Thymocytes, pre-B cells, and organ changes in a mouse model of chronic ethanol ingestion--absence of subset-specific glucocorticoid-induced immune cell loss

BACKGROUND: The well-known immune deficiency of the chronic alcoholic dictates the need for a long-term rodent ethanol administration model to evaluate the baseline immunologic effects of chronic ethanol abuse, and investigate the genetic determinants of those effects. Much published work with rodents has shown clearly that acute ethanol administration and short-term ethanol-containing liquid diets both cause elevated corticosterone and can cause significant thymocyte, pre-B cell and peripheral lymphocyte losses. Such losses may mask more subtle alterations in immune homeostasis, and in any case are generally short-lived compared with the span of chronic ethanol abuse. Thus, it is important to have a model in which long-term immune alterations can be studied free of corticosteroid-induced cell losses. METHODS: We have utilized chronic 20% (w/v) ethanol in water administration to several mouse strains for prolonged periods of time and evaluated serum corticosterone, immunologic stress parameters, and other organ changes by standard methods. RESULTS: We now confirm earlier reports that chronic ethanol in water administration to mice does not produce net elevations of corticosterone, although diurnal variation is altered. Importantly, there is neither selective loss of immune cell populations known to be corticosteroid sensitive, CD4+CD8+ thymocytes and pre-B cells, nor are changes observed in the histologic appearance of the thymus. Nonetheless, there are significant chronic ethanol effects in other tissues, including reduced heart weight, mild hepatic steatosis, alterations of gut flora, increased serum peptidoglycan, and as published elsewhere, immune system abnormalities. CONCLUSIONS: This model of ethanol administration is convenient, sustainable for up to 1 year, demonstrably feasible in several mouse strains, permits good weight gains in most strains, and results in significant changes in a number of organs. The administration method also will permit modeling of long-term steady abuse punctuated by major binges, and is suitable for supplementation studies using water soluble additives. Overall, the method is useful for a wide range of studies requiring a chronic low-stress method of ethanol administration.     

Unique and redundant roles of alpha4 and beta2 integrins in kinetics of recruitment of lymphoid vs myeloid cell subsets to the inflamed peritoneum revealed by studies of genetically deficient mice

OBJECTIVE: Leukocyte recruitment to inflammatory sites is a prominent feature of acute and chronic inflammation. Instrumental in this process is the coordinated upregulation of leukocyte integrins (among which alpha4beta1 and beta2 integrins are major players) and their cognate receptors in inflamed tissues. To avoid the ambiguity of previous short-term antibody-based studies and to allow for long-term observation, we used genetically deficient mice to compare roles of alpha4 and beta2 integrins in leukocyte trafficking. MATERIALS AND METHODS: Aseptic peritonitis was induced in alpha4 or beta2 integrin-deficient (conditional and conventional knockouts, respectively) and control mice, and recruitment of major leukocyte subsets to the inflamed peritoneum was followed for up to 4 days. RESULTS: Despite normal chemokine levels in the peritoneum and adequate numbers, optimal recruitment of myeloid cells was impaired in both alpha4- and beta2-deficient mice. Furthermore, clearance of recruited neutrophils and macrophages was delayed in these mice. Lymphocyte migration to the peritoneum in the absence of alpha4 integrins was drastically decreased, both at steady state and during inflammation, a finding consistent with impaired lymphocyte in vitro adhesion and signaling. By contrast, in the absence of beta2 integrins, defects in lymphocyte recruitment were only evident when peritonitis was established. CONCLUSIONS: Our data with concurrent use of genetic models of integrin deficiency reveal nonredundant functions of alpha4 integrins in lymphocyte migration to the peritoneum and further refine specific roles of alpha4 and beta2 integrins concerning trafficking and clearance of other leukocyte subsets at homeostasis and during inflammation.     

