Showing papers by "University of Turin published in 2005"

IKK-beta links inflammation to obesity-induced insulin resistance.

Abstract: Inflammation may underlie the metabolic disorders of insulin resistance and type 2 diabetes. IkappaB kinase beta (IKK-beta, encoded by Ikbkb) is a central coordinator of inflammatory responses through activation of NF-kappaB. To understand the role of IKK-beta in insulin resistance, we used mice lacking this enzyme in hepatocytes (Ikbkb(Deltahep)) or myeloid cells (Ikbkb(Deltamye)). Ikbkb(Deltahep) mice retain liver insulin responsiveness, but develop insulin resistance in muscle and fat in response to high fat diet, obesity or aging. In contrast, Ikbkb(Deltamye) mice retain global insulin sensitivity and are protected from insulin resistance. Thus, IKK-beta acts locally in liver and systemically in myeloid cells, where NF-kappaB activation induces inflammatory mediators that cause insulin resistance. These findings demonstrate the importance of liver cell IKK-beta in hepatic insulin resistance and the central role of myeloid cells in development of systemic insulin resistance. We suggest that inhibition of IKK-beta, especially in myeloid cells, may be used to treat insulin resistance.

Gene copy number for epidermal growth factor receptor (EGFR) and clinical response to antiEGFR treatment in colorectal cancer: a cohort study

Abstract: Summary Background The antiepidermal growth factor receptor (antiEGFR) monoclonal antibodies cetuximab and panitumumab have good clinical activity in about 10% of patients with metastatic colorectal cancer that is resistant to chemotherapy. The molecular mechanisms underlying clinical response or resistance to these agents are unknown. Methods Tumours from 31 patients with metastatic colorectal cancer who had either an objective response (n=10) or stable disease or progressive disease (n=21) after treatment with cetuximab or panitumumab were screened for genetic changes in EGFR or its immediate intracellular effectors. Specifically, we assessed the EGFR copy number and the mutation profile of the EGFR catalytic domain and of selected exons in KRAS , BRAF , and PIK3CA . Results Eight of nine of patients with objective responses who were assessable by fluorescence in-situ hybridisation (FISH) had an increased EGFR copy number. By contrast, one of 21 non-responders assessable by FISH had an increased EGFR copy number (p vs non-responders, Fisher's exact test). The mutation status of the EGFR catalytic domain and its immediate downstream effectors PIK3CA , KRAS , and BRAF did not correlate with disease response. In colorectal-cancer cell lines, the concentration of cetuximab that completely inhibited proliferation of cells with amplified EGFR copy number did not affect proliferation of cells with unamplified EGFR . Interpretation We propose that the response to antiEGFR treatment has a genetic basis and suggest that patients might be selected for treatment on the basis of EGFR copy number. Published online April 14, 2005 DOI 10.1016/S1470-2045(05)70102-9

The extraordinary ligand binding properties of human serum albumin

Abstract: Human serum albumin (HSA), the most prominent protein in plasma, binds different classes of ligands at multiple sites HSA provides a depot for many compounds, affects pharmacokinetics of many drugs, holds some ligands in a strained orientation providing their metabolic modification, renders potential toxins harmless transporting them to disposal sites, accounts for most of the antioxidant capacity of human serum, and acts as a NO-carrier The globular domain structural organization of monomeric HSA is at the root of its allosteric properties which are reminiscent of those of multimeric proteins Here, structural, functional, biotechnological, and biomedical aspects of ligand binding to HSA are summarized

Meat, Fish, and Colorectal Cancer Risk: The European Prospective Investigation into Cancer and Nutrition

