The effect of lipoic acid and vitamin E therapies in individuals with the metabolic syndrome.

The metabolic syndrome is associated with abnormal glucose and lipid metabolism, insulin resistance, increased oxidative stress and pro-inflammatory activity that increase the risk of type 2 diabetes and cardiovascular disease. The aim of this study was to investigate the effect of treatment with the antioxidant α-lipoic acid (ALA) with or without vitamin E supplementation, on markers of insulin resistance and systemic inflammation and plasma nonesterified fatty acid (NEFA) concentrations in individuals with the metabolic syndrome. In a randomized, double-blind, placebo-controlled trial, subjects with the metabolic syndrome received ALA (600 mg/day, n = 34), vitamin E (100 IU/day, n = 36), both ALA and vitamin E (n = 41), or matching placebo (n = 40) for 1 year. Fasting circulating concentrations of glucose and insulin were measure every 3 months and NEFA, markers of inflammation, adiponectin and vitamin E were measured at 6 monthly intervals. Plasma NEFA concentrations decreased [-10 (-18, 0)%] at a marginal level of significance (p = 0.05) in those who received ALA alone compared with placebo and decreased [-8 (-14, -1)% (95% CI)] significantly (P = 0.02) in participants who were randomised to ALA with and without vitamin E compared with those who did not receive ALA. Fasting glucose, insulin, homeostatic model assessment of insulin resistance, adiponectin, and markers of inflammation did not change significantly during the study. These data suggest that prolonged treatment with ALA may modestly reduce plasma NEFA concentrations but does not alter insulin or glucose levels in individuals with the metabolic syndrome.

Pair bonds: arrival synchrony in migratory birds.

Synchronous arrival of pairs of migratory birds at their breeding grounds is important for maintaining pair bonds and is achieved by pairs that remain together all year round. Here we show that arrival is also synchronized in paired individuals of a migratory shorebird, the black-tailed godwit (Limosa limosa islandica), even though they winter hundreds of kilometres apart and do not migrate together. The mechanisms required to achieve this synchrony and prevent 'divorce' illustrate the complexity of migratory systems.

Predictions of biodiversity response to genetically modified herbicide-tolerant crops.

We simulated the effects of the introduction of genetically modified herbicide-tolerant (GMHT) crops on weed populations and the consequences for seed-eating birds. We predict that weed populations might be reduced to low levels or practically eradicated, depending on the exact form of management. Consequent effects on the local use of fields by birds might be severe, because such reductions represent a major loss of food resources. The regional impacts of GMHT crops are shown to depend on whether the adoption of GMHT crops by farmers covaries with current weed levels.

One hundred questions of importance to the conservation of global biological diversity.

We identified 100 scientific questions that, if answered, would have the greatest impact on conservation practice and policy. Representatives from 21 international organizations, regional sections and working groups of the Society for Conservation Biology, and 12 academics, from all continents except Antarctica, compiled 2291 questions of relevance to conservation of biological diversity worldwide. The questions were gathered from 761 individuals through workshops, email requests, and discussions. Voting by email to short-list questions, followed by a 2-day workshop, was used to derive the final list of 100 questions. Most of the final questions were derived through a process of modification and combination as the workshop progressed. The questions are divided into 12 sections: ecosystem functions and services, climate change, technological change, protected areas, ecosystem management and restoration, terrestrial ecosystems, marine ecosystems, freshwater ecosystems, species management, organizational systems and processes, societal context and change, and impacts of conservation interventions. We anticipate that these questions will help identify new directions for researchers and assist funders in directing funds.

WITHDRAWN: GLP-1 Has an Anti-Inflammatory Effect on Adipose Tissue Expression of Cytokines, Chemokines, and Receptors in Obese Women.

The above-named article by Manning PJ, Dixit P, Satthenapalli VR, Katare R, and Sutherland WHF (J Clin Endocrinol Metab. [published online ahead of print 21 May 2019]; doi: 10.1210/jc.2018-00197) has been withdrawn by the authors. The authors report, "The reason for this decision is that the statistical methodology we used did not adequately limit the impact of outlier data points on our findings. This was evident after reanalysis of the data using a different method." doi: 10.1210/jc.2019-01393.

