Cumulative inactivation of N-type CaV2.2 calcium channels modified by alternative splicing

The Ca(V)2 family of voltage-gated calcium channels, present in presynaptic nerve terminals, regulates exocytosis and synaptic transmission. Cumulative inactivation of these channels occurs during trains of action potentials, and this may control short-term dynamics at the synapse. Inactivation during brief, repetitive stimulation is primarily attributed to closed-state inactivation, and several factors modulate the susceptibility of voltage-gated calcium channels to this form of inactivation. We show that alternative splicing of an exon in a cytoplasmic region of the Ca(V)2.2 channel modulates its sensitivity to inactivation during trains of action potential waveforms. The presence of this exon, exon 18a, protects the Ca(V)2.2 channel from entry into closed-state inactivation specifically during short (10 ms to 3 s) and small depolarizations of the membrane potential (-60 mV to -50 mV). The reduced sensitivity to closed-state inactivation within this dynamic range likely underlies the differential responsiveness of Ca(V)2.2 splice isoforms to trains of action potential waveforms. Regulated alternative splicing of Ca(V)2.2 represents a possible mechanism for modulating short-term dynamics of synaptic efficacy in different regions of the nervous system.     

Are symptom reports useful for differentiating between acute rejection and pulmonary infection after lung transplantation?

BACKGROUND: Prompt treatment of acute rejection and pulmonary infection reduces morbidity and mortality in lung transplant recipients. Symptoms, spirometry, and bronchoscopy are used to detect these complications. Of these, symptom reporting is the least invasive, yet has received little critical examination. OBJECTIVE: To examine the potential for using reports of symptoms, such as cough and shortness of breath, to recognize clinically significant acute rejection and pulmonary infection after lung transplantation. METHODS: Symptoms reported during routine follow-up visits were compared between lung transplant recipients (LTR) with clinically significant acute rejection (grade >or= A2) and those without (grade A0 or A1) and between LTR with rejection (grade >or= A2) and those with pulmonary infection. RESULTS: LTR with rejection (grade >or= A2) reported more symptoms (P < .01) than did those without (grade A0, A1); however, the magnitude of difference was minimal. LTR with clinically significant acute rejection (grade >or= A2) reported symptoms at a rate comparable with those having pulmonary infection. CONCLUSIONS: Although symptoms may alert LTR to changes in their condition, no symptoms (respiratory, general, or activities of daily living [ADL]) differentiate between grades of rejection or pulmonary infection.     

Beyond Efficacy and Effectiveness: Conducting Economic Analyses During Clinical Trials

Few studies have examined cost issues in the field of dysphagia. This study presents cost data collected during a clinical trial in speech–language pathology, demonstrating the types of cost analyses that can be conducted and highlighting obstacles and issues facing investigators who seek to conduct economic analyses in this arena. Seventy-nine patients were enrolled in the clinical trial to assess the impact of a swallowing intervention on swallowing and speech function. The patients were at least one year past treatment for head and neck cancer. No significant intervention differences were detected in these outcomes. A companion economic analysis was conducted in 37 of these patients using patient diaries and followup with identified health care providers. Analyses indicated that (1) the intervention did not significantly reduce health care expenditures; (2) indirect costs and costs of hospitalizations are both important factors to consider during a trial; and (3) health care costs of this population are high relative to the rest of the U.S. population. Attrition from the overall study population can pose a serious threat to the viability of an economic study. The article concludes with a discussion of how these issues can be addressed in future studies.This research was supported by NIH/NCI P01 CA40007 and NIDCD U01 DC03206.     

