Improvement in Insulin Sensitivity and B-Cell Function Following Ileal Interposition with Sleeve Gastrectomy in Type 2 Diabetic Patients: Potential Mechanisms

Bariatric surgery in morbidly obese type 2 diabetic (T2DM) patients is associated with high rates of diabetes remission. We investigated the mechanisms of the anti-diabetic effect of the laparoscopic ileal interposition with sleeve gastrectomy (LII-SG) in normal weight (NW), overweight (OW) and obese (OB) T2DM patients. Ninety-four patients (aged 54 +/- 8 years) with long-standing (median 10 years), treated diabetes (median HbA(1c) = 8.6%), who were NW (15), OW (64) or OB (15) based on BMI, underwent LII-SG. Insulin sensitivity and parameters of -cell function were measured from an Oral Glycaemic Tolerance Test pre- and post-operatively. At a median of 13.4 months post-operatively, weight loss averaged 9.4 +/- 1.3, 16.8 +/- 0.8 and 23.2 +/- 1.7 kg in NW, OW and OB subjects, respectively (p < 0.0001). Insulin sensitivity was fully restored (395 [108] vs 208 [99] ml min(-1) m(-2)), fasting insulin secretion rate decreased (68 [52] vs 146 [120] pmol min(-1) m(-2)) and total insulin output increased (52 [26] vs 39 [28] nmol m(-2), all p a parts per thousand currency signaEuro parts per thousand 0.001). -cell glucose sensitivity doubled (37 [33] vs 18 [24] mol min(-1) m(-2) mM(-1), p < 0.0001). The only parameter predicting remission of diabetes was a lower baseline insulin sensitivity (p = 0.005). LII-SG induced changes on T2DM by mechanisms in part distinct from weight loss, principally involving restoration of insulin sensitivity and improvement of -cell function.

Low- and high-density lipoprotein cholesterol goal attainment in dyslipidemic women: The Lipid Treatment Assessment Project (L-TAP) 2

Background Differences between women and men have been documented for both diagnostic testing and treatment in cardiology. This analysis evaluates whether low-density lipoprotein cholesterol (LDL-C) success rates according to current guidelines and high-density lipoprotein cholesterol (HDL-C) levels differ by gender in the L-TAP 2 population. Methods Patients aged >= 20 years with dyslipidemia on stable lipid-lowering therapy were assessed in 9 countries between September 2006 and April 2007. Low-density lipoprotein cholesterol goal attainment by cardiovascular risk level and region and determinants of low HDL-C were compared between genders. Results Of 9,955 patients (45.3% women) evaluated, women had a significantly lower overall LDL-C success rate than men (71.5% vs 73.7%, P = .014), due entirely to the difference in the high-risk/coronary heart disease (CHD) group (LDL-C goal <100 mg/dL, 62.6% vs 70.6%, P < .0001) Among CHD patients with >= 2 additional risk factors, only 26.7% of women and 31.5% of men (P = .021) attained the optional LDL-C goal of <70 mg/dL. High-density lipoprotein cholesterol was <50 mg/dL in 32.2% of women and <40 mg/dL in 26.8% of men (P < .0001), including 38.2% of women and 29.8% of men in the high risk/CHD group (P < .0001). Predictors of low HDL-C in women included diabetes, smoking, waist circumference, and hypertension. Conclusions Cholesterol treatment has, improved substantially since the original L-TAP a decade ago, when only 39% of women attained their LDL-C goal. However, high-risk women are undertreated compared to men, and a substantial opportunity remains to reduce their cardiovascular risk. (Am Heart J 2009; 158:860-6.)

