Methylation alterations are not a major cause of PTTG1 misregulation.

BACKGROUND On its physiological cellular context, PTTG1 controls sister chromatid segregation during mitosis. Within its crosstalk to the cellular arrest machinery, relies a checkpoint of integrity for which gained the over name of securin. PTTG1 was found to promote malignant transformation in 3T3 fibroblasts, and further found to be overexpressed in different tumor types. More recently, PTTG1 has been also related to different processes such as DNA repair and found to trans-activate different cellular pathways involving c-myc, bax or p53, among others. PTTG1 over-expression has been correlated to a worse prognosis in thyroid, lung, colorectal cancer patients, and it can not be excluded that this effect may also occur in other tumor types. Despite the clinical relevance and the increasing molecular characterization of PTTG1, the reason for its up-regulation remains unclear. METHOD We analysed PTTG1 differential expression in PC-3, DU-145 and LNCaP tumor cell lines, cultured in the presence of the methyl-transferase inhibitor 5-Aza-2'-deoxycytidine. We also tested whether the CpG island mapping PTTG1 proximal promoter evidenced a differential methylation pattern in differentiated thyroid cancer biopsies concordant to their PTTG1 immunohistochemistry status. Finally, we performed whole-genome LOH studies using Affymetix 50 K microarray technology and FRET analysis to search for allelic imbalances comprising the PTTG1 locus. CONCLUSION Our data suggest that neither methylation alterations nor LOH are involved in PTTG1 over-expression. These data, together with those previously reported, point towards a post-transcriptional level of misregulation associated to PTTG1 over-expression.

Thickening of the skin on the forehead: a quiz. Acanthosis nigricans with forehead location.

Publicado en la Sección Quiz de la revista.

Breast cancer prognostic classification in the molecular era: the role of histological grade.

Breast cancer is a heterogeneous disease with varied morphological appearances, molecular features, behavior, and response to therapy. Current routine clinical management of breast cancer relies on the availability of robust clinical and pathological prognostic and predictive factors to support clinical and patient decision making in which potentially suitable treatment options are increasingly available. One of the best-established prognostic factors in breast cancer is histological grade, which represents the morphological assessment of tumor biological characteristics and has been shown to be able to generate important information related to the clinical behavior of breast cancers. Genome-wide microarray-based expression profiling studies have unraveled several characteristics of breast cancer biology and have provided further evidence that the biological features captured by histological grade are important in determining tumor behavior. Also, expression profiling studies have generated clinically useful data that have significantly improved our understanding of the biology of breast cancer, and these studies are undergoing evaluation as improved prognostic and predictive tools in clinical practice. Clinical acceptance of these molecular assays will require them to be more than expensive surrogates of established traditional factors such as histological grade. It is essential that they provide additional prognostic or predictive information above and beyond that offered by current parameters. Here, we present an analysis of the validity of histological grade as a prognostic factor and a consensus view on the significance of histological grade and its role in breast cancer classification and staging systems in this era of emerging clinical use of molecular classifiers.

A novel study of copy number variations in Hirschsprung disease using the multiple ligation-dependent probe amplification (MLPA) technique.

BACKGROUND Hirschsprung disease (HSCR) is a congenital malformation of the hindgut produced by a disruption in neural crest cell migration during embryonic development. HSCR has a complex genetic etiology and mutations in several genes, mainly the RET proto-oncogene, have been related to the disease. There is a clear predominance of missense/nonsense mutations in these genes whereas copy number variations (CNVs) have been seldom described, probably due to the limitations of conventional techniques usually employed for mutational analysis. METHODS In this study we have aimed to analyze the presence of CNVs in some HSCR genes (RET, EDN3, GDNF and ZFHX1B) using the Multiple Ligation-dependent Probe Amplification (MLPA) approach. RESULTS Two alterations in the MLPA profiles of RET and EDN3 were detected, but a detailed inspection showed that the decrease in the corresponding dosages were due to point mutations affecting the hybridization probes regions. CONCLUSION Our results indicate that CNVs of the gene coding regions analyzed here are not a common molecular cause of Hirschsprung disease. However, further studies are required to determine the presence of CNVs affecting non-coding regulatory regions, as well as other candidate genes.