Abstract: Background: Current evidence suggests that high red meat intake is associated with increased colorectal cancer risk. High fi sh intake may be associated with a decreased risk, but the existing evidence is less convincing. Methods: We prospectively followed 478 040 men and women from 10 European countries who were free of cancer at enrollment between 1992 and 1998. Information on diet and lifestyle was collected at baseline. After a mean follow-up of 4.8 years, 1329 incident colorectal cancers were documented. We examined the relationship between intakes of red and processed meat, poultry, and fi sh and colorectal cancer risk using a proportional hazards model adjusted for age, sex, energy (nonfat and fat sources), height, weight, workrelated physical activity, smoking status, dietary fi ber and folate, and alcohol consumption, stratifi ed by center. A calibration substudy based on 36 994 subjects was used to correct hazard ratios (HRs) and 95% confi dence intervals (CIs) for diet measurement errors. All statistical tests were two-sided. Results: Colorectal cancer risk was positively associated with intake of red and processed meat (highest [>160 g/day] versus lowest [ 80 g/day versus <10 g/day, HR = 0.69, 95 % CI = 0.54 to 0.88; P trend <.001), but was not related to poultry intake. Correcting for measurement error strengthened the associations between colorectal cancer and red and processed meat intake (per 100-g increase HR = 1.25, 95% CI =1.09 to 1.41, P trend = .001 and HR = 1.55, 95% CI = 1.19 to 2.02, P trend = .001 before and after calibration, respectively) and for fi sh (per 100 g increase HR = 0.70, 95% CI = 0.57 to 0.87, P trend <.001 and HR = 0.46, 95% CI = 0.27 to 0.77, P trend = .003; before and after correction, respectively). In this study population, the absolute risk of development of colorectal cancer within 10 years for a study subject aged 50 years was 1.71% for the highest category of red and processed meat intake and 1.28% for the lowest category of intake and was 1.86% for subjects in the lowest category of fi sh intake and 1.28% for subjects in the highest category of fi sh intake. Conclusions: Our data confi rm that colorectal cancer risk is positively associated with high consumption of red and processed meat and support an inverse association with fi sh intake. [J Natl Cancer Inst 2005;97:906–16]

Blockade of PI3Kgamma suppresses joint inflammation and damage in mouse models of rheumatoid arthritis

Abstract: Phosphoinositide 3-kinases (PI3K) have long been considered promising drug targets for the treatment of inflammatory and autoimmune disorders as well as cancer and cardiovascular diseases. But the lack of specificity, isoform selectivity and poor biopharmaceutical profile of PI3K inhibitors have so far hampered rigorous disease-relevant target validation. Here we describe the identification and development of specific, selective and orally active small-molecule inhibitors of PI3Kgamma (encoded by Pik3cg). We show that Pik3cg(-/-) mice are largely protected in mouse models of rheumatoid arthritis; this protection correlates with defective neutrophil migration, further validating PI3Kgamma as a therapeutic target. We also describe that oral treatment with a PI3Kgamma inhibitor suppresses the progression of joint inflammation and damage in two distinct mouse models of rheumatoid arthritis, reproducing the protective effects shown by Pik3cg(-/-) mice. Our results identify selective PI3Kgamma inhibitors as potential therapeutic molecules for the treatment of chronic inflammatory disorders such as rheumatoid arthritis.

Insulin resistance in non-diabetic patients with non-alcoholic fatty liver disease: sites and mechanisms

Abstract: Non-alcoholic fatty liver disease (NAFLD) has been associated with the metabolic syndrome. However, it is not clear whether insulin resistance is an independent feature of NAFLD, and it remains to be determined which of the in vivo actions of insulin are impaired in this condition. We performed a two-step (1.5 and 6 pmol min−1 kg−1) euglycaemic insulin clamp coupled with tracer infusion ([6,6-2H2]glucose and [2H5]glycerol) and indirect calorimetry in 12 non-obese, normolipidaemic, normotensive, non-diabetic patients with biopsy-proven NAFLD and six control subjects. In NAFLD patients, endogenous glucose production (basal and during the clamp) was normal; however, peripheral glucose disposal was markedly decreased (by 30% and 45% at the low and high insulin doses, respectively, p<0.0001) at higher plasma insulin levels (p=0.05), due to impaired glucose oxidation (p=0.003) and glycogen synthesis (p<0.001). Compared with control subjects, glycerol appearance and lipid oxidation were significantly increased in NAFLD patients in the basal state, and were suppressed by insulin to a lesser extent (p<0.05–0.001). The lag phase of the in vitro copper-catalysed peroxidation of LDL particles was significantly shorter in the patients than in the control subjects (48±12 vs 63±13 min, p<0.04). Lipid oxidation was significantly related to endogenous glucose production, glucose disposal, the degree of hepatic steatosis, and LDL oxidisability. Insulin resistance appears to be an intrinsic defect in NAFLD, with the metabolic pattern observed indicating that adipose tissue is an important site.