Transfer of Cholesterol and Other Lipids From a Lipid Nanoemulsion to High-density Lipoprotein in Heart Transplant Patients

Background: Beyond the first year after a heart transplant (HT) procedure, patients often develop dyslipidemias, which may be implicated in the genesis of transplant coronary heart disease. High-density lipoprotein (HDL) has a several anti-atherogenic properties, but the status of HDL in HT patients is still controversial. Nonetheless, determination of HDL cholesterol concentration is not sufficient for evaluation of the overall HDL protective role. In this study, a fundamental functional property of HDL, the ability to simultaneously receive the major lipid classes, was tested in HT patients. Methods: Twenty HT patients and 20 healthy normolipidemic subjects paired for gender, age and body mass index were studied. Blood samples were collected after 12-hour fasting for determination of plasma lipids, glucose, paraxonase I (PON 1) activity, HDL diameter and transfer of labeled lipids from an artificial nanoemulsion to HDL. Results: Plasma triglycerides (159 +/- 63 vs 94 +/- 35 mg/dl) and glucose (104 +/- 20 vs 86 +/- 10 mg/dl) were greater in HT patients than in control subjects. HDL cholesterol was lower and HDL diameter was smaller in the HT group (HDL cholesterol: 44 +/- 11 vs 55 +/- 15 mg/dl; HDL diameter: 8.8 +/- 0.6 vs 9.0 +/- 1.2 nm). PON 1 activity did not differ (87 +/- 47 vs 75 +/- 37 nmol/min/ml). The transfer rates of free cholesterol and cholesteryl esters were diminished in HT patients (HT: 8.4 +/- 1.2% and 3.8 +/- 0.6%; controls: 9.7 +/- 1.9% and 4.7 +/- 1.2%, respectively). Conclusions: The transfer of free cholesterol and cholesteryl esters to HDL is diminished in HT patients; disturbance in the ability of HDL to receive lipids may affect the anti-atherogenic properties of the lipoprotein. J Heart Lung Transplant 2009;28:1075-80. Copyright (C) 2009 by the International Society for Heart and Lung Transplantation.

Lipid Treatment Assessment Project 2 A Multinational Survey to Evaluate the Proportion of Patients Achieving Low-Density Lipoprotein Cholesterol Goals

Background-Information about physicians` adherence to cholesterol management guidelines remains scant. The present survey updates our knowledge of lipid management worldwide. Methods and Results-Lipid levels were determined at enrollment in dyslipidemic adult patients on stable lipid-lowering therapy in 9 countries. The primary end point was the success rate, defined as the proportion of patients achieving appropriate low-density lipoprotein cholesterol (LDL-C) goals for their given risk. The mean age of the 9955 evaluable patients was 62 +/- 12 years; 54% were male. Coronary disease and diabetes mellitus had been diagnosed in 30% and 31%, respectively, and 14% were current smokers. Current treatment consisted of a statin in 75%. The proportion of patients achieving LDL-C goals according to relevant national guidelines ranged from 47% to 84% across countries. In low-, moderate-, and high-risk groups, mean LDL-C was 119, 109, and 91 mg/dL and mean high-density lipoprotein cholesterol was 62, 49, and 50 mg/dL, respectively. The success rate for LDL-C goal achievement was 86% in low-, 74% in moderate-, and 67% in high-risk patients (73% overall). However, among coronary heart disease patients with >= 2 risk factors, only 30% attained the optional LDL-C goal of < 70 mg/dL. In the entire cohort, high-density lipoprotein cholesterol was < 40 mg/dL in 19%, 40 to 60 mg/dL in 55%, and > 60 mg/dL in 26% of patients. Conclusions-Although there is room for improvement, particularly in very-high-risk patients, these results indicate that lipid-lowering therapy is being applied much more successfully than it was a decade ago. (Circulation. 2009; 120: 28-34.)

Is Coronary Artery Calcification Associated with Vertebral Bone Density in Nondialyzed Chronic Kidney Disease Patients?