Importance of chronic obstructive pulmonary disease for prognosis and diagnosis of congestive heart failure in patients with acute myocardial infarction

AIMS: To evaluate the importance of chronic obstructive pulmonary disease for prognosis and diagnosis of congestive heart failure in patients with acute myocardial infarction. METHOD AND RESULTS: Prospective registration of 6669 consecutive patients admitted with infarction and screened for a randomised controlled trial. A history of COPD was present in 765 (11.5%) patients. Thirty-day and 5-year survival in patients with chronic obstructive pulmonary disease was 86.3 and 42.9%. In patients without pulmonary disease the figures were 87.7 and 57.5%, respectively, giving a relative risk of 1.49 (1.35-1.65). In multivariate analysis the relative risk was 1.15 (1.04-1.28). The prevalence of congestive heart failure was 65.9% in patients with chronic obstructive pulmonary disease and 52.0% in patients without. This difference was most distinct in patients with normal or only slightly decreased left ventricular systolic function. In patients without congestive heart failure, chronic obstructive pulmonary disease was of prognostic importance [RR=1.44 (1.17-1.78)], but not in patients with congestive heart failure [RR=1.09 (0.96-1.23)]. CONCLUSION: Chronic obstructive pulmonary disease is a predictor of long-term mortality in patients with acute myocardial infarction without congestive heart failure, but is also a confounding factor for the diagnosis of congestive heart failure.     

Getting a Grip on Arthritis: an educational intervention for the diagnosis and treatment of arthritis in primary care

OBJECTIVE: To evaluate a community-based educational intervention designed to improve the diagnosis and treatment of arthritis in primary care. METHODS: The educational intervention, entitled "Getting a Grip on Arthritis", consisted of a 2-day workshop and followup reinforcement activities for healthcare providers (providers) and was supported by a toolkit of written materials for providers and clients. The content of the intervention was designed around 10 arthritis best practices derived from published arthritis guidelines. Five community health centers (CHC) participated as intervention sites and 2 as control sites. Intervention impact was determined through a mailed survey to clients with arthritis. Primary outcome analysis compared responses to questions about arthritis best practices between intervention and control sites at baseline and followup. RESULTS: The workshop was attended by 21 multidisciplinary providers from intervention CHC. At baseline, 423 of 624 eligible and consenting clients completed the survey and 376 of 593 completed the followup survey. At followup clients in the intervention group reported significantly higher referrals to The Arthritis Society therapy program, and were more often provided information on type of arthritis, medications and their side effects, disease management strategies, and arthritis community resources. CONCLUSION: This demonstration project is one of the first to show changes in the management of arthritis in a primary care setting. This project has recently received funding from Health Canada's Primary Health Care Transition Fund for implementation across Canada and is expected to provide a template for use in other chronic diseases.     

Psychosocial situation and physical health in 50 patients > 1 year after lung transplantation

BACKGROUND: Lung transplants have been performed worldwide since the early 1980s. While numerous studies have been published on somatic aspects after lung transplantation, there is considerably less information available on psychosocial aspects and on the correlation between the physical and the psychosocial state of health after transplantation. METHODS: Between 1992 and 2002, 125 patients underwent lung transplantation at University Hospital Zurich. To be included into the study, patients had to have received a lung transplant > 12 months previously and to have good knowledge of the German or Italian languages. With the aid of standardized questionnaires, psychosocial variables such as levels of anxiety and depression, self-esteem, and social support were determined. In addition, self-assessments of physical and psychological health were obtained. The medical data included information on FEV1, complications such as pulmonary infections, acute or chronic allograft rejection, and assessment of the patient's physical and psychological health by the treating doctors. RESULTS: The overall degree of anxiety and depression of the lung transplant recipients was comparable to standard samples of an average population. However, male lung transplant recipients were significantly more depressed than female recipients. Self-esteem was higher than in clinical comparison samples. Preceding pulmonary complications had long-lasting effects on the level of anxiety, whereas nonpulmonary complications did not have such an effect. CONCLUSIONS: Overall, the psychological well-being of patients after lung transplantation is similar to the normal population. Subgroups of patients with increased psychological distress have been identified.     