Neurobiological Mechanisms of the Placebo Effect

Abstract: Any medical treatment is surrounded by a psychosocial context that affects the therapeutic outcome. If we want to study this psychosocial context, we need to eliminate the specific action of a therapy and to simulate a context that is similar in all respects to that of a real treatment. To do this,

Isolation of Renal Progenitor Cells from Adult Human Kidney

Abstract: We describe here isolation and characterization of CD133+ cells derived from normal adult human kidney. These cells lacked the expression of hematopoietic markers and expressed PAX-2, an embryonic renal marker, suggesting their renal origin. Renal tissue-derived CD133+ cells and clones of individual cells were capable of expansion and limited self-renewal and differentiated in vitro into epithelial or endothelial cells. On subcutaneous implantation in SCID mice, the undifferentiated cells formed tubular structures expressing renal epithelial markers. At variance, when differentiated in endothelial cells, these cells formed functional vessels. On intravenous injection in SCID mice with glycerol-induced tubulonecrosis, the in vitro expanded renal-derived CD133+ cells homed into the injured kidney and integrated in tubules. We propose that CD133+ cells from kidney represent a multipotent adult resident stem cell population that may contribute to the repair of renal injury.

Continuous positive airway pressure for treatment of postoperative hypoxemia: a randomized controlled trial

Abstract: ContextHypoxemia complicates the recovery of 30% to 50% of patients after abdominal surgery; endotracheal intubation and mechanical ventilation may be required in 8% to 10% of cases, increasing morbidity and mortality and prolonging intensive care unit and hospital stay.ObjectiveTo determine the effectiveness of continuous positive airway pressure compared with standard treatment in preventing the need for intubation and mechanical ventilation in patients who develop acute hypoxemia after elective major abdominal surgery.Design and SettingRandomized, controlled, unblinded study with concealed allocation conducted between June 2002 and November 2003 at 15 intensive care units of the Piedmont Intensive Care Units Network in Italy.PatientsConsecutive patients who developed severe hypoxemia after major elective abdominal surgery. The trial was stopped for efficacy after 209 patients had been enrolled.InterventionsPatients were randomly assigned to receive oxygen (n = 104) or oxygen plus continuous positive airway pressure (n = 105).Main Outcome MeasuresThe primary end point was incidence of endotracheal intubation; secondary end points were intensive care unit and hospital lengths of stay, incidence of pneumonia, infection and sepsis, and hospital mortality.ResultsPatients who received oxygen plus continuous positive airway pressure had a lower intubation rate (1% vs 10%; P = .005; relative risk [RR], 0.099; 95% confidence interval [CI], 0.01-0.76) and had a lower occurrence rate of pneumonia (2% vs 10%, RR, 0.19; 95% CI, 0.04-0.88; P = .02), infection (3% vs 10%, RR, 0.27; 95% CI, 0.07-0.94; P = .03), and sepsis (2% vs 9%; RR, 0.22; 95% CI, 0.04-0.99; P = .03) than did patients treated with oxygen alone. Patients who received oxygen plus continuous positive airway pressure also spent fewer mean (SD) days in the intensive care unit (1.4 [1.6] vs 2.6 [4.2], P = .09) than patients treated with oxygen alone. The treatments did not affect the mean (SD) days that patients spent in the hospital (15 [13] vs 17 [15], respectively; P = .10). None of those treated with oxygen plus continuous positive airway pressure died in the hospital while 3 deaths occurred among those treated with oxygen alone (P = .12).ConclusionContinuous positive airway pressure may decrease the incidence of endotracheal intubation and other severe complications in patients who develop hypoxemia after elective major abdominal surgery.

Colorectal cancer: mutations in a signalling pathway.

Abstract: Protein kinases are enzymes that are important for controlling cellular growth and invasion, and their malfunction is implicated in the development of some tumours We analysed human colorectal cancers for genetic mutations in 340 serine/threonine kinases and found mutations in eight genes, including in three members of the phosphatidylinositol-3-OH kinase (PI(3)K) pathway The discovery of this mutational activation of a key cell-signalling pathway may provide new targets for therapeutic intervention

Grey matter pathology in multiple sclerosis.

