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Background: To examine sex differences in pain and associated symptoms in patients with exercise-related ischemia, as well as the independence of these findings from other clinical factors., Methods: Prospective study of 482 women and 425 men (mean age 58 years) undergoing exercise stress testing with myocardial perfusion imaging (MPI). Analyses were performed on 38 women and 94 men with both angina and MPI evidence of ischemia during exercise., Measures: Chest pain localization, extension, intensity, quality, and presence of various non-pain-related symptoms., Results: Women rated their pain as more intense, used different words to describe it, and reported more non-pain-related symptoms than men (P < .05). They experienced pain and other sensations in the neck area more frequently (P < .05). Most of these differences remained after controlling for clinical or psychological variables, with the exception of pain intensity measures., Conclusions: Sex differences in the experience of symptoms associated with MPI evidence of myocardial ischemia may complicate timely and accurate diagnosis of ischemia in women.

Unlabelled: The relation between psychological factors and angina has mostly been studied in male patients with confirmed CAD and few have evaluated this relation during actual provocation of ischemia. This study evaluated gender differences in the association between psychological distress and angina pain experience in 907 Caucasian patients (479 women, mean age = 60 years) undergoing exercise stress testing with thallium scintigraphy. Data were analyzed separately for patients with and without exercise related ischemia using a series of 2 (low/high distress) x 2 (gender) ANOVAs as well as binary logistic regressions. Among all patients, distress and gender were associated with greater risk and intensity of angina pain during testing (p < 0.05) and more angina following exertion (p < 0.05) or stress (p < 0.05) at home., Conclusion: angina pain was more severe in women and individuals with high levels of distress, regardless of their ischemic status. A generalized hypersensitivity to pain/symptoms may be indicated in these patients.

Introduction: The Quality of Life Systemic Inventory (QLSI) measures patients' goal attainment based on the system control theory. It quantifies the perceived impact of the disorder and the gap between the present and aspired states., Purpose: To evaluate concurrent validity and responsiveness of the QLSI among workers on sick leave due to musculoskeletal disorders (MSDs)., Methods: Participants (10 women; 29 men) were recruited at a work rehabilitation centre and had more than 4 weeks of absence from work due to MSDs compensated by the Workers' Compensation Board. Concurrent validity and external responsiveness were based on baseline and post-treatment measures of external criteria. Criteria and related instruments were the following: perception of disability (Roland-Morris Disability Questionnaire); health-related quality of life (SF-12); stress (Psychological Stress Measure) and distress (Psychological Distress Index)., Results: Regression analyses revealed significant correlations between QLSI scores and the Psychological Distress Index (r2 = .11 to .19 and .66; p < .001), with either the SF-12 mental component scale (r2 = .18 and .11; p < .01) or the Roland-Morris Disability Questionnaire (r2 = .04 and .10; p < .05). All measures showed highly significant change over time., Conclusion: Results support the concurrent validity and responsiveness of the QLSI, with an MSD population., Significance: This instrument could serve in future research as an outcome measurement instrument in the evaluation of more long-term effects of rehabilitation programs.

Background: Quality of life (QoL) in valvular surgery may differ according to the underlying pathology and surgical technique used., Method: 82 adults undergoing their first elective surgery for valve repair (VP; n = 9) or valve replacement (VR) with a mechanical valve (MVR; n = 57) or bioprosthesis (BVR; n = 16) were assessed before surgery and three months afterwards., Dependent Variables: delta scores (postoperative-preoperative) on QoL measures (Quality of Life Systemic Inventory (QLSI) and SF-36)., Analyses: Paired t tests and ANCOVAs with age and preoperative QoL scores as covariates., Results: QoL improves after surgery according to most subscales. According to group comparisons, patients with an MVR improve more than those with a BVR on the mental health subscale. In physical roles, patients with an MVR improve while those with a BVR deteriorate. In emotional roles, patients with a VR improve while those with a VP deteriorate. However, they are similar on all other subscales. Women improve more than men on leisure, affectivity and social functioning while the opposite holds true for mental health., Conclusion: QoL improves after surgery. However, significant differences between groups are small because of a lack of statistical power.

