Calcium dynamics in bovine adrenal medulla chromaffin cell secretory granules

The secretory granules constitute one of the less well-known compartments in terms of Ca2+ dynamics. They contain large amounts of total Ca2+, but the free intragranular [Ca2+] ([Ca2+]SG), the mechanisms for Ca2+ uptake and release from the granules and their physiological significance regarding exocytosis are still matters of debate. We used in the present work an aequorin chimera targeted to the granules to investigate [Ca2+]SG homeostasis in bovine adrenal chromaffin cells. We found that most of the intracellular aequorin chimera is present in a compartment with 50-100 microM Ca2+. Ca2+ accumulation into this compartment takes place mainly through an ATP-dependent mechanism, namely, a thapsigargin-sensitive Ca2+-ATPase. In addition, fast Ca2+ release was observed in permeabilized cells after addition of inositol 1,4,5-trisphosphate (InsP3) or caffeine, suggesting the presence of InsP3 and ryanodine receptors in the vesicular membrane. Stimulation of intact cells with the InsP3-producing agonist histamine or with caffeine also induced Ca2+ release from the vesicles, whereas acetylcholine or high-[K+] depolarization induced biphasic changes in vesicular[Ca2+], suggesting heterogeneous responses of different vesicle populations, some of them releasing and some taking up Ca2+during stimulation. In conclusion, our data show that chromaffin cell secretory granules have the machinery required for rapid uptake and release of Ca2+, and this strongly supports the hypothesis that granular Ca2+ may contribute to its own secretion.     

The inflammatory response to colloids and crystalloids used for pump priming during cardiopulmonary bypass

Background: Systemic inflammatory response frequently occurs after coronary artery bypass surgery and is strongly correlated with the risk of postoperative morbidity and mortality. This study tests the hypothesis that the priming of the extracorporeal circuit with colloid solutions results in less inflammation in patients undergoing cardiac surgery than priming with crystalloid solutions. Methods: A prospective, randomized study was designed. Forty‐four patients undergoing elective coronary artery bypass grafting were randomly allocated to one of two groups: 22 patients primed with Ringer's lactate (RL) solution and 22 patients primed with gelatin‐containing solution during the surgery. Plasma levels of interleukin (IL)‐6, IL‐8, tumor necrosis factor (TNF)‐α, C‐reactive protein (CRP) and, complement 4 were measured during the surgical intervention and over the following 48 postoperative hours. Cytokine levels were measured by enzyme‐linked assays from plasma samples obtained at specific time points pre‐ and post‐operatively. Results: In both groups the serum levels of the pro‐inflammatory cytokines (IL‐6, IL‐8, TNF‐α), CRP, complement 4, and leukocytes increased significantly over the baseline, although no significant differences were observed between the two groups. The operation time, blood loss, need for inotropic support, extubation time, and length of intensive care unit stay did not differ significantly between the two groups. Conclusion: Priming with gelatin vs. RL produces no significant differences in the inflammatory response in patients undergoing coronary artery bypass grafting with cardiopulmonary bypass.     

Comparing serologic response against enteric pathogens with reported diarrhea to assess the impact of improved household drinking water quality

We evaluated enteric infection serology as an alternative outcome measure to diarrhea prevalence in a randomized controlled trial of household-based drinking water treatment; 492 households were randomly assigned to 5 household-based water treatment interventions or control. Individuals were followed weekly over 52 weeks to measure diarrhea prevalence. Study subjects of age 相似文献   

Selective serotonin reuptake inhibitor use by patients with acute coronary syndromes

Background

Selective serotonin reuptake inhibitors are commonly used to treat anxiety, depression, and other conditions that commonly affect patients with coronary artery disease. Selective serotonin reuptake inhibitors inhibit platelet activation and may, therefore, affect outcomes in patients with acute coronary syndromes.

Methods

A retrospective study was performed of 1254 patients with acute coronary syndromes comparing in-hospital bleeding and cardiac event rates in 158 patients who received a selective serotonin reuptake inhibitor and a propensity score-matched group of patients who did not. All patients were treated with a glycoprotein IIb/IIIa inhibitor and almost all also received aspirin, clopidogrel, and heparin.

Results

Patients who received a selective serotonin reuptake inhibitor were significantly more likely to experience any bleeding (37.3% vs 26.6%, OR 1.65, 95% confidence interval (CI), 1.02-2.66, P =.04) and significantly less likely to experience recurrent myocardial ischemia, heart failure, or asymptomatic cardiac enzyme elevation while in the hospital (7.0% vs 13.9%, OR 0.46, 95% CI, 0.22-0.99, P =.04). No differences were observed in death, myocardial infarction during the hospitalization, urgent revascularization, or major bleeding. Bleeding and cardiac events were not affected by antidepressants other than selective serotonin reuptake inhibitors.