Abstract: The aim of our study is to evaluate the extent and distribution of grey matter demyelinating lesions in multiple sclerosis (MS), addressing also neuronal loss and synaptic loss. Whole coronal sections of 6 MS brains and 6 control brains were selected. Immunohistochemistry was performed for myelin basic protein, neurofilaments, synaptophysin, ubiquitin, and activated caspase-3. Neuronal density and optical density of synaptophysin staining were estimated in cortical lesions and compared with those observed in corresponding areas of normal (i.e. nondemyelinated) cortex in the same section. Demyelinating lesions were observed in the cerebral cortex, in the thalamus, basal ganglia, and in the hippocampus. The percentage of demyelinated cortex was remarkable in 2 cases of secondary progressive MS (48% and 25.5%, respectively). Neuronal density was significantly reduced in cortical lesions (18-23% reduction), if compared with adjacent normal cortex, in the 2 cases showing the higher extent of cortical demyelination; in the same cases, very rare apoptotic neurons expressing caspase-3 were observed in cortical lesions and not in adjacent normal cortex. No significant decrease in optical density of synaptophysin staining was observed in cortical lesions. Grey matter demyelination and neuronal loss could contribute to disability and cognitive dysfunctions in MS.

Postmenopausal serum androgens, oestrogens and breast cancer risk: the European prospective investigation into cancer and nutrition

Abstract: Considerable experimental and epidemiological evidence suggests that elevated endogenous sex steroids - notably androgens and oestrogens - promote breast tumour development. In spite of this evidence, postmenopausal androgen replacement therapy with dehydroepiandrosterone (DHEA) or testosterone has been advocated for the prevention of osteoporosis and improved sexual wellbeing. We have conducted a case-control study nested within the European Prospective Investigation into Cancer and Nutrition. Levels of DHEA sulphate (DHEAS), (Delta 4-androstenedione), testosterone, oestrone, oestradiol and sex-hormone binding globulin (SHBG) were measured in prediagnostic serum samples of 677 postmenopausal women who subsequently developed breast cancer and 1309 matched control subjects. Levels of free testosterone and free oestradiol were calculated from absolute concentrations of testosterone, oestradiol and SHBG. Logistic regression models were used to estimate relative risks of breast cancer by quintiles of hormone concentrations. For all sex steroids the androgens as well as the oestrogens - elevated serum levels were positively associated with breast cancer risk, while SHBG levels were inversely related to risk. For the androgens, relative risk estimates (95% confidence intervals) between the top and bottom quintiles of the exposure distribution were: DHEAS 1.69 (1.23-2.33), androstenedione 1.94 (1.40-2.69), testosterone 1.85 (1.33-2.57) and free testosterone 2.50 (1.76-3.55). For the oestrogens, relative risk estimates were: oestrone 2.07 (1.42-3.02), oestradiol 2.28 (1.61-3.23) and free oestradiol (odds ratios 2.13 (1,52-2.98)). Adjustments for body mass index or other potential confounding factors did not substantially alter any of these relative risk estimates. Our results have shown that, among postmenopausal women, not only elevated serum oestrogens but also serum androgens are associated with increased breast cancer risk. Since DHEAS and androstenedione are largely of adrenal origin in postmenopausal women, our results indicated that elevated adrenal androgen synthesis is a risk factor for breast cancer. The results from this study caution against the use of DHEA(S), or other androgens, for postmenopausal androgen replacement therapy.

Colchicine in addition to conventional therapy for acute pericarditis: results of the COlchicine for acute PEricarditis (COPE) trial.

Abstract: Background— Colchicine is effective and safe for the treatment and prevention of recurrent pericarditis and might ultimately serve as the initial mode of treatment, especially in idiopathic cases. The aim of this work was to verify the safety and efficacy of colchicine as an adjunct to conventional therapy for the treatment of the first episode of acute pericarditis. Methods and Results— A prospective, randomized, open-label design was used. A total of 120 patients (mean age 56.9±18.8 years, 54 males) with a first episode of acute pericarditis (idiopathic, viral, postpericardiotomy syndromes, and connective tissue diseases) were randomly assigned to conventional treatment with aspirin (group I) or conventional treatment plus colchicine 1.0 to 2.0 mg for the first day and then 0.5 to 1.0 mg/d for 3 months (group II). Corticosteroid therapy was restricted to patients with aspirin contraindications or intolerance. The primary end point was recurrence rate. During the 2873 patient-month follow-up, colchicine ...