BACKGROUND: Neutrophils represent the first line of defence against aggressions. The programmed death of neutrophils is delayed by pro-inflammatory stimuli to ensure a proper resolution of the inflammation in time and place. The pro-inflammatory stimuli include granulocyte-macrophage colony-stimulating factor (GM-CSF). Recently, we have demonstrated that although neutrophils have an identical spontaneous apoptosis in elderly subjects compared to that in young subjects, the GM-CSF-induced delayed apoptosis is markedly diminished. The present study investigates whether an alteration of the GM-CSF stimulation of MAPKs play a role in the diminished rescue from apoptosis of PMN of elderly subjects. METHODS: Neutrophils were separated from healthy young and elderly donors satisfying the SENIEUR protocol. Neutrophils were stimulated with GM-CSF and inhibitors of the MAPKinase pathway. Apoptosis commitment, phosphorylation of signaling molecules, caspase-3 activities as well as expression of pro- and anti-apoptotic molecules were performed in this study. Data were analyzed using Student's two-tailed t-test for independent means. Significance was set for p

T lymphocytes are key players of immune responses that are associated with immune senescence because their functions are the most affected with aging. Defects in signal delivery to the nucleus have been demonstrated, by our group and others, in human aging and may explain the dysfunctions that occur in T cells with aging. Although aging has been related to a decline in several biological functions, it is also associated with a basal low-grade proinflammatory state and an increase in oxidative stress that lead to changes and damage. However, there are no clear data concerning the basal state of activation of T lymphocytes and its putative link with the low-grade inflammation observed with aging. Since membrane microdomains (lipid rafts) are specialized plasma membrane structures involved in T-lymphocyte activation, we studied the effect of aging on the phosphorylation state of signaling molecules associated with lipid rafts. We found that the signaling molecules in T lymphocytes from elderly donors were hyperphosphorylated and that the high basal state of phosphorylation did not allow activation exposure to a T-cell stimulus. We found that the cholesterol composition is changed in lipid rafts of resting T cells. We analyzed lipid raft distribution in situ using confocal microscopy and found a disorganization of these microdomains in T cells from aged donors. In conclusion, we show a link between aging, T-lymphocyte lipid rafts, immune senescence, and low-grade inflammation.

Objectives: The POST CABG (Post Coronary Artery Bypass Graft) Trial showed that aggressive lowering of low-density lipoprotein (LDL) cholesterol levels reduced the progression of atherosclerosis in saphenous vein grafts. In the extended follow-up phase, aggressive lowering of LDL cholesterol levels was associated with reduced rates of clinical events. Low-dose anticoagulation therapy did not reduce the progression of atherosclerosis. We conducted this analysis to determine the effects of both lipid-lowering and low-dose anticoagulation therapy on health-related quality of life (HRQL)., Design: Randomized clinical trial, factorial design., Setting: Outpatients in five tertiary care medical centers., Patients: A cohort of 852 patients enrolled in the POST CABG Trial completed an HRQL questionnaire at baseline, and at the year 2 and year 4 follow-up visits., Intervention: Aggressive LDL cholesterol lowering vs moderate LDL cholesterol lowering, and low-dose warfarin vs placebo., Measurements: Domains included emotional status, basic physical and social functioning, perceived health status, symptoms of pain, a variety of physical symptoms, and global life satisfaction., Results: Overall, there were no indications of systematic differences among treatment groups for any of the HRQL parameters at baseline, year 2, or year 4., Conclusions: These data indicate that patients did not experience detrimental or beneficial effects on HRQL parameters while receiving LDL cholesterol-lowering therapy that had demonstrable benefits for treatment of atherosclerosis.

It is well known that the immune response decreases during aging, leading to a higher susceptibility to infections, cancers and autoimmune disorders. Most widely studied have been alterations in the adaptive immune response. Recently, the role of the innate immune response as a first-line defence against bacterial invasion and as a modulator of the adaptive immune response has become more widely recognized. One of the most important cell components of the innate response is neutrophils and it is therefore important to elucidate their function during aging. With aging there is an alteration of the receptor-driven functions of human neutrophils, such as superoxide anion production, chemotaxis and apoptosis. One of the alterations underlying these functional changes is a decrease in signalling elicited by specific receptors. Alterations were also found in the neutrophil membrane lipid rafts. These alterations in neutrophil functions and signal transduction that occur during aging might contribute to the significant increase in infections in old age.