Factors predicting for efficacy and safety of docetaxel in a compassionate-use cohort of 825 heavily pretreated advanced breast cancer patients.

PURPOSE: To identify predictive factors for efficacy and safety in advanced breast cancer (ABC) patients treated in the French compassionate-use docetaxel program. PATIENTS AND METHODS: A total of 825 ABC patients treated with docetaxel (100 mg/m(2) every 3 weeks) were source-reviewed and analyzed for prognostic factors associated with overall response rate (ORR), time to treatment failure (TTF), overall survival (OS), febrile neutropenia, mucositis, and severe fluid retention syndrome by univariate and multivariate analysis. RESULTS: The ORR was 22.9% (95% confidence interval, 20.2% to 26.2%). The median TTF and OS were 4.0 and 9.8 months, respectively. By multivariate analysis, secondary anthracycline-resistant disease was significantly associated (P <. 05) with lower ORR and shorter TTF and OS, whereas anthracycline-refractory disease was associated with shorter OS. Poor performance status was associated with lower ORR, shorter TTF, and shorter OS. Liver dysfunction (transaminase levels > 1.5 times the upper limit of normal [ULN] and alkaline phosphatase [AP] level > three times ULN) and time since first relapse less than 24 months were associated with shorter TTF and OS. Other significant correlations included the following: elevated CA 15-3 serum level with lower ORR; more than two involved sites, and minor transaminase and AP level abnormalities with shorter OS; and no previous chemotherapy for ABC with shorter TTF. According to multivariate analysis, ORR, TTF, and OS were not decreased in patients with liver metastases but without liver dysfunction. CONCLUSION: Docetaxel activity was maintained in heavily pretreated ABC patients and in those with liver metastasis; docetaxel must be used cautiously, however, in patients with liver dysfunction in whom high morbidity risk necessitates strict adherence to dose-adaptation guidelines.

Dispersal, eviction, and conflict in meerkats (Suricata suricatta): an evolutionarily stable strategy model.

Decisions regarding immigration and emigration are crucial to understanding group dynamics in social animals, but dispersal is rarely treated in models of optimal behavior. We developed a model of evolutionarily stable dispersal and eviction strategies for a cooperative mammal, the meerkat Suricata suricatta. Using rank and group size as state variables, we determined state-specific probabilities that subordinate females would disperse and contrasted these with probabilities of eviction by the dominant female, based on the long-term fitness consequences of these behaviors but incorporating the potential for error. We examined whether long-term fitness considerations explain group size regulation in meerkats; whether long-term fitness considerations can lead to conflict between dominant and subordinate female group members; and under what circumstances those conflicts were likely to lead to stability, dispersal, or eviction. Our results indicated that long-term fitness considerations can explain group size regulation in meerkats. Group size distributions expected from predicted dispersal and eviction strategies matched empirical distributions most closely when emigrant survival was approximately that determined from the field study. Long-term fitness considerations may lead to conflicts between dominant and subordinate female meerkats, and eviction is the most likely result of these conflicts. Our model is computationally intensive but provides a general framework for incorporating future changes in the size of multimember cooperative breeding groups.

Impaired endothelial function following a meal rich in used cooking fat.

OBJECTIVES: The purpose of this study was to test the hypothesis that intake of used cooking fat is associated with impaired endothelial function. BACKGROUND: Diets containing high levels of lipid oxidation products may accelerate atherogenesis, but the effect on endothelial function is unknown. METHODS: Flow-mediated endothelium-dependent dilation and glyceryl trinitrate-induced endothelium-independent dilation of the brachial artery were investigated in 10 men. Subjects had arterial studies before and 4 h after three test meals: 1) a meal (fat 64.4 g) rich in cooking fat that had been used for deep frying in a fast food restaurant; 2) the same meal (fat 64.4 g) rich in unused cooking fat, and 3) a corresponding low fat meal (fat 18.4 g) without added fat. RESULTS: Endothelium-dependent dilation decreased between fasting and postprandial studies after the used fat meal (5.9 +/- 2.3% vs. 0.8 +/- 2.2%, p = 0.0003), but there was no significant change after the unused fat meal (5.3 +/- 2.1% vs. 6.0 +/- 2.5%) or low fat meal (5.3 +/- 2.3% vs. 5.4 +/- 3.3%). There was no significant difference in endothelium-independent dilation after any of the meals. Plasma free fatty acid concentration did not change significantly during any of the meals. The level of postprandial hypertriglyceridemia was not associated with change in endothelial function. CONCLUSIONS: Ingestion of a meal rich in fat previously used for deep frying in a commercial fast food restaurant resulted in impaired arterial endothelial function. These findings suggest that intake of degradation products of heated fat contribute to endothelial dysfunction.

