Insulin Resistance Is Associated With Diminished Endoplasmic Reticulum Stress Responses in Adipose Tissue of Healthy and Diabetic Subjects

We recently showed that insulin increased ER stress in human adipose tissue. The effect of insulin resistance on ER stress is not known. It could be decreased, unchanged, or increased, depending on whether insulin regulates ER stress via the metabolic/phosphoinositide 3-kinase (PI3K) or alternate signaling pathways. To address this question, we examined effects of lipid-induced insulin resistance on insulin stimulation of ER stress. mRNAs of several ER stress markers were determined in fat biopsies obtained before and after 8-h hyperglycemic-hyperinsulinemic clamping in 13 normal subjects and in 6 chronically insulin-resistant patients with type 2 diabetes mellitus (T2DM). In normal subjects, hyperglycemia-hyperinsulinemia increased after/before mRNA ratios of several ER stress markers (determined by ER stress pathway array and by individual RT-PCR). Lipid infusion was associated with inhibition of the PI3K insulin-signaling pathway and with a decrease of hyperinsulinemia-induced ER stress responses. In chronically insulin-resistant patients with T2DM, hyperglycemic-hyperinsulinemia did not increase ER stress response marker mRNAs. In summary, insulin resistance, either produced by lipid infusions in normal subjects or chronically present in T2DM patients, was associated with decreased hyperinsulinemia-induced ER stress responses. This suggests, but does not prove, that these two phenomena were causally related.     

Coagulation changes and edema formation during long-distance bus travel.

Long-distance travel in a cramped position by aircraft or by bus and car has been suggested to be associated with an increased risk for thromboembolic events. Recently, we demonstrated moderate activation of coagulation after a long-haul flight. At present the single contributing factors (i.e. hypoxia and low humidity on board an aircraft and prolonged sitting in an aircraft, car or bus inducing venous stasis) have not yet been investigated. Therefore we measured markers of coagulation and fibrinolysis as well as functional parameters of coagulation using activated thrombelastography in 19 healthy volunteers before, during and after a real 10-h bus journey. In addition, changes in leg volume were measured. Thrombelastography revealed moderate activation of coagulation in all travelers, which was accompanied by a significant increase in prothrombin fragment F1 + 2. Thrombin-antithrombin III complexes and D-dimer remained unchanged, and tissue-type plasminogen activator and plasminogen-activator inhibitor 1 decreased after travel. After the travel we found a significant increase in leg volume that was exclusively distributed in the calf. We conclude that beside long-haul flights also long-distance bus travel induces a certain activation of the coagulation system. Thus, it is questionable whether hypoxia is the crucial risk factor for thromboembolic events after long-haul flights.     

Inconsistencies Between Actual and Estimated Blood Alcohol Concentrations in a Field Study of College Students: Do Students Really Know How Much They Drink?

BACKGROUND: Alcohol use by college students is commonly measured through the use of surveys. The validity of such data hinge on the assumption that students are aware of how much alcohol they actually consume. Recent studies call this assumption into question. Students tend to overestimate the appropriate sizes of standard drinks, suggesting that they might underestimate how much alcohol they consume. If this is true, then students' actual blood alcohol concentrations (BACs) should be higher than BACs estimated based on self-report data. The present study examined this issue METHODS: Breathalyzer readings and self-reported drinking data were collected from 152 college students during the fall of 2004. Estimated BACs were calculated by means of a standard formula, and the relation between actual and estimated BACs was examined. Factors contributing to discrepancies between the two values were identified RESULTS: Estimated BAC levels were significantly higher, not lower, than breath BAC measures. The accuracy of estimated BACs decreased as the number of drinks and amount of time spent drinking increased. Being male and drinking only beer predicted greater accuracy of estimated BACs CONCLUSIONS: Although laboratory data suggest that students underestimate how much they drink, the hypothesis was not supported by data collected in the field. It appears that students might actually overestimate rather than underestimate their levels of consumption when surveyed in the midst of a night of drinking. The findings corroborate observations made by other researchers and suggest that the findings of laboratory studies on college drinking do not necessarily extend to real-world settings.     

A Systematic Analysis of the Sensitivity of Plasma Pharmacokinetics to Detect Differences in the Pulmonary Performance of Inhaled Fluticasone Propionate Products Using a Model-Based Simulation Approach

The role of plasma pharmacokinetics (PK) for assessing bioequivalence at the target site, the lung, for orally inhaled drugs remains unclear. A validated semi-mechanistic model, considering the presence of mucociliary clearance in central lung regions, was expanded for quantifying the sensitivity of PK studies in detecting differences in the pulmonary performance (total lung deposition, central-to-peripheral lung deposition ratio, and pulmonary dissolution characteristics) between test (T) and reference (R) inhaled fluticasone propionate (FP) products. PK bioequivalence trials for inhaled FP were simulated based on this PK model for a varying number of subjects and T products. The statistical power to conclude bioequivalence when T and R products are identical was demonstrated to be 90% for approximately 50 subjects. Furthermore, the simulations demonstrated that PK metrics (area under the concentration time curve (AUC) and C_max) are capable of detecting differences between T and R formulations of inhaled FP products when the products differ by more than 20%, 30%, and 25% for total lung deposition, central-to-peripheral lung deposition ratio, and pulmonary dissolution characteristics, respectively. These results were derived using a rather conservative risk assessment approach with an error rate of <10%. The simulations thus indicated that PK studies might be a viable alternative to clinical studies comparing pulmonary efficacy biomarkers for slowly dissolving inhaled drugs. PK trials for pulmonary efficacy equivalence testing should be complemented by in vitro studies to avoid false positive bioequivalence assessments that are theoretically possible for some specific scenarios. Moreover, a user-friendly web application for simulating such PK equivalence trials with inhaled FP is provided.