Keystroke analysis of free text

Abstract: Keystroke dynamics can be useful to ascertain personal identity even after an authentication phase has been passed, provided that we are able to deal with the typing rhythms of free text, chosen and entered by users without any specific constraint. In this paper we present a method to compare typing samples of free text that can be used to verify personal identity. We have tested our technique with a wide set of experiments on 205 individuals, obtaining a False Alarm Rate of less than 5% and an Impostor Pass Rate of less than 0.005%. Different trade-offs are, however, possible. Our approach can rely on what is typed by people because of their normal job, and a few lines of text, even collected in different working sessions, are sufficient to reach a high level of accuracy, which improves proportionally to the amount of available information: As a consequence, we argue that our method can be useful in computer security as a complementary or alternative way to user authentication and as an aid to intrusion detection.

Arbuscular Mycorrhizal Fungi Elicit a Novel Intracellular Apparatus in Medicago truncatula Root Epidermal Cells before Infection

Abstract: The penetration of arbuscular mycorrhizal (AM) fungi through the outermost root tissues of the host plant is a critical step in root colonization, ultimately leading to the establishment of this ecologically important endosymbiotic association. To evaluate the role played by the host plant during AM infection, we have studied in vivo cellular dynamics within Medicago truncatula root epidermal cells using green fluorescent protein labeling of both the plant cytoskeleton and the endoplasmic reticulum. Targeting roots with Gigaspora hyphae has revealed that, before infection, the epidermal cell assembles a transient intracellular structure with a novel cytoskeletal organization. Real-time monitoring suggests that this structure, designated the prepenetration apparatus (PPA), plays a central role in the elaboration of the apoplastic interface compartment through which the fungus grows when it penetrates the cell lumen. The importance of the PPA is underlined by the fact that M. truncatula dmi (for doesn't make infections) mutants fail to assemble this structure. Furthermore, PPA formation in the epidermis can be correlated with DMI-dependent transcriptional activation of the Medicago early nodulin gene ENOD11. These findings demonstrate how the host plant prepares and organizes AM infection of the root, and both the plant-fungal signaling mechanisms involved and the mechanistic parallels with Rhizobium infection in legume root hairs are discussed.

Severely increased risk of amyotrophic lateral sclerosis among Italian professional football players

Abstract: Summary The cause of amyotrophic lateral sclerosis (ALS) is still unknown. A possible relationship between ALS and sport participation has been supposed, but never definitely demonstrated. We studied a cohort of 7325 male professional football players engaged by a football team from the Italian First or Second Division in the period 1970‐2001. ALS cases were identified using different concurrent sources. Standardized morbidity ratios (SMRs) were calculated. During the 137 078 person-years of followup, five ALS cases were identified (mean age of onset, 43.4 years). Three cases had a bulbar onset, significantly more than expected (P = 0.003). Since the number of expected cases was 0.77, the overall SMR was 6.5 [95% confidence interval (CI), 2.1‐15.1]. The SMR was significantly increased for an ALS onset before 49 years, but not for older subjects. A significant increase of the SMR was found in the periods 1980‐1989 and 1990‐ 2001, whereas no ALS case was found in the 1970‐1979 period. A dose‐response relationship between the duration of professional football activity and the risk of ALS was found (>5 years, 15.2, 95% CI, 3.1‐44.4; <5 years, 3.5, 95% CI, 0.4‐12.7). Our findings seem to indicate that playing professional football is a strong risk factor for ALS.

Placebos and painkillers: is mind as real as matter?

Abstract: Considerable progress has been made in our understanding of the neurobiological mechanisms of the placebo effect, and most of our knowledge originates from the field of pain and analgesia. Today, the placebo effect represents a promising model that could allow us to shed new light on mind-body interactions. The mental events induced by placebo administration can activate mechanisms that are similar to those activated by drugs, which indicates a similarity between psychosocial and pharmacodynamic effects. These new neurobiological advances are already changing our conception of how clinical trials and medical practice must be viewed and conducted.

