Increased CD8+ T Cell Apoptosis in Scleroderma Is Associated with Low Levels of NF-κB

Our objectives were (1) to compare lymphocyte subpopulation apoptosis rates in SSc patients versus healthy controls and (2) to compare Bcl-2 and NF-kappa B expression in cultured CD8 lymphocytes of SSc patients versus controls. Peripheral blood samples were obtained from 27 SSc patients meeting the American College of Rheumatology criteria for SSc and 28 healthy individuals. Mononuclear cells were isolated by Ficoll-Hypaque density gradient separation and cultured for 48 hr. For determination of apoptosis within specific cell populations, samples were labeled with PE-conjugated monoclonal antibody to CD8, CD4, and a FITC-conjugated monoclonal antibody to Annexin V. Flow cytometry was carried out with a FACS operating with Cellquest software. CD8+ lymphocytes were positively selected with magnetic microbeads conjugated to antihuman CD8. CD8 T cells were separated, then incubated with activation for 48 hr, and NF-kappa B and Bcl-2 analysis was carried out using Western immunoblotting. The CD4:CD8 ratio was increased in SSc compared to controls (2.6 +/- 1.13 vs.1.87 +/- 0.76; P = 0.018). The spontaneous apoptosis rate of SSc CD8 lymphocytes was increased compared to that of controls of (21.9 +/- 13.7 vs. 13.3 +/- 9.9; P = 0.019). No difference was found in the rate of CD4 apoptosis of SSc patients versus controls (9.8 +/- 5.2 vs. 7.18 +/- 4.89%; P = ns). The expression of NF-kappa B in SSc CD8 lymphocytes was decreased compared with that of CD8 lymphocytes from healthy controls (144 +/- 13 vs. 188 +/- 11; P = 0.018). Whereas expression of Bcl-2 was similar in activated CD8+ T cells of SSc patients and healthy controls, CD8+ T cell apoptosis rate was found to be in reverse correlation with expression of NF-kappa B in these cells ( r = - 0.53, P = 0.029). The increased CD4:CD8 ratio in SSC may result from increased CD8+ T cell apoptosis. Increased SSc CD8 T cell apoptosis is associated with low levels of NF-kappa B.     

COMT Gene Polymorphism Is Associated with Declarative Memory in Adulthood and Old Age

Variation in memory performance is to a large extent explained by genes. In the prefrontal cortex, the catechol O-methyltransferase (COMT) gene is essential in the metabolic degradation of dopamine, a neurotransmitter implicated in cognitive functions. The present study examined the effect of a polymorphism in the COMT gene on individual differences and changes in memory in adulthood and old age. Tests assessing episodic and semantic memory were administered to 286 men (initially aged 35-85 years) from a random sample of the population (i.e., the Betula prospective cohort study) at two occasions followed over a 5-year period. Carriers of the Met/Met genotype (with low enzyme activity) performed better on episodic and semantic memory, as compared to carriers of the Val allele (with higher enzyme activity). Division of episodic memory into its recall and recognition components showed that the difference was specific to episodic recall, not recognition tasks; an effect that was observed across three age groups (middle-age, young-old, and old-old adults) and over a 5-year period. The COMT gene is a plausible candidate gene for memory functioning in adulthood and old age.     

Semaphorins: Their Dual Role in Regulating Immune-Mediated Diseases

The semaphorin family members were originally considered to play a role in neurodevelopment, angiogenesis, tumor development, and metastasis. Over the past few years, a growing body of data indicates that semaphorins are involved in the regulation of the immune system, identified in this case as the “immune semaphorins.” These semaphorins are involved in almost all phases of both normal and pathological immune responses and were demonstrated to participate in allergic diseases as well as in auto-immune pathologies. Some of them, such as semaphorin 3A (sema3A), is important in downregulating autoimmune diseases by suppressing the over-activity of both T and B cell autoimmunity. In addition, sema3A was shown to enhance the ability of T and B cell regulatory properties and by doing so to control autoimmune diseases, such as systemic lupus erythematosus. Other semaphorins, such as semaphorins 4D and 4A are important in stimulating T and B cells, thus keeping these immune responses on-going. However, when overexpressed, they can induce the induction of many immune-mediated diseases. The importance of all this is to develop targeting therapies that could possibly enhance or alternatively suppress these molecules. In this review, we will focus on several immune semaphorins—their role in immune homeostasis and in immune-mediated diseases.     

Reducing breast cancer recurrence with weight loss,a vanguard trial: The Exercise and Nutrition to Enhance Recovery and Good Health for You (ENERGY) Trial

Breast cancer is the most common invasive cancer among women in developed countries. Obesity is a major risk factor for breast cancer recurrence and mortality in both pre- and postmenopausal women. Co-morbid medical conditions are common among breast cancer survivors. The Exercise and Nutrition to Enhance Recovery and Good Health for You (ENERGY) study is a 4-year randomized clinical trial of 693 overweight/obese women aged ≥ 21 years diagnosed with any early stage breast cancer (stages I[≥ 1 cm]-III) within the previous five years, designed to demonstrate the feasibility of achieving sustained weight loss and to examine the impact of weight loss on quality of life and co-morbidities, and to enable future exploration of biochemical mechanisms linking obesity to lower likelihood of disease-free survival. This trial is strategically designed as a vanguard for a fully-powered trial of women who will be evaluated for breast cancer recurrence and disease-free survival. Participants were recruited between 2010 and 2012 at four sites, had completed initial therapies, and had a body mass index between 25 and 45 kg/m². The intervention featured a group-based cognitive-behavioral weight loss program with telephone counseling and tailored newsletters to support initial weight loss and subsequent maintenance, with the goal of 7% weight loss at two years. This study has high potential to have a major impact on clinical management and outcomes after a breast cancer diagnosis. This trial initiates the effort to establish weight loss support for overweight or obese breast cancer survivors as a new standard of clinical care.     