Conclusions

Selective serotonin reuptake inhibitor use during a hospitalization for an acute coronary syndrome is associated with reduced rates of recurrent ischemia, heart failure, or cardiac enzyme elevation at the expense of increased bleeding in patients receiving maximal conventional antiplatelet medications and heparin. Clinicians should be aware of this association when treating patients with an acute coronary syndrome.     

Massive infection and loss of CD4+ T cells occurs in the intestinal tract of neonatal rhesus macaques in acute SIV infection

Rapid, profound, and selective depletion of memory CD4+ T cells has now been confirmed to occur in simian immunodeficiency virus (SIV)-infected adult macaques and human immunodeficiency virus (HIV)-infected humans. Within days of infection, marked depletion of memory CD4+ T cells occurs primarily in mucosal tissues, the major reservoir for memory CD4+ T cells in adults. However, HIV infection in neonates often results in higher viral loads and rapid disease progression, despite the paucity of memory CD4+ T cells in the peripheral blood. Here, we examined the immunophenotype of CD4+ T cells in normal and SIV-infected neonatal macaques to determine the distribution of naive and memory T-cell subsets in tissues. We demonstrate that, similar to adults, neonates have abundant memory CD4+ T cells in the intestinal tract and spleen and that these are selectively infected and depleted in primary SIV infection. Within 12 days of SIV infection, activated (CD69+), central memory (CD95+CD28+) CD4+ T cells are marked and persistently depleted in the intestine and other tissues of neonates compared with controls. The results in dicate that "activated" central memory CD4+ T cells are the major target for early SIV infection and CD4+ T cell depletion in neonatal macaques.     

Reduced-intensity conditioning for allogeneic haematopoietic stem cell transplantation in relapsed and refractory Hodgkin lymphoma: impact of alemtuzumab and donor lymphocyte infusions on long-term outcomes

The introduction of reduced-intensity conditioning (RIC) has enabled the role of allogeneic transplantation to be re-evaluated in Hodgkin lymphoma (HL). While T-cell depletion reduces graft-versus-host disease (GvHD), it potentially abrogates graft-versus-tumour activity and increases infective complications. We compared the results in 67 sibling donor transplantations following RIC in multiply relapsed patients from two national phase II studies conditioned with fludarabine/melphalan. One used cyclosporine/alemtuzumab (MF-A, n = 31), the other used cyclosporine/methotrexate (MF, n = 36) as GvHD prophylaxis. There was a small excess of chemorefractory cases in the MF cohort (P = NS). MF-A resulted in significantly lower incidences of non-relapse mortality, acute and chronic GvHD, but no significant excess of relapse/progression. Post donor lymphocyte infusion (DLI) disease responses occurred in 8/14 (57%) and 6/11 (55%) patients in the MF-A and MF groups, respectively. Current progression-free survival (CPFS) was superior with MF-A (univariate analysis), with durable responses to DLI contributing to the favourable outcome (43% vs. 25%, P = 0.0356). Disease status at transplantation significantly influenced overall survival (P = 0.0038) and CPFS (P = 0.0014), retaining significance in multivariate analyses, which demonstrated a trend towards improved CPFS with T-cell depletion (P = 0.0939). These data suggest that alemtuzumab significantly reduced GvHD without resulting in a deleterious impact on survival outcomes following RIC in HL, and that durable responses to DLI may be more common following the inclusion of alemtuzumab in the conditioning protocol.     

The use of taxanes in the neoadjuvant treatment of breast cancer: a review of randomized phase II/III trials

This review examines all randomized studies that evaluated the role of taxanes in the neoadjuvant treatment of breast cancer and have reported results in terms of efficacy and tolerance. The primary objective of this review was to evaluate whether, at this point in time, there is sufficient evidence to support the routine use of taxanes in the neoadjuvant treatment of breast cancer. Other objectives were to determine the optimal schedule in which to administer taxanes and anthracyclines and whether the addition of other antitumor drugs improves the efficacy of these anthracycline/taxane-based schedules. A literature search revealed 9 major randomized clinical trials published to date. To facilitate analysis, they were classified according to their protocol design. Five trials evaluated the effect of the addition of a taxane to an anthracycline-based schedule, either concomitantly or sequentially. The remaining 4 trials contained taxanes in both treatment arms in an attempt to optimize the administration schedule of anthracyclines and taxanes, or to improve efficacy by adding a further antitumor drug. This type of analysis has provided the opportunity to draw some conclusions regarding the optimal use of taxanes.