Stat3 is required for ALK-mediated lymphomagenesis and provides a possible therapeutic target

Abstract: Anaplastic large cell lymphomas (ALCLs) are caused by chromosomal translocations that juxtapose the anaplastic lymphoma kinase (ALK) proto-oncogene to a dimerization partner, resulting in constitutive expression of ALK and ALK tyrosine kinase activity. One substrate of activated ALK in human ALCLs is the transcription factor Stat3, and its phosphorylation is accurately recapitulated in a new nucleophosmin (NPM)-ALK transgenic mouse model of lymphomagenesis. Here we show by gene targeting that Stat3 is required for the transformation of mouse embryonic fibroblasts in vitro, for the development of B-cell lymphoma in transgenic mice and for the growth and survival of both human and mouse NPM-ALK-transformed B and T cells. Ablation of Stat3 expression by antisense oligonucleotides significantly (P < 0.0001) impaired the growth of human and mouse NPM-ALK tumors in vivo. Pharmacological ablation of Stat3 represents a new candidate approach for the treatment of human lymphoma

Physics potential and experimental challenges of the LHC luminosity upgrade

Abstract: We discuss the physics potential and the experimental challenges of an upgraded LHC running at an instantaneous luminosity of 1035 cm-2s-1. The detector R&D needed to operate ATLAS and CMS in a very high radiation environment and the expected detector performance are discussed. A few examples of the increased physics potential are given, ranging from precise measurements within the Standard Model (in particular in the Higgs sector) to the discovery reach for several New Physics processes.

Current controversies in oral lichen planus : Report of an international consensus meeting. Part 2. Clinical management and malignant transformation

Abstract: Despite recent advances in understanding the immunopathogenesis of oral lichen planus (LP), the initial triggers of lesion formation and the essential pathogenic pathways are unknown. It is therefore not surprising that the clinical management of oral LP poses considerable difficulties to the dermatologist and the oral physician. A consensus meeting was held in France in March 2003 to discuss the most controversial aspects of oral LP. Part 1 of the meeting report focused on (1) the relationship between oral LP and viral infection, with special emphasis on hepatitis C virus (HCV), and (2) oral LP pathogenesis, in particular the immune mechanisms resulting in lymphocyte infiltration and keratinocyte apoptosis. Part 2 focuses on patient management and therapeutic approaches and includes discussion on malignant transformation of oral LP.

Plasma Adiponectin in Nonalcoholic Fatty Liver Is Related to Hepatic Insulin Resistance and Hepatic Fat Content, Not to Liver Disease Severity

Abstract: Plasma levels of adiponectin are decreased in patients with nonalcoholic fatty liver disease (NAFLD), but the relationship among plasma adiponectin, insulin sensitivity, and histological features is unclear. In 174 NAFLD patients and 42 controls, we examined plasma adiponectin concentrations in relation to 1) lipid profile, indices of insulin resistance, and features of the metabolic syndrome (n = 174); 2) hepatic insulin resistance (clamp technique with tracer infusion) (10 patients); and 3) histological features at liver biopsy (n = 116). When the data from all subjects were combined, plasma adiponectin levels were positively associated with increased age, female gender, and plasma high-density lipoprotein levels, and negatively associated with waist circumference, body mass index, triglycerides, indices of insulin resistance, and aminotransferase levels, and also predicted the presence of the metabolic syndrome. In step-wise regression, increased age, female gender, waist circumference, triglyceride levels, and homeostasis model assessment independently associated with adiponectin (adjusted R(2), 0.329). In NAFLD, adiponectin was only associated with increased age, female gender, and triglycerides (adjusted R(2), 0.245). When the measured histological parameters were included in the model, plasma adiponectin levels were also inversely proportional to the percentage of hepatic fat content (adjusted R(2), 0.221), whereas necroinflammation and fibrosis did not fit in the model. Adiponectin was negatively correlated with insulin-suppressed endogenous glucose production during the clamp (P = 0.011). The results demonstrate that decreased levels of circulating adiponectin in NAFLD are related to hepatic insulin sensitivity and to the amount of hepatic fat content. Hypoadiponectinemia in NAFLD is part of a metabolic disturbance characterized by ectopic fat accumulation in the central compartment.