The aim of this study was to replicate and extend the findings of O'Connor, Bélanger, Marchand, Dupuis, Elie, and Boyer [Addict. Behav. 24 (1999) 537], which had established a psychosocial profile associated with psychological distress in benzodiazepine (BZD) use. Forty-one participants with anxiety or insomnia, receiving maintenance therapy of BZD for at least 8 weeks, participated in a 20-week, tapered discontinuation protocol with physician counselling. Drug type and use was monitored throughout. Questionnaire measures of anxiety, behavioural inhibition, neuroticism, withdrawal complaints, social support, psychological distress, self-efficacy in coping without BZD, quality of life, positive and negative life events, were completed at baseline, postdiscontinuation, and at 3-month follow-up. Measures of baseline psychological distress and anxiety inhibition were consistently associated with both discontinuation and the emergence of withdrawal complaints. Successful withdrawal was characterized by low baseline neuroticism, low behavioural inhibition, higher number of positive events, and higher level of social support satisfaction. Higher dosage (in diazepam equivalent dose) was associated with both poorer outcome and the emergence of withdrawal symptoms. Self-efficacy in coping was negatively associated with relapse but not with outcome. Psychosocial factors play a role at different stages of the BZD withdrawal process and could be targeted in treatment.

G protein-coupled receptors (GPCRs) represent a vast family of transmembrane proteins involved in the regulation of several physiological responses. The thromboxane A2 receptor (present as two isoforms: TP alpha and TP beta) is a GPCR displaying diverse pharmacological effects. As seen for many other GPCRs, TP beta is regulated by agonist-induced internalization. In the present study, we report the identification by yeast two-hybrid screening of Nm23-H2, a nucleoside diphosphate kinase, as a new interacting molecular partner with the C-terminal tail of TP beta. This interaction was confirmed in a cellular context when Nm23-H2 was co-immunoprecipitated with TP beta in HEK293 cells, a process dependent on agonist stimulation of the receptor. We observed that agonist-induced internalization of TP beta was regulated by Nm23-H2 through modulation of Rac1 signaling. Immunofluorescence microscopy in HEK293 cells revealed that Nm23-H2 had a cytoplasmic and nuclear localization but was induced to translocate to the plasma membrane upon stimulation of TP beta to show extensive co-localization with the receptor. Our findings represent the first demonstration of an interaction of an Nm23 protein with a membrane receptor and constitute a novel molecular regulatory mechanism of GPCR endocytosis.

Aging is associated with a decline in immune functions. Among them, T-cell activation is altered at several points of the signaling cascade following TCR engagement. Recent findings suggest that lipid rafts act as a platform in the initiation of T-cell activation. We have previously demonstrated that cholesterol content in T-cells increased with aging, especially in lipid rafts. Cholesterol, which is a major component of lipid rafts, serves to stabilize their structure. We hypothesized that restoring T-cell cholesterol content and membrane fluidity would restore, at least in part, T-cell function via lipid rafts. We measured the lipid rafts coalescence, the p56(Lck) and linker of activated T-cell (LAT) signaling molecules recruitment and activation, the cholesterol content and fluidity in T-cell membrane after different methyl-beta-cyclodextrin (MBCD) treatments. Our results show that high concentration of MBCD (10 mM) completely disorganized the lipid rafts in T-cell membranes of young and elderly donors, however, T-cells from elderly donors were less sensitive than T-cells of young donors to low concentration of MBCD (0.5 mM). p56(Lck) and LAT recruitment and activation were affected in T-cells of both aged groups. MBCD treatment did not affect the cholesterol content and fluidity of T-cell membranes of young donors, while the cholesterol content was decreased and fluidity increased in lipid rafts of elderly donors. These results suggested that cholesterol extraction by MBCD increased the fluidity and disrupted lipid rafts organization. The increase in cholesterol content in lipid rafts with aging and its decrease by biochemical extraction were able to affect early signaling molecules activation. Restoring cholesterol content and fluidity may have beneficial effects, however, MBCD disorganized the membrane and this might not completely restore the T-cell activation via lipid rafts with aging. Altogether these results suggest that defects in cholesterol cellular homeostasis may be part of T-cell immunosenescence via lipid rafts dysfunction.