Influence of a fat overload on lipogenic regulators in metabolic syndrome patients

Several epidemiological studies have related an increase of lipids in the postprandial state to an individual risk for the development of CVD, possibly due to the increased plasma levels of TAG and fatty acids (FA) through enzymes of FA metabolism. The interaction between nutrition and the human genome determines gene expression and metabolic response. The aim of the present study was to evaluate the influence of a fat overload on the gene mRNA levels of lipogenic regulators in peripheral blood mononuclear cells (PBMC) from patients with the metabolic syndrome. The study included twenty-one patients with criteria for the metabolic syndrome who underwent a fat overload. Measurements were made before and after the fat overload of anthropometric and biochemical variables and also the gene mRNA levels of lipogenic factors. The main results were that the fat overload led to an increased mRNA levels of sterol regulatory element binding protein-1 (SREBP1), retinoid X receptor α (RXRα) and liver X receptor α (LXRα) in PBMC, and this increase was associated with the FA synthase (FASN) mRNA levels. We also found that TAG levels correlated with FASN mRNA levels. In addition, there was a positive correlation of SREBP1 with RXRα and of LXRα with the plasma lipoperoxide concentration. The fat overload led to an increase in regulators of lipogenesis in PBMC from patients with the metabolic syndrome.

Decreased STAMP2 expression in association with visceral adipose tissue dysfunction.

CONTEXT Six-transmembrane protein of prostate 2 (STAMP2) is a counter-regulator of inflammation and insulin resistance according to findings in mice. However, there have been contradictory reports in humans. OBJECTIVE We aimed to explore STAMP2 in association with inflammatory and metabolic status of human obesity. DESIGN, PATIENTS, AND METHODS STAMP2 gene expression was analyzed in adipose tissue samples (171 visceral and 67 sc depots) and during human preadipocyte differentiation. Human adipocytes were treated with macrophage-conditioned medium, TNF-α, and rosiglitazone. RESULTS In visceral adipose tissue, STAMP2 gene expression was significantly decreased in obese subjects, mainly in obese subjects with type 2 diabetes. STAMP2 gene expression and protein were significantly and inversely associated with obesity phenotype measures (body mass index, waist, hip, and fat mass) and obesity-associated metabolic disturbances (systolic blood pressure and fasting glucose). In addition, STAMP2 gene expression was positively associated with lipogenic (FASN, ACC1, SREBP1, THRSP14, TRα, and TRα1), CAV1, IRS1, GLUT4, and CD206 gene expression. In sc adipose tissue, STAMP2 gene expression was not associated with metabolic parameters. In both fat depots, STAMP2 gene expression in stromovascular cells was significantly higher than in mature adipocytes. STAMP2 gene expression was significantly increased during the differentiation process in parallel to adipogenic genes, being increased in preadipocytes derived from lean subjects. Macrophage-conditioned medium (25%) and TNF-α (100 ng/ml) administration increased whereas rosiglitazone (2 μM) decreased significantly STAMP2 gene expression in human differentiated adipocytes. CONCLUSIONS Decreased STAMP2 expression (mRNA and protein) might reflect visceral adipose dysfunction in subjects with obesity and type 2 diabetes.

Increased soluble Fas plasma levels in subjects at high cardiovascular risk - Atorvastatin on inflammatory markers (AIM) study, a substudy of ACTFAST