Background and objectives Low bone mineral density and coronary artery calcification (CAC) are highly prevalent among chronic kidney disease (CKD) patients, and both conditions are strongly associated with higher mortality. The study presented here aimed to investigate whether reduced vertebral bone density (VBD) was associated with the presence of CAC in the earlier stages of CKD. Design, setting, participants, & measurements Seventy-two nondialyzed CKD patients (age 52 +/- 11.7 years, 70% male, 42% diabetics, creatinine clearance 40.4 +/- 18.2 ml/min per 1.73 m(2)) were studied. VBD and CAC were quantified by computed tomography. Results CAC > 10 Agatston units (AU) was observed in 50% of the patients (median 120 AU [interquartile range 32 to 584 AU]), and a calcification score >= 400 AU was found in 19% (736 [527 to 1012] AU). VBD (190 +/- 52 Hounsfield units) correlated inversely with age (r = -0.41, P < 0.001) and calcium score (r = -0.31, P = 0.01), and no correlation was found with gender, creatinine clearance, proteinuria, lipid profile, mineral parameters, body mass index, and diabetes. Patients in the lowest tertile of VBD had expressively increased calcium score in comparison to the middle and highest tertile groups. In the multiple logistic regression analysis adjusting for confounding variables, low VBD was independently associated with the presence of CAC. Conclusions Low VBD was associated with CAC in nondialyzed CKD patients. The authors suggest that low VBD might constitute another nontraditional risk factor for cardiovascular disease in CKD. Clin J Am Soc Nephrol 6: 1456-1462, 2011. doi: 10.2215/CJN.10061110

Reaching C-Reactive Protein and Low-Density Lipoprotein Cholesterol Goals in Dyslipidemic Patients (from the Lipid Treatment Assessment Project [L-TAP] 2)

The purpose of the present substudy of the Lipid Treatment Assessment Project 2 was to assess dual C-reactive protein (CRP) and low-density lipoprotein (LDL) cholesterol goal attainment across a spectrum of low-, moderate-, and high-risk patients with dyslipidemia in 8 countries in North America, Latin America, Europe, and Asia. Of the 9,518 patients studied overall, 45% were women, 64% had hypertension, 31% had diabetes, 14% were current smokers, 60% were high risk, and 79% were taking a statin. The median CRP level was 1.5 mg/L (interquartile range 0.2 to 2.8). On multivariate analysis, higher CRP levels were associated with older age, female gender, hypertension, current smoking, greater body mass index, larger waist circumference, LDL cholesterol level, and triglyceride/high-density lipoprotein cholesterol ratio. In contrast, being from Asia or taking a statin was associated with lower levels. Across all risk groups, 59% of patients attained the CRP target of <2 mg/L, and 33% had <1 mg/L. Overall, 44% of patients attained both their National Cholesterol Education Program Adult Treatment Panel III LDL cholesterol target and a CRP level of <2 mg/L, but only 26% attained their LDL cholesterol target and a CRP level of <1 mg/L. In the very high-risk group with coronary heart disease and >= 2 risk factors, only 19% attained both their LDL cholesterol goal and a CRP level of <2 mg/L and 12% their LDL cholesterol goal and a CRP level of <1 mg/L. In conclusion, with current treatment, most dyslipidemic patients do not reach the dual CRP and LDL cholesterol goals. Smoking cessation, weight reduction, and the greater use of more potent statins at higher doses might be able to improve these outcomes. (C) 2011 Elsevier Inc. All rights reserved. (Am J Cardiol 2011;107:1639-1643)

A synergistic relationship of elevated low-density lipoprotein cholesterol levels and systolic blood pressure with coronary artery calcification