Serum Sex Steroids in Premenopausal Women and Breast Cancer Risk Within the European Prospective Investigation into Cancer and Nutrition (EPIC)

Abstract: Background. Contrasting etiologic hypotheses about the role of endogenous sex steroids in breast cancer development among premenopausal women implicate ovarian androgen excess and progesterone deficiency, estrogen excess, estrogen and progesterone excess, and both an excess or lack of adrenal androgens (dehydroepiandrosterone [DHEA] or its sulfate [DHEAS]) as risk factors. We conducted a case-control study nested within the European Prospective Investigation into Cancer and Nutrition cohort to examine associations among premenopausal serum concentrations of sex steroids and subsequent breast cancer risk. Methods: Levels of DHEAS, (Delta 4-)androstenedione, testosterone, and sex hormone binding globulin (SHBG) were measured in single prediagnostic serum samples from 370 premenopausal women who subsequently developed breast cancer (case patients) and from 726 matched cancer-free control subjects. Levels of progesterone, estrone, and estradiol were also measured for the 285 case patients and 555 matched control subjects who had provided information about the day of menstrual cycle at blood donation. Conditional logistic regression models were used to estimate relative risks of breast cancer by quartiles of hormone concentrations. All statistical tests were two-sided. Results: Increased risks of breast cancer were associated with elevated serum concentrations of testosterone (odds ratio [OR] for highest versus lowest quartile = 1.73, 95% confidence interval [CI] = 1.16 to 2.57; P-trend =.01), androstenedione (OR for highest versus lowest quartile = 1.569 95% CI = 1.05 to 2.32; P-trend =.01), and DHEAS (OR for highest versus lowest quartile = 1.48, 95% CI = 1.02 to 2.14; P-trend =.10) but not SHBG. Elevated serum progesterone concentrations were associated with a statistically significant reduction in breast cancer risk (OR for highest versus lowest quartile = 0.61, 95% CI = 0.38 to 0.98; P-trend =.06). The absolute risk of breast cancer for women younger than 40 followed up for 10 years was estimated at 2.6% for those in the highest quartile of serum testosterone versus 1.5% for those in the lowest quartile; for the highest and lowest quartiles of progesterone, these estimates were 1.7% and 2.6%, respectively. Breast cancer risk was not statistically significantly associated with serum levels

Obesity surgery: evidence-based guidelines of the European Association for Endoscopic Surgery (EAES).

Abstract: The increasing prevalence of morbid obesity together with the development of laparoscopic approaches has led to a steep rise in the number of bariatric operations. These guidelines intend to define the comparative effectivness and surrounding circumstances of the various types of obesity surgery. A consensus panel representing the fields of general/endoscopic surgery, nutrition and epidemiology convened to agree on specific questions in obesity surgery. Databases were systematically searched for clinical trial results in order to produce evidence-based recommendations. Following two days of discussion by the experts and a plenary discussion, the final statements were issued. After the patient’s multidisciplinary evaluation, obesity surgery should be considered in adults with a documented BMI greater than or equal to 35 and related comorbidity, or a BMI of at least 40. In addition to standard laboratory testing, chest radiography, electrocardiography, spirometry, and abdominal ultrasonography, the preoperative evaluation of obesity surgery patients also includes upper gastrointestinal endoscopy or radiologic evaluation with a barium meal. Psychiatric consultation and polysomnography can safely be restricted to patients with clinical symptoms on preoperative screening. Adjustable gastric banding (GB), vertical banded gastroplasty (VBG), Roux-en-Y gastric bypass (RYGB) and biliopancreatic diversion (BPD) are all effective in the treatment of morbid obesity, but differ in degree of weight loss and range of complications. The choice of procedure therefore should be tailored to the individual situation. There is evidence that a laparoscopic approach is advantageous for LAGB, VBG, and GB (and probably also for BPD). Antibiotic and antithromboembolic prophylaxis should be used routinely. Patients should be seen 3 to 8 times during the first postoperative year, 1 to 4 times during the second year and once or twice a year thereafter. Outcome assessment after surgery should include weight loss and maintainance, nutritional status, comorbidities and quality-of-life.