OBJECTIVE Increasing evidence indicates that the Fas/Fas ligand interaction is involved in atherogenesis. We sought to analyze soluble Fas (sFas) and soluble Fas ligand (sFasL) concentrations in subjects at high cardiovascular risk and their modulation by atorvastatin treatment. METHODS AND RESULTS ACTFAST was a 12-week, prospective, multicenter, open-label trial which enrolled subjects (statin-free or statin-treated at baseline) with coronary heart disease (CHD), CHD-equivalent, or 10-year CHD risk > 20%. Subjects with LDL-C between 100 to 220 mg/dL (2.6 to 5.7 mmol/L) and triglycerides < or = 600 mg/dL (6.8 mmol/L) were assigned to a starting dose of atorvastatin (10 to 80 mg/d) based on LDL-C at screening. Of the 2117 subjects enrolled in ACTFAST, AIM sub-study included the 1078 statin-free patients. At study end, 85% of these subjects reached LDL-C target. Mean sFas levels were increased and sFasL were reduced in subjects at high cardiovascular risk compared with healthy subjects. Atorvastatin reduced sFas in the whole population as well as in patients with metabolic syndrome or diabetes. Minimal changes were observed in sFasL. CONCLUSIONS sFas concentrations are increased and sFasL are decreased in subjects at high cardiovascular risk, suggesting that these proteins may be novel markers of vascular injury. Atorvastatin reduces sFas, indicating that short-term treatment with atorvastatin exhibits antiinflammatory effects in these subjects.

Retroperitoneoscopy to extract dropped gallstones after laparoscopic cholecystectomy

Complications resulting from gallstones left in the peritoneal cavity are most often reported after laparoscopic treatment of cholelitiasis. Gallstones are frequently dropped in the posterior subhepatic space, which can lead to the development of abscesses that usually require laparotomy for extraction of the stones. We present a novel technique for treating collections associated with dropped gallstones, using retroperitoneoscopy with two 10-mm ports after ultrasound localization of the abscess. We carried out this procedure in two patients and successfully extracted the gallstones without postoperative complications or recurrences. We consider this approach to be technically feasible, safe, and effective. It avoids the usual inefficacy of simple percutaneous drainage of these collections and the complications associated with the drainage of intra-abdominal abscesses by laparotomy.

Evolución de parámetros bioquímicos nutricionales en pacientes de hemodiálisis durante un año de seguimiento

Current high survival in hemodialysis patients (52% at 5 years) have made the chronic manifestations to emerge such as the high hyponutrition prevalence of these patients, as well as the importance of the nutritional status in their morbimortality. The reason for protein-caloric hyponutrition is multifactorial, although chronic inflammatory conditions associated to the dialysis technique are becoming more and more relevant. The variations in several nutritional biochemical parameters (total proteins, plasma albumin, transferrin, and total cholesterol) have been assessed in 73 hemodialysis patients for one year. The mean age of the patients was 53.3 +/- 18.69 years (43 males and 30 females). The average on hemodialysis program was 43 +/- 33 months, with a mean session duration of 246 +/- 24 minutes, and mean hemodialysis dose administered of 1.37 +/- 0.27 (KT/V) (second generation Daurgidas). A decrease in all the biochemical parameters assessed has been observed, with statistically significant differences: total proteins (p < 0.001), albumin (p < 0.00001), total cholesterol (p < 0.05), and transferrin (p < 0.01). The evolution of the nutritional biochemical parameters assessed showed an important nutritional deterioration of the patients remaining stable with the therapy.

Balón intragástrico en el tratamiento de la obesidad

Obesity is considered a chronic and epidemic illness, hece difficult to treat. As conservative treatment has a high rate of failure, and considering morbimortality and sequels of surgery, less invasive techniques appeared to contribute to the treatment of this illness. The most implanted technique nowadays is the Intragastric Balloon, considered more efficient as conservative treatments and with less risks tan surgery, but having today a lack of consensus on indications and few information on his limitations, while its apparition in medias promote an important expansion in the 4 last years. In this publication, we do a critical revision, and describe limitations of this treatment, based on the evidences given by literature. We conclude this revision with some recommendations concerning the technique and indications, material and human requiring, need of a Multidisciplinary Team, as well as an adequate control and following.

