting the relationship between human adipose tissue angiogenesis and obesity-associated insulin resistance (IR). RESULTS Our aim was to analyze and compare angiogenic factor expression levels in both subcutaneous (SC) and omentum (OM) adipose tissues from morbidly obese patients (n = 26) with low (OB/L-IR) (healthy obese) and high (OB/H-IR) degrees of IR, and lean controls (n = 17). Another objective was to examine angiogenic factor correlations with obesity and IR.Here we found that VEGF-A was the isoform with higher expression in both OM and SC adipose tissues, and was up-regulated 3-fold, together with MMP9 in OB/L-IR as compared to leans. This up-regulation decreased by 23% in OB/-H-IR compared to OB/L-IR. On the contrary, VEGF-B, VEGF-C and VEGF-D, together with MMP15 was down-regulated in both OB/H-IR and OB/L-IR compared to lean patients. Moreover, MMP9 correlated positively and VEGF-C, VEGF-D and MMP15 correlated negatively with HOMA-IR, in both SC and OM. CONCLUSION We hereby propose that the alteration in MMP15, VEGF-B, VEGF-C and VEGF-D gene expression may be caused by one of the relevant adipose tissue processes related to the development of IR, and the up-regulation of VEGF-A in adipose tissue could have a relationship with the prevention of this pathology.

DRB1*03:01 haplotypes: differential contribution to multiple sclerosis risk and specific association with the presence of intrathecal IgM bands.

BACKGROUND Multiple sclerosis (MS) is a multifactorial disease with a genetic basis. The strongest associations with the disease lie in the Human Leukocyte Antigen (HLA) region. However, except for the DRB1*15:01 allele, the main risk factor associated to MS so far, no consistent effect has been described for any other variant. One example is HLA-DRB1*03:01, with a heterogeneous effect across populations and studies. We postulate that those discrepancies could be due to differences in the diverse haplotypes bearing that allele. Thus, we aimed at studying the association of DRB1*03:01 with MS susceptibility considering this allele globally and stratified by haplotypes. We also evaluated the association with the presence of oligoclonal IgM bands against myelin lipids (OCMB) in cerebrospinal fluid. METHODS Genotyping of HLA-B, -DRB1 and -DQA1 was performed in 1068 MS patients and 624 ethnically matched healthy controls. One hundred and thirty-nine MS patients were classified according to the presence (M+, 58 patients)/absence (M-, 81 patients) of OCMB. Comparisons between groups (MS patients vs. controls and M+ vs. M-) were performed with the chi-square test or the Fisher exact test. RESULTS Association of DRB1*03:01 with MS susceptibility was observed but with different haplotypic contribution, being the ancestral haplotype (AH) 18.2 the one causing the highest risk. Comparisons between M+, M- and controls showed that the AH 18.2 was affecting only M+ individuals, conferring a risk similar to that caused by DRB1*15:01. CONCLUSIONS The diverse DRB1*03:01-containing haplotypes contribute with different risk to MS susceptibility. The AH 18.2 causes the highest risk and affects only to individuals showing OCMB.