The effect of hormone replacement therapy on cardiovascular risk factors in type 2 diabetes: a randomized controlled trial.

BACKGROUND: Postmenopausal women with diabetes are at high risk for cardiovascular disease, compared with their nondiabetic counterparts. Combined continuous hormone replacement therapy (HRT) is associated with improvements in serum lipoprotein levels in nondiabetic women; however, the effect in women with diabetes has not been determined. We evaluated the effect of combined continuous HRT on lipoprotein and coagulation factor concentrations and glycemic control in postmenopausal women with type 2 diabetes mellitus. METHODS: In a randomized controlled crossover study, 61 subjects received combined continuous HRT or placebo. Each treatment phase was of 6 months' duration, with an 8-week washout phase between treatment phases. RESULTS: Total cholesterol concentration decreased by 7% (95% confidence interval [CI], 4%-11%) during HRT. For low-density lipoprotein concentration, the mean decrease with HRT was 12% (95% CI, 6%-17%). Apolipoprotein B levels decreased in keeping with the reduction in low-density lipoprotein cholesterol concentrations. There were no significant changes in concentrations of high-density lipoprotein, its subfractions, or triglycerides. Lipoprotein(a) and fibrinogen concentrations were reduced by 21% (95% CI, 10%-31%) and 8% (95% CI, 2%-13%), respectively, with HRT. Fructosamine concentrations declined by 5% (95% CI, 2%-9%) during HRT. CONCLUSIONS: In postmenopausal women with type 2 diabetes mellitus, combined continuous HRT has beneficial effects on lipoprotein concentrations and improves some markers of coagulation and glycemic control.

Effect of supplementation with tomato juice, vitamin E, and vitamin C on LDL oxidation and products of inflammatory activity in type 2 diabetes.

OBJECTIVE: To compare the effects of short-term dietary supplementation with tomato juice, vitamin E, and vitamin C on susceptibility of LDL to oxidation and circulating levels of C-reactive protein (C-RP) and cell adhesion molecules in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: There were 57 patients with well-controlled type 2 diabetes aged <75 years treated with placebo for 4 weeks and then randomized to receive tomato juice (500 ml/day), vitamin E (800 U/day), vitamin C (500 mg/day), or continued placebo treatment for 4 weeks. Susceptibility of LDL to oxidation (lag time) and plasma concentrations of lycopene, vitamin E, vitamin C, C-RP, vascular cell adhesion molecule 1, and intercellular adhesion molecule 1 were measured at the beginning of the study, after the placebo phase, and at the end of the study. RESULTS: Plasma lycopene levels increased nearly 3-fold (P = 0.001), and the lag time in isolated LDL oxidation by copper ions increased by 42% (P = 0.001) in patients during supplementation with tomato juice. The magnitude of this increase in lag time was comparable with the corresponding increase during supplementation with vitamin E (54%). Plasma C-RP levels decreased significantly (-49%, P = 0.004) in patients who received vitamin E. Circulating levels of cell adhesion molecules and plasma glucose did not change significantly during the study. CONCLUSIONS: This study indicates that consumption of commercial tomato juice increases plasma lycopene levels and the intrinsic resistance of LDL to oxidation almost as effectively as supplementation with a high dose of vitamin E, which also decreases plasma levels of C-RP, a risk factor for myocardial infarction, in patients with diabetes. These findings may be relevant to strategies aimed at reducing risk of myocardial infarction in patients with diabetes.

Prolonged neutropenia in a novel mouse granulocyte colony-stimulating factor neutralizing auto-immunoglobulin G mouse model.