We sought to evaluate this ""response-to-injury"" hypothesis of atherosclerosis by studying the interaction between systolic blood pressure (SBP) and LDL-cholesterol (LDL-C) in predicting the presence of coronary artery calcification (CAC) in asymptomatic men. We Studied 526 men (46 +/- 7 years of age) referred for electron-beam tomography (EBT) exam. The prevalence of CAC was determined across LDL-C tertiles (low: <115 mg/dl; middle: 115-139 mg/dl high: >= 140 mg/dl) within tertiles of SBP (low: <121 mmHg; middle: 121-130 mmHg; high: >= 131 mmHg). CAC was found in 220 (42%) men. There was no linear trend in the presence of CAC across LDL-C tertiles in the low (p = 0.6 for trend) and middle (p = 0.3 for trend) SBP tertile groups, respectively. In contrast, there was a significant trend for increasing CAC with increasing LDL-C (1st: 44%; 2nd: 49%; 3rd: 83%; p < 0.0001 for trend) in the high SBP tertile group. In multivariate logistic analyses (adjusting for age, smoking, triglyceride levels, HDL-cholesterol levels, body mass index, and fasting glucose levels), the odds ratio for any CAC associated with increasing LDL-C was significantly higher in those with highest SBP levels, whereas no such relationship was observed among men with SBP in the lower two tertiles. An interaction term (LDL-C x SBP) incorporated in the multivariate analyses was statistically significant (p = 0.038). The finding of an interaction between SBP and LDL-C relation to CAC in asymptomatic men support the response-to-injury model of atherogenesis. (C) 2007 Elsevier Ireland Ltd. All rights reserved.

Phase I trial of DNA-hsp65 immunotherapy for advanced squamous cell carcinoma of the head and neck

Considering that mycobacterial heat-shock protein 65 (hsp65) gene transfer can elicit a profound antitumoral effect, this study aimed to establish the safety, maximum-tolerated dose (MTD) and preliminary efficacy of DNA-hsp65 immunotherapy in patients with advanced head and neck squamous cell carcinoma (HNSCC). For this purpose, 21 patients with unresectable and recurrent HNSCC were studied. Each patient received three ultrasound-guided injections at 21-day intervals of: 150, 600 or 400 mu g of DNA-hsp65. Toxicity was graded according to CTCAE directions. Tumor volume was measured before and after treatment using computed tomography scan. The evaluation included tumor mass variation, delayed-type hypersensitivity response and spontaneous peripheral blood mononuclear cell proliferation before and after treatment. The MTD was 400 mg per dose. DNA-hsp65 immunotherapy was well tolerated with moderate pain, edema and infections as the most frequent adverse effects. None of the patients showed clinical or laboratory alterations compatible with autoimmune reactions. Partial response was observed in 4 out of 14 patients who completed treatment, 2 of which are still alive more than 3 years after the completion of the trial. Therefore, DNA-hsp65 immunotherapy is a feasible and safe approach at the dose of 400 mg per injection in patients with HNSCC refractory to standard treatment. Further studies in a larger number of patients are needed to confirm the efficacy of this novel strategy.

Effects of immunosuppressants on hepatocyte cell mitosis during liver regeneration in growing animal models of partial hepatectomy

Objective. We sought to evaluate the effects of immunosuppressant drugs (corticosteroid, cyclosporine [CsA], and tacrolimus [Tac]) on liver regeneration in growing animals submitted to 70% hepatectomy. Materials and Methods. Newborn and weaning rats were submitted to 70% hepatectomy receiving separately methylprednisolone, CsA, or Tac. All animals were sacrificed 24 hours after the procedure. The remnant liver lobes were subjected to histomorphometric analyses with determination of hepatocyte mitotic index. Results., Administration of immunosuppressants did not change the mitotic index of the regenerating liver in newborn animals. In weaning rats, methylprednisolone reduced the mitotic index (P = .01) and Tac caused a greater increase in this rate (P = .001). CsA had no effect on mitotic index. The number of hepatocyte mitoses in newborn animal livers was greater than that in weaning animal livers (P = .001). Conclusion. In situations in which intense, fast processes of liver regeneration are crucial, the advantages of the use of Tac must be considered, such as in pediatric transplant patients.