Comparison between a second and a third generation parathyroid hormone assay in hemodialysis patients

Objective

Third generation parathyroid hormone (PTH) assays are new generation assays that do not recognize the PTH_7–84 fragment whereas second generation assays detect both PTH_1–84 and PTH_7–84 fragments. Despite the excellent correlation between both assays in chronic renal failure (CRF) subjects, the mean PTH levels are typically 50% lower with the third compared to the second generation assays. The assessment of third generation PTH assays has not been extensively studied in hemodialysis subjects. The purpose of our study was to compare a third generation PTH assay to a second generation one in a population of hemodialysis subjects.

Materials and methods

92 haemodialysis subjects (36 women and 56 men) with a mean age of 67±12.9 years were included in this study. Anthropometric and clinical parameters (Body Mass Index (BMI) and blood pressure) were measured. Second and third generation PTH assays (Cis biomedical and Diasorin respectively) were performed in each subject. In addition, the following biochemical tests were measured: 25-hydroxyvitamin D (25-(OH)D), 1,25-hydroxyvitamin D (1,25-(OH)₂D), crosslaps and alkaline phosphatase.

Results

The mean second and third generation PTHs are respectively 211±205 pg/ml and 151±164 pg/ml. The mean third generation PTH values are 28.4% lower compared to the second generation ones. Both methods are strongly correlated (r = 0.923, p < 0.001). This correlation persisted without any significant difference after controlling for gender, age, BMI and Blood Pressure. However, the difference between both methods increases when baseline PTH increases. Each of the second and third generation method is significantly correlated with hemodialysis duration (p < 0.01), crosslaps (p < 0.001), alkaline phosphatase (p < 0.05), but not with age, BMI, Blood Pressure, 25-(OH)D or 1,25-(OH) ₂D levels.

Conclusion

Our results show that both second and third generation PTH methods are strongly correlated in hemodialysis patients mainly when PTH values are low. However, the difference between both methods increases when PTH values are high. More research is needed to establish which method is the gold standard when PTH values are high.     

Complete response in myeloma extends survival without, but not with history of prior monoclonal gammopathy of undetermined significance or smouldering disease

Complete response (CR) is still considered an important surrogate marker for outcome in multiple myeloma (MM). Long-term survival after transplantation, however, has been observed in a substantial proportion of patients who never achieved CR. The tandem transplant trial, Total Therapy 2, enrolled 668 patients, who were randomised up-front to thalidomide (THAL) or no THAL; 56 patients were identified as having had, for at least 6 months prior to initiation of therapy, monoclonal gammopathy of undetermined significance (MGUS, n = 21), smouldering MM (SMM, n = 22) or solitary plasmacytoma of bone (SPC, n = 13). The clinical characteristics and outcomes of patients with such 'evolved' MM (E-MM) and of those with 'unknown' prior history (U-MM) were compared. Fewer patients with MGUS/SMM-E-MM had anaemia or renal failure; CR was lower (22% vs. 48%) but 4-year estimates of event-free survival (54% vs. 56% with U-MM) and overall survival (65% vs. 70% with U-MM) were similar to those with SPC-E-MM or U-MM. In the latter group, achieving CR was associated with prolonged survival. In comparison with U-MM, E-MM evolved from MGUS/SMM was associated with lower CR rate without adversely affecting survival. In contrast, CR was an independent favourable feature for survival in U-MM.     

Influenza vaccination and risk of mortality among adults hospitalized with community-acquired pneumonia

BACKGROUND: Influenza vaccination has been shown to reduce illness and all-cause mortality in vulnerable populations through the prevention of influenza infection. Attenuation of the severity of illness by vaccination has been reported for respiratory tract infections due to bacterial pathogens and would represent an important additional health benefit of influenza vaccination. We evaluated the impact of prior influenza vaccination on in-hospital mortality and other health outcomes among hospitalized adults with community-acquired pneumonia (CAP). METHODS: Consecutive individuals hospitalized with CAP during "influenza season" (November to April, 1999-2003) at hospitals operated by Tenet HealthCare were identified using a database constructed to improve quality of patient care. Associations between vaccination status and all-cause in-hospital mortality were evaluated using logistic regression models. RESULTS: Among 17 393 adults hospitalized with CAP during the study period, 1590 (19% of those with recorded vaccine status) had a history of influenza vaccination in the current or most recent influenza season. Vaccine recipients were less likely to die in hospital of any cause than individuals without vaccination (odds ratio, 0.30; 95% confidence interval, 0.22-0.41). These effects remained significant after adjustment for the presence of comorbid illnesses and pneumococcal vaccination (adjusted odds ratio for death, 0.61; 95% confidence interval, 0.43-0.87) and under widely varying assumptions about individuals with missing vaccination status. CONCLUSIONS: Prior influenza vaccination was associated with improved survival in hospitalized patients with CAP during influenza season. This observation, if confirmed by other studies, would represent an important additional benefit of enhanced influenza vaccine coverage.