Therapeutic use of recombinant human cytokines in humans can result in the generation of drug-specific antibodies. To predetermine the maximum potential effects of a granulocyte colony-stimulating factor (G-CSF) neutralizing auto-immunoglobulin G (auto-IgG) response during recombinant human G-CSF therapy, we developed a mouse model of mouse G-CSF (mG-CSF) neutralizing auto-IgG response. Mice were immunized and boosted with mG-CSF chemically conjugated to either keyhole limpet hemocyanin or ovalbumin on an alternating schedule. Sera were analyzed for mG-CSF-specific titers and full blood counts were performed on a Technicon H-1E. On day 252, tissues were collected for histology. IgG was protein A affinity purified from pooled mG-CSF autoimmune sera. Mice immunized with mG-CSF conjugates produced mG-CSF-specific auto-IgG responses that lasted for the length of the study. Significant neutropenia (p(max) < 0.004) was concurrent with the rise in mG-CSF-specific IgG titers. However, neutrophil counts remained at approximately 20% of preimmunization levels through day 252. Endogenous mG-CSF neutralizing auto-IgG had no significant effect on hemoglobin, erythrocyte, lymphocyte, eosinophil, basophil, and platelet counts, and had minor, transient, or no effects on monocyte counts. Bone marrow colony assays from mG-CSF autoimmune mice demonstrated no significant effect of G-CSF neutralization on the numbers or proliferative capacity of preneutrophil lineage progenitors. Purified IgG from mG-CSF autoimmune mice neutralized mG-CSF in vitro. High-titer G-CSF neutralizing auto-IgG in adult mice partially inhibited steady-state granulopoiesis and had little or no effect on steady-state levels of other hematopoietic cells.

A new form of Filgrastim with sustained duration in vivo and enhanced ability to mobilize PBPC in both mice and humans.

Granulocyte colony-stimulating factor (G-CSF) has proven effective in the prophylaxis of chemotherapy-induced neutropenia and as a mobilizer of peripheral blood progenitor cells. The longevity of G-CSF action is limited by its removal from the body by two mechanisms. The first is thought to be mediated via receptors (receptor mediated clearance [RMC]) predominantly on neutrophils, the second process is likely the result of renal clearance. With the intention of developing a novel form of Filgrastim (r-met HuG-CSF) with a sustained duration of action in vivo, a new derivative named SD/01 has been made by association of Filgrastim with poly(ethylene glycol). The desired properties of this new agent would include a prolonged duration of action sufficient to cover a complete single course of chemotherapy. SD/01 is shown here to sustain significantly elevated neutrophil counts in hematopoietically normal mice for 5 days. In neutropenic mice effects were noted for at least 9 days, accompanying a significant reduction in the duration of chemotherapy induced neutropenia. Normal human volunteers showed higher than baseline ANC for around 9 to 10 days after a single injection of SD/01. Data from these normal volunteers also indicate that mobilization of CD34+ cells and progenitors may occur in a more timely manner and to around the same absolute numbers as with repeated daily injections of unmodified Filgrastim. These data indicate that SD/01 represents an efficacious novel form of Filgrastim with actions sustained for between one and two weeks from a single injection.

Plasma cholesterol esterification and transfer, the menopause, and hormone replacement therapy in women.

With the onset of the menopause, plasma lipids and lipoprotein metabolism changes toward a more atherogenic profile that is improved by HRT. To determine whether cholesterol esterification rate (CER) and transfer of cholesteryl esters from high density lipoproteins to apolipoprotein B-containing lipoproteins are affected by menopause and HRT, plasma newly synthesized cholesteryl ester transfer (NCET) activity, CER and plasma lipids, lipoproteins, and apolipoprotein concentrations were measured in perimenopausal women (age range: 40-55 yr), including 49 premenopausal women and 32 postmenopausal women who were subsequently randomized to receive either placebo or 17-beta estradiol/norethisterone for 6 months. Plasma NCET (P = 0.03) and CER (P = 0.008) were significantly higher in postmenopausal women. Plasma low density lipoprotein cholesterol concentration, high density lipoprotein concentration, and body mass index were independent predictors of plasma NCET in premenopausal women, and plasma triglyceride and apolipoprotein B concentrations were corresponding predictors in postmenopausal women. When data were adjusted for plasma triglyceride, plasma NCET activity was no longer significantly different (P = 0.81) between premenopausal and postmenopausal women. Plasma NCET and CER did not change significantly in postmenopausal women during HRT. These data suggest that the determinants of plasma NCET activity after menopause and increased levels of triglyceride-rich lipoprotein acceptors of cholesteryl esters may lead to increased plasma NCET that is not reduced by HRT in postmenopausal women.