Estimated age effects in athletic events and chess

Rates of decline are estimated using record bests by age for chess and for various track and field, road running, and swimming events. Using a fairly flexible functional form, the estimates show linear percent decline between age 35 and about age 70 and then quadratic decline after that. Chess shows much less decline than the physical activities. Rates of decline are generally larger for the longer distances, and for swimming they are larger for women than for men. An advantage of using best-performance records to estimate rates of decline is that the records are generally based on very large samples. In addition, the age range is large. In this study the age range is 35 to 100 for swimming, 35 to 98 for track and field and running, and 35 to 94 for chess. The estimates also do not suffer from traditional forms of selection bias.     

A randomized trial of integrated group therapy versus group drug counseling for patients with bipolar disorder and substance dependence

OBJECTIVE: Although bipolar disorder and substance use disorder frequently co-occur, there is little information on the effectiveness of behavioral treatment for this population. Integrated group therapy, which addresses the two disorders simultaneously, was compared with group drug counseling, which focuses on substance use. The authors hypothesized that patients receiving integrated group therapy would have fewer days of substance use and fewer weeks ill with bipolar disorder. METHOD: A randomized controlled trial compared 20 weeks of integrated group therapy or group drug counseling with 3 months of posttreatment follow-up. Sixty-two patients with bipolar disorder and current substance dependence, treated with mood stabilizers for >or=2 weeks, were randomly assigned to integrated group therapy (N=31) or group drug counseling (N=31). The primary outcome measure was the number of days of substance use. The primary mood outcome was the number of weeks ill with a mood episode. RESULTS: Intention-to-treat analysis revealed significantly fewer days of substance use for integrated group therapy patients during treatment and follow-up. Groups were similar in the number of weeks ill with bipolar disorder during treatment and follow-up, although integrated group therapy patients had more depressive and manic symptoms. CONCLUSIONS: Integrated group therapy, a new treatment developed specifically for patients with bipolar disorder and substance dependence, appears to be a promising approach to reduce substance use in this population.     

Non-motor symptoms: identification and management

Non-motor symptoms are an important part of Parkinson's disease (PD) symptoms complex. They cause a significant burden on the quality of life of patients and their carers and remain a major cause of hospitalisation. Treatment of non-motor symptoms can be challenging as these symptoms are often unresponsive to conventional dopaminergic therapy. However, awareness that these symptoms are related to PD is vital as research into treatment and causation will be the cornerstone for delivering a comprehensive modern treatment for PD.     

Assessing normal pulse wave velocity in the proximal pulmonary arteries using transit time: a feasibility, repeatability, and observer reproducibility study by cardiovascular magnetic resonance

PURPOSE: To calculate pulse wave velocity (PWV) in the proximal pulmonary arteries (PAs) by cardiovascular magnetic resonance (CMR) using the transit-time method, and address respiratory variation, repeatability, and observer reproducibility. MATERIALS AND METHODS: A 1.9-msec interleaved phase velocity sequence was repeated three times consecutively in 10 normal subjects. Pulse wave (PW) arrival times (ATs) were determined for the main and branch PAs. The PWV was calculated by dividing the path length traveled by the difference in ATs. Respiratory variation was considered by comparing acquisitions with and without respiratory gating. RESULTS: For navigated data the mean PWVs for the left PA (LPA) and right PA (RPA) were 2.09 +/- 0.64 m/second and 2.33 +/- 0.44 m/second, respectively. For non-navigated data the mean PWVs for the LPA and RPA were 2.14 +/- 0.41 m/second and 2.31 +/- 0.49 m/second, respectively. No statistically significant difference was found between respiratory non-navigated data and navigated data. Repeated on-table measurements were consistent (LPA non-navigated P = 0.95, RPA non-navigated P = 0.91, LPA navigated P = 0.96, RPA navigated P = 0.51). The coefficients of variation (CVs) were 12.2% and 12.5% for intra- and interobserver assessments, respectively. CONCLUSION: One can measure PWV in the proximal PAs using transit-time in a reproducible manner without respiratory gating.