Three-dimensional model for multi-component reactive transport with variable density groundwater flow

PHWAT is a new model that couples a geochemical reaction model (PHREEQC-2) with a density-dependent groundwater flow and solute transport model (SEAWAT) using the split-operator approach. PHWAT was developed to simulate multi-component reactive transport in variable density groundwater flow. Fluid density in PHWAT depends not on only the concentration of a single species as in SEAWAT, but also the concentrations of other dissolved chemicals that can be subject to reactive processes. Simulation results of PHWAT and PHREEQC-2 were compared in their predictions of effluent concentration from a column experiment. Both models produced identical results, showing that PHWAT has correctly coupled the sub-packages. PHWAT was then applied to the simulation of a tank experiment in which seawater intrusion was accompanied by cation exchange. The density dependence of the intrusion and the snow-plough effect in the breakthrough curves were reflected in the model simulations, which were in good agreement with the measured breakthrough data. Comparison simulations that, in turn, excluded density effects and reactions allowed us to quantify the marked effect of ignoring these processes. Next, we explored numerical issues involved in the practical application of PHWAT using the example of a dense plume flowing into a tank containing fresh water. It was shown that PHWAT could model physically unstable flow and that numerical instabilities were suppressed. Physical instability developed in the model in accordance with the increase of the modified Rayleigh number for density-dependent flow, in agreement with previous research. (c) 2004 Elsevier Ltd. All rights reserved.

The assessment of oral cytology utilizing ploidy analysis and virtual microscopy for the early detection of epithelial dysplasia and neoplasia in oral mucosal lesions

Oral squamous cell carcinoma (OSCC) is associated with high morbidity and mortality which is due, at least in part, to late detection. Precancerous and cancerous oral lesions may mimic any number of benign oral lesions, and as such may be left without investigation and treatment until they are well advanced. Over the past several years there has been renewed interest in oral cytology as an adjuvant clinical tool in the investigation of oral mucosal lesions. The purpose of the present study was to compare the usefulness of ploidy analysis after Feulgen stained cytological thin-prep specimens with traditional incisional biopsy and routine histopathological examination for the assessment of the pre-malignant potential of oral mucosal lesions. An analysis of the cytological specimens was undertaken with virtual microscopy which allowed for rapid and thorough analysis of the complete cytological specimen. 100 healthy individuals between 30 and 70 years of age, who were non-smokers, non-drinkers and not taking any medication, had cytological specimens collected from both the buccal mucosa and lateral margin of tongue to establish normal cytology parameters within a control population. Patients with a presumptive clinical diagnosis of lichen planus, leukoplakia or OSCC had lesional cytological samples taken prior to their diagnostic biopsy. Standardised thin preparations were prepared and each specimen stained by both Feuglen and Papanicolau methods. High speed scanning of the complete slide at 40X magnification was undertaken using the Aperio Scanscope TM and the green channel of the resultant image was analysed after threshold segmentation to isolate only nuclei and the integrated optical density of each nucleus taken as a gross measure of the DNA content (ploidy). Preliminary results reveal that ploidy assessment of oral cytology holds great promise as an adjunctive prognostic factor in the analysis of the malignant potential of oral mucosal lesions.

Anthropometric measures in relation to Basal Cell Carcinoma: a longitudinal study

Background: The relationship between anthropometric indices and risk of basal cell carcinoma ( BCC) is largely unknown. We aimed to examine the association between anthropometric measures and development of BCC and to demonstrate whether adherence to World Health Organisation guidelines for body mass index, waist circumference, and waist/ hip ratio was associated with risk of BCC, independent of sun exposure. Methods: Study participants were participants in a community- based skin cancer prevention trial in Nambour, a town in southeast Queensland ( latitude 26 degrees S). In 1992, height, weight, and waist and hip circumferences were measured for all 1621 participants and weight was remeasured at the end of the trial in 1996. Prevalence proportion ratios were calculated using a log- binomial model to estimate the risk of BCC prior to or prevalent in 1992, while Poisson regression with robust error variances was used to estimate the relative risk of BCC during the follow- up period. Results: At baseline, 94 participants had a current BCC, and 202 had a history of BCC. During the 5- year follow- up period, 179 participants developed one or more new BCCs. We found no significant association between any of the anthropometric measures or indices and risk of BCC after controlling for potential confounding factors including sun exposure. There was a suggestion that short- term weight gain may increase the risk of developing BCC for women only. Conclusion: Adherence to World Health Organisation guidelines for body mass index, waist circumference and waist/ hip ratio is not significantly associated with occurrence of basal cell carcinomas of the skin.