Oxaliplatin clinical activity: a review.

Oxaliplatin (Eloxatin), a recently developed third-generation cisplatin analogue with a 1,2-diaminocyclohexane (DACH) carrier ligand, has displayed preclinical and clinical activity in a wide variety of tumour types. Synergistic with 5-FU in colorectal cancer (CRC), the combination has proven efficacy in 5-FU-resistant advanced disease and in previously untreated CRC, as demonstrated in controlled phase III trials, while evaluation in the adjuvant setting is ongoing. Due to its excellent safety profile, its unique mechanism of action and lack of cross-resistance with other active agents in CRC, oxaliplatin has also been combined with CPT-11 and Raltitrexed with promising results. Trials in pretreated and untreated advanced ovarian cancer (AOC), as a single agent or in combination with cisplatin, cyclophosphamide or paclitaxel, indicate a yet to be defined role in AOC and confirm its lack of cross-resistance with cis/carboplatin. Clinical investigations of single agent and combination therapies in breast, lung, prostate and germ-cell carcinomas, non-Hodgkin's lymphoma and malignant mesothelioma are being pursued. While the role of oxaliplatin in medical oncology is yet to be fully defined, it appears to be an important new anticancer agent.

Adiposity, lipids, alcohol consumption, smoking, and gender.

Indices of obesity, plasma lipids, and lipoprotein levels, plasma cholesteryl ester fatty acid composition, reported alcohol consumption and smoking habits were measured in 88 men and 87 women, ages over 15 years, randomly selected from the total respondents (1192) to a health survey. Most indices of obesity were related to plasma triglycerides and high-density lipoprotein levels in both sexes; to very low-density lipoprotein levels in men only; and to plasma cholesteryl ester fatty acid linoleic acid proportions in women only. The correlations with high-density lipoprotein cholesterol levels were dependent on very low-density lipoprotein triglyceride levels in men but not in women. Indices of obesity were significantly higher in nonsmoking women and reported alcohol consumption correlated with Quetelet's index (body mass index) in men. Smoking habits, but not alcohol consumption, influenced correlations between indices of obesity and plasma triglycerides and very low-density lipoprotein triglyceride levels in men. The present results showed several sex-related differences in relationships with indices of obesity. Lower very low-density lipoprotein levels, higher skinfold measurements, higher cholesteryl ester fatty acid linoleic acid proportions and lower alcohol intake in women than in men may be responsible. The data suggested that in women, altered diet composition may be linked with obesity.

Physical activity and plasma lipoprotein lipid concentrations in men.

Twenty-three apparently normal untrained men aged 20--55 participated in a 4-month self-regulated training programme ending in a marathon run. Fasting plasma and lipoprotein lipid concentrations, adipose tissue lipoprotein lipase activity, anthropometric data, alcohol consumption, smoking habits, weekly mileage run and performance on a bicycle ergometer were recorded before and after the training period. Training induced an increase in high density lipoprotein cholesterol (HDL-C) concentration which was not directly related to concomitant decreases in mean very low density lipoprotein cholesterol (VLDL-C) concentration or mean total skinfold thickness. The degree of the changes in VLDL lipids and HDL-C levels were related to pretraining values, and changes in HDL-C and VLDL triglycerides (VLDL-TG) were also associated. Initial total skinfold thickness correlated inversely with the change in VLDL-TG levels during training. The pretaining concentration of VLDL-C was related to the corresponding value for HDL-C after training. The magnitude of exercise-induced changes in VLDL-C and HDL-C levels are more related to pre-training levels than to changes in measured exercise parameters, indices of obesity or adipose tissue lipoprotein lipase activity. However, the level of adiposity of subjects at the beginning of the study influenced the response of VLDL-TG levels to increased physical activity. The data suggest that VLDL contributes to the increase in HDL-C levels with exercise but is not the major source of the increment.