Electronic supplementary material

The online version of this article (doi:10.1208/s12248-015-9768-y) contains supplementary material, which is available to authorized users.Key words: bioequivalence, inhaled corticosteroids, pharmacokinetics, pharmacometrics, trial simulation     

Amount of systemic steroid medication is a strong predictor for the use of complementary and alternative medicine in patients with inflammatory bowel disease: results from a German national survey

OBJECTIVES: Previous studies have suggested that inflammatory bowel disease (IBD) patients rank high among users of complementary and alternative medicine (CAM). To further elucidate this phenomenon, we sent questionnaires to a large sample of IBD patients in Germany to determine the patterns and predictors of their CAM use. METHODS: Pretested 73-item questionnaires were mailed to a randomly selected representative sample of 1000 IBD patients from the approximately 16,000 members and associates of the German Crohn's and Colitis Association. Predictors of CAM use were evaluated by logistic regression models. RESULTS: Completed questionnaires were returned by 684 patients (female patients, 61.4%; Crohn's disease patients, 58.3%; ulcerative colitis patients, 38.2%). Of the 671 adult respondents, 344 (51.3%) had experience with CAM, and significantly more of the ulcerative colitis patients (59.8%) than the Crohn's disease patients (48.3%) had experience with CAM. There was no difference by gender. Homeopathy (52.9%) and herbal medicine (43.6%) were the most commonly used types of CAM. The most frequent personal reasons for CAM use were the search for an "optimum treatment" (78.9%) and the wish to stop taking steroids (63.8%). Using logistic regression, we found that total cortisone intake (P = 0.0077), but not duration of disease, was a strong predictor of CAM use. Other predictors were experience with psychosomatic and psychotherapeutic support (P = 0.0029), relaxation techniques (P = 0.0284), an academic education (P = 0.0173), a diet utilizing whole grains (P = 0.0123), and a normal body weight (P = 0.0215). Although 80% of patients indicated that they were interested in using CAM in the future, only 24.7% felt sufficiently informed about it. CONCLUSIONS: More than 50% of a large group of German IBD patients had used CAM. Prolonged or intensive steroid treatment, an academic education, active ways of coping, and a health-conscious life-style are associated with CAM use. Given the potential side effects and interactions, the treating physician should focus on thorough information about the benefits and limitations of conventional and complementary treatment options, especially for IBD patients who have received prolonged or intensive steroid treatment.     

Adoptive immunotherapy in chimeras with donor lymphocytes

Allogeneic stem cell transplantation has a well-defined indication in the treatment of hematological malignancies. The beneficial immune effect of allogeneic marrow transplantation has long been known, but only recently have methods been developed to separate the graft-versus-leukemia (GVL) effect from graft-versus-host disease (GVHD). Animal experiments have shown that lymphocytes from the marrow donor can be transfused without causing severe GVHD if stable chimerism and tolerance is established. First clinical studies have been preformed in patients with recurrent chronic myelogenous leukemia. In these patients complete molecular remissions were induced that persist without further maintenance treatment. These results have been confirmed in larger multicenter studies in Europe and the USA. The best results were obtained in chronic myelogenous leukemia (CML); repeated successes have been reported in relapsing acute myeloid leukemia (AML), myelodysplastic syndromes and multiple myeloma (MMY), and rare responses were reported for acute lymphoid leukemia. Contrary to animal experiments GVHD has been observed in human patients although to a lesser extent than expected in transplants not given immunosuppression. Secondly myelosuppression has been observed in patients treated with relapsing CML. In CML the incidence of GVHD could be reduced by depleting CD8+ T cells from the donor lymphocyte concentrate. Alternatively only small numbers of T lymphocytes can be transfused and in the case of failing responses, the numbers of donor lymphocytes may be increased. Results in recurrent AML have been improved by the use of low-dose cytosine arabinoside, granulocyte-macrophage colony-stimulating factor and granulocyte colony-stimulating factor mobilized blood cells as compared to lymphocytes only. In MMY the response rate is higher than in AML, but the remissions are of limited duration in most patients. Several protocols have been designed to include preemptive donor lymphocyte transfusion in patients with a high relapse risk after transplantation. Problems remain to avoid chronic GVHD and to circumvent the immune escape mechanisms of leukemia.     

Expressionsanalysen bei der rheumatoiden Arthritis

Inflammatory rheumatic diseases with their unclear aetiology are a challenge for the routine clinical practice. The dominating inflammatory processes with many facets of autoimmune phenomena have been extensively studied during the last decades. Modern high throughput technologies provide for the first time the opportunity to obtain an insight into the many different molecular aspects in one patient in parallel. Step by step, concepts can be developed to understand the relationships and interdependencies of the molecular processes and to place them in order of importance for each individual separately. Thus, studies have demonstrated that the risk of disease severity can be estimated and the response to therapy can be objectified based on molecular investigations. Exemplarily, the potential has been demonstrated that the therapeutic outcome towards a defined treatment may be predicted. Despite the high cost, it is becoming more and more obvious that an extensive increase of knowledge depends on the detection of a multitude of parameters, a task which will need to be accomplished in the near future.