Lovastatin controls signal transduction in vascular smooth muscle cells by modulating phosphorylation levels of mevalonate-independent pathways

Lovastatin has been proven to effectively lower circulating LDL cholesterol and to exert antiproliferative effects on various cell lines, the latter effect being only incompletely understood. We found that lovastatin modulates the signal transducing phosphorylation cascade in vascular smooth muscle cells in a mevalonate-independent manner. Lovastatin was found to distinctively increase total phosphotyrosine levels in smooth muscle cells, an effect which could not be restored by mevalonate. At a concentration of 5 μmol/L lovastatin had a highly specific effect on the mitogen-activated protein kinase pathway. The expression of p42/44 mitogen-activated protein kinase (MAPK) was clearly reduced, but could be restored by addition of mevalonate, while the phosphorylation of p44 was mildly suppressed and the phosphorylation of p42 MAPK was reduced to non-detectable levels. While the phosphorylation of p44 MAPK could partially be restored by addition of mevalonate, the reduced phosphorylation of p42 MAPK could not be restored by addition of excessive doses of mevalonate or stimulation of the cells with basic fibroblast growth factor. Concurrently the expression of the GTP-binding Ras protein was significantly elevated at 5 and 20 μmol/L lovastatin, this effect being attenuated by addition of mevalonate to cell cultures. The data indicate that lovastatin is capable of modulating cellular signaling independently of the cholesterol synthesis pathway. Received: 30 August 2000, Returned for 1. revision: 20 September 2000, 1. Revision received: 14 November 2000, Returned for 2. revision: 28 November 2000, 2. Revision received: 11 December 2000, Accepted: 12 December 2000     

Ghrelin action in the brain controls adipocyte metabolism

Many homeostatic processes, including appetite and food intake, are controlled by neuroendocrine circuits involving the CNS. The CNS also directly regulates adipocyte metabolism, as we have shown here by examining central action of the orexigenic hormone ghrelin. Chronic central ghrelin infusion resulted in increases in the glucose utilization rate of white and brown adipose tissue without affecting skeletal muscle. In white adipocytes, mRNA expression of various fat storage-promoting enzymes such as lipoprotein lipase, acetyl-CoA carboxylase alpha, fatty acid synthase, and stearoyl-CoA desaturase-1 was markedly increased, while that of the rate-limiting step in fat oxidation, carnitine palmitoyl transferase-1alpha, was decreased. In brown adipocytes, central ghrelin infusion resulted in lowered expression of the thermogenesis-related mitochondrial uncoupling proteins 1 and 3. These ghrelin effects were dose dependent, occurred independently from ghrelin-induced hyperphagia, and seemed to be mediated by the sympathetic nervous system. Additionally, the expression of some fat storage enzymes was decreased in ghrelin-deficient mice, which led us to conclude that central ghrelin is of physiological relevance in the control of cell metabolism in adipose tissue. These results unravel the existence of what we believe to be a new CNS-based neuroendocrine circuit regulating metabolic homeostasis of adipose tissue.     

Methamphetamine administration reduces hippocampal vesicular monoamine transporter-2 uptake

Repeated high-dose injections of methamphetamine (METH) rapidly decrease dopamine uptake by the vesicular monoamine transporter-2 (VMAT-2) associated with dopaminergic nerve terminals, as assessed in nonmembrane-associated vesicles purified from striata of treated rats. The purpose of this study was to determine whether METH similarly affects vesicular uptake in the hippocampus; a region innervated by both serotonergic and noradrenergic neurons and profoundly affected by METH treatment. Results revealed that repeated high-dose METH administrations rapidly (within 1 h) reduced hippocampal vesicular dopamine uptake, as assessed in vesicles purified from treated rats. This reduction was likely associated with serotonergic nerve terminals because METH did not further reduce vesicular monoamine uptake in para-chloroamphetamine-lesioned animals. Pretreatment with the serotonin transporter inhibitor fluoxetine blocked both this acute effect on VMAT-2 and the decrease in serotonin content observed 7 days after METH treatment. In contrast, there was no conclusive evidence that METH affected vesicular dopamine uptake in noradrenergic neurons or caused persistent noradrenergic deficits. These findings suggest a link between METH-induced alterations in serotonergic hippocampal vesicular uptake and the persistent hippocampal serotonergic deficits induced by the stimulant.