Metabolic syndrome features small, apolipoprotein A-I-poor, triglyceride-rich HDL3 particles with defective anti-apoptotic activity

The metabolic syndrome (MetS) phenotype is typically characterized by visceral obesity, insulin resistance, atherogenic dyslipidemia involving hypertriglyceridemia and subnormal levels of high density lipoprotein-cholesterol (HDL-C), oxidative stress and elevated cardiovascular risk. The potent antioxidative activity of small HDL3 is defective in MetS [Hansel B, et al. J Clin Endocrinol Metab 2004;89:4963-71]. We evaluated the functional capacity of small HDL3 particles from MetS subjects to protect endothelial cells from apoptosis induced by mildly oxidized low-density lipoprotein (oxLDL). MetS subjects presented an insulin-resistant obese phenotype, with hypertriglyceridemia, elevated apolipoprotein B and insulin levels, but subnormal HDL-C concentrations and chronic low grade inflammation (threefold elevation of C-reactive protein). When human microvascular endothelial cells (HMEC-1) were incubated with oxLDL (200 jig apolipoprotein B/ml) in the presence or absence of control HDL subfiractions (25 mu g protein/ml), small, dense HDL3b and 3c significantly inhibited cellular annexin V binding and intracellular generation of reactive oxygen species. The potent anti-apoptotic activity of small HDL3c particles was reduced (-35%; p < 0.05) in MetS subjects (n = 16) relative to normolipidemic controls (n = 7). The attenuated anti-apoptotic activity of HDL3c correlated with abdominal obesity, atherogenic dyslipidemia and systemic oxidative stress (p < 0.05), and was intimately associated with altered physicochemical properties of apolipoprotein A-I (apoA-I-poor HDL3c, involving core cholesteryl ester depletion and triglyceride enrichment. We conclude that in MetS, apoA-I-poor, small, dense HDL3c exert defective protection of endothelial cells from oxLDL-induced apoptosis, potentially reflecting functional anomalies intimately associated with abnormal neutral lipid core content. (c) 2007 Elsevier Ireland Ltd. All rights reserved.

Immunohistochemical analysis of p53, APE1, hMSH2 and ERCC1 proteins in actinic cheilitis and lip squamous cell carcinoma

Aims: This study has compared the tissue expression of the p53 tumour suppressor protein and DNA repair proteins APE1, hMSH2 and ERCC1 in normal, dysplastic and malignant lip epithelium. Methods and results: Morphological analysis and immunohistochemistry were performed on archived specimens of normal lip mucosa (n = 15), actinic cheilitis (AC) (n = 30), and lip squamous cell carcinoma (LSCC) (n = 27). AC samples were classified morphologically according to the severity of epithelial dysplasia and risk of malignant transformation. LSCC samples were morphologically staged according to WHO and invasive front grading (IFG) criteria. Differences between groups and morphological stages were determined by bivariate statistical analysis. Progressive increases in the percentage of epithelial cells expressing p53 and APE1 were associated with increases in morphological malignancy from normal lip mucosa to LSCC. There was also a significant reduction in epithelial cells expressing hMSH2 and ERCC1 proteins in the AC and LSCC groups. A higher percentage of malignant cells expressing APE1 was found in samples with an aggressive morphological IFG grade. Conclusions: Our data showed that epithelial cells from premalignant to malignant lip disease exhibited changes in the expression of p53, APE1, hMSH2 and ERCC1 proteins; these molecular change might contribute to lip carcinogenesis.