Oxidation of heparin-treated low density lipoprotein by peroxidases.

Low density lipoproteins (LDL) can bind to glycosaminoglycans and proteoglycans rich in heparin and chondroitin sulphate in the arterial intima and may become a target for atherogenic modification by myeloperoxidase activity. We have examined the susceptibility of resolubilized LDL, that has been precipitated from serum with heparin (HepLDL), to peroxidase-H2O2-catalysed oxidation and the effects of antioxidants and components of human serum on the oxidation. HepLDL was oxidised rapidly by horse radish peroxidase (HRP) and H2O2 (mean t1/2max for conjugated diene formation, 3 min) while there was little oxidation of native LDL or native LDL precipitated with polyethyleneglycol and resolubilised during the 30 min incubation period. The formation of thiobarbituric acid reacting substances (TBARS) essentially paralleled that of conjugated dienes during oxidation of HepLDL. HepLDL was also more rapidly oxidised than native LDL by myeloperoxidase-H2O2. Oxidation of HepLDL by peroxidases did not require free tyrosine, was almost totally inhibited by butylated hydroxytoluene (BHT) and ascorbate, and was unaffected by vitamin E and urate. Increasing concentrations (0-14.9%) of beta-lipoprotein deficient serum (BLPDS) significantly (P<0.0001) inhibited the formation of TBARS during HepLDL oxidation catalysed by HRP and partially inhibited the corresponding myeloperoxidase-catalysed oxidation. This inhibitory activity was removed by dialysis and gel-filtration of BLPDS and was not restored by addition of magnesium ions used in the isolation of BLPDS, or physiological levels of ascorbate, tyrosine and reduced thiols (cysteine) to gel-filtered BLPDS. The results indicate that LDL from complexes with glycosaminoglycans are highly susceptible to oxidation by peroxidases, particularly at low levels of water soluble antioxidants, and that vulnerability of these LDL to myeloperoxidase oxidation remains in the presence of serum components that should exist in the arterial intima. These findings may be relevant to the oxidative modification of LDL that becomes trapped by binding to arterial proteoglycans and to the formation of myeloperoxidase-modified LDL in the artery wall.

High density lipoprotein levels in children of young men with ischaemic heart disease.

This study was designed to assess HDL levels in children of young men with IHD, compared with children of asymptomatic men. Like their fathers, sons of patients with heart disease, had significantly lower HDL cholesterols than controls. This difference was independent of fasting triglycerides, obesity, diet or physical activity, and was the only "coronary risk factor" in this young age group.

Lecithin: cholesterol acyl transferase activity in the serum of rats fed saturated and unsaturated fats.

Groups of rats were fed diets containing either butter, beef, fat or safflower oil. After 20 or 70 days of feeding, blood was taken from the animals in a postabsorptive state. Serum lipid levels and lecithin: cholesterol acyl transferase activity were measured. Feeding the different fats did not alter serum total cholesterol levels but free cholesterol and triglycerides were significantly lower in the safflower oil-fed group. Net cholesterol esterification in vitro was also significantly depressed in the safflower oil-fed group and this was shown to be due to the inability of the lipoprotein substrate to support the reaction rather than because of low LCAT enzyme activity.

Modification of nicotinic acid and prostaglandin E1 antilipolytic action in vitro.

In epididymal adipose tissue from rats, human serum antagonizes inhibition of basal lipolysis by nicotinic acid in vitro. Under similar conditions caffeine-stimulated lipolysis was unaffected by the presence of human serum. Very low density (VLDL), low density (LDL) and high density (HDL) lipoproteins were all found to antagonize the action of nicotinic acid on basal lipolysis. VLDL also antagonized prostaglandin E1 (PGE1)-inhibition of basal lipolysis in vitro. The fat cell membrane was suggested as the site at which human serum lipoproteins antagonize nicotinic acid or PGE1 antilipolytic action on basal lipolysis in vitro.