Standardisation of the waist circumference (WC) for each range of body mass index (BMI) in adult outpatients attended to in Endocrinology and Nutrition departments

By this study we seek the expectable range of waist circumference (WC) for every degree of body mass index (BMI), which will serve to studies targeting ascertaining the health risk. We studied 2,932 patients (39.6% men and 60.4% women, between 18 and 96 years ) of the same ethnic group who consecutively attended outpatient departments of our clinics between 2000 and 2004. BMI correlated linearly with the WC (cc: 0.85; p < 0.001). The men, the obese, and diabetics were older (p < 0.001). BMI was greater in women and WC in men. The women had a greater WC if they had diabetes (p < 0.01), being equal to diabetic males. The men had greater WC when they had diabetes (p < 0.001). Waist at risk was detected (men > or = 102 cm and women > or = 88 cm) in 94.3% of the obese, in 32.3% of overweight patients, in 3.8% of patients with BMI < 25, in 84.3% of diabetics, and in 72.6% of patients without diabetes. We made graphic standardisation of WC with regard to BMI, and we calculated the percentiles 10, 25, 50, 75 and 90, grouping in ranges of 2 kg/m(2) of BMI. The diabetic patients are grouped in ranges of 4 kg/m(2). As conclusion we present a standardisation of the WC measurement of patients attended to in our Endocrinology and Nutrition practices distributed in percentiles as a clinically usable tool to define the ranges of WC for every BMI value.

Vitaminas B y homocisteína en la insuficiencia renal crónica

Metabolic, biochemical, and hormonal changes occur in chronic renal failure usually associated with hyponutrition states. In predialysis patients, knowing the nutritional state about water-soluble vitamins such as thiamine, riboflavin, pyridoxine, cianocobalamine, and folic acid is becoming more and more important since some of the manifestations of chronic renal failure may be due to the deficiency of some of these water-soluble vitamins. The metabolic pathways in which most of these vitamins participate are interrelated and it is difficult to understand how the individual deficits of each vitamin affect renal pathology. This work aims at reviewing not only this issue but also the status of these water-soluble vitamins that different authors have found in groups of predialysis patients. On the other hand, the issue on the high prevalence of hyperhomocysteinemia in chronic renal failure as the main mortality risk factor due to cardiovascular pathologies as well as the implication of these vitamins in the metabolism of homocysteine, and consequently in plasma levels of this metabolite in predialysis patients is reviewed.

Tratamiento nutricional del fallo intestinal y potenciales mecanismos de estimulación.

Severe forms of intestinal failure represent one of the most complex pathologies to manage, in both children and adults. In adults, the most common causes are chronic intestinal pseudo-obstruction and severe short bowel syndrome following large intestinal resections, particularly due to massive mesenteric ischemic, within the context of cardiopathies occurring with atrial fibrillation. The essential management after stabilizing the patient consists in nutritional support, either by parenteral or enteral routes, with tolerance to oral diet being the final goal of intestinal adaptation in these pathologies. Surgery may be indicated in some cases to increase the absorptive surface area. Parenteral nutrition is an essential support measure that sometimes has to be maintained for long time, even forever, except for technique-related complications or unfavorable clinical course that would lead to extreme surgical alternatives such as intestinal transplantation. Hormonal therapy with trophism-stimulating factors opens new alternatives that are already being tried in humans.

Perspectivas en el diseño y desarrollo de productos para nutrición enteral

Enteral nutrition is a technique that even though it was used in times immemorial, in the last 25 years has suffered a considerable development, from being considered a secondary therapeutic weapon destined only to feed the patient, to occupying an important status that goes beyond the single act of nourishing. The quantitative composition but overall the qualitative one, is object of an interesting argument in which a profile allowing the modulation of certain aspects of the organism response through the supplementation with different nutrients is searched. That includes from the keeping of the intestinal trophism and of the anti-bacteria intestinal barrier, so important to avoid the frightening multiple organ dysfunction, up to the lessening of the Systemic Response Inflammatory Syndrome (SRIS), going through the immuno-modulative feeding concepts, specific-feeding, pharmaco-nutrient or eco-nutrition. In this new dynamic not only certain nutrients such as glutamine, arginine, nucleotides, omega-3 fatty acids and many antioxidants have acquired importance, but also the manipulation of other molecules of a non- nutritional nature, such as hormones, cytokines and blockers. These aspects that imply passionate ways of investigation for the future are born from the better knowledge that is being acquired from such a severe pathophysiology processes such as sepsis and the organism response before fast and severe aggression; therefore, the modulation of that response through changes in the quantitative and qualitative formulas composition is being attempted.