Aging is associated with a decline in T cell activation and proliferation, but the underlying mechanisms are not fully understood. Recent findings suggest that lipid rafts act as a platform in the initiation of T cell activation by selectively recruiting signaling proteins associated with formation of the initial complex of signal transduction. We tested the hypothesis that lipid raft properties are altered in T lymphocytes from elderly, healthy individuals in comparison with young subjects. Results showed that the cholesterol content of lipid rafts derived from these cells was consistently higher in the case of elderly donors and that membrane fluidity was decreased. In addition, lipid rafts coalescence to the site of T cell receptor engagement was impaired in T cells from elderly donors. The recruitment of p56(lck), linker of activated T cells, and their tyrosine-phosphorylated forms to lipid rafts was decreased in activated T cells from aged individuals. CD45 was not recruited to the lipid raft fractions in either group of subjects. Our data suggest that some properties of lipid rafts are altered in aging, and this finding may be part of the causes for the decline in T cell functions that are observed in elderly individuals.

The Panton-Valentine leukocidin is associated with staphylococcal skin and pulmonary infections. We describe a school outbreak of skin infections and the public health response to it. Nasal carriage of a Panton-Valentine leukocidin-positive Staphylococcus aureus clone was detected only in previously ill classmates and their family members.

Background: Women undergoing coronary artery bypass graft (CABG) surgery have a worse medical condition and fewer social and financial resources than men. Some studies have found that women recover less well than men after CABG, whereas others have found women's outcomes comparable to those of men. Past studies of health-related quality of life after CABG have too few women for adequate comparison with men and have not included patients whose data are not available at baseline (eg, emergency CABG), limiting generalizability., Methods: A longitudinal study of symptoms and health-related quality of life was conducted among patients from four clinical centers enrolling both men (n = 405) and women (n = 269) in the Post CABG Biobehavioral Study in the United States and Canada., Results: After 6 weeks from CABG (average 81 days), both men and women had less anxiety and symptoms related to depression than before surgery (P <.001). After 6 months (average 294 days), both men and women improved in physical and social functioning (P <.001). Although changes in scale scores were similar for men and women at each time point, women scored lower than men on these domains (P <.001, adjusted for baseline medical and sociodemographic differences) and had more symptoms related to depression through 1 year after CABG (P =.003)., Conclusions: Both male and female patients improve in physical, social, and emotional functioning after CABG, and recovery over time is similar in men and women. However, women's health-related quality-of-life scale scores remained less favorable than men's through 1 year after surgery.

This article reviews the literature concerning addiction to benzodiazepine (BZD) in the elderly population of 65 and over. While the negative consequences related to a prolonged use of BZD are well known, much less is known on the phenomenon of dependency to these substances in this population. There is still no consensus on the definition of the problem. The continuous use of BZD may be more problematic in the elderly for whom tolerance to chemical agents diminishes with age. The risk factors involved in the chronic use are an interactive combination between the characteristics of the elderly as well as the physicians who prescribe such medication. Paths of research to support a paradigmatic change are presented in order to improve the research in this field.

Background: The Post-Coronary Artery Bypass Graft (CABG) biobehavioral study measured the heart rate (HR) and blood pressure (BP) responses to mental stress testing (MST) after surgery and prospectively observed the clinical events in patients who had undergone recent CABG surgery. To the extent that CABG surgery restores myocardial blood flow and prevents myocardial ischemia, patients who have recently recovered from CABG surgery may have nearly normal HR and BP responses to MST., Methods: A study population of 521 patients (351 men,170 women) from the cohort of 759 patients in the Post-CABG biobehavioral Study was monitored during a mirror tracing test (MTT) and a speech test task (STT) at the 6-month post-CABG surgery follow-up. Medical status for as long as 3 years after CABG surgery was ascertained from questionnaires and medical records., Results: The HR and BP responses during MTT and STT were similar to those reported in other studies of healthy individuals and patients without myocardial ischemia during MST. In contrast to results from other studies of patients with coronary artery disease, the quartile of Post-CABG biobehavioral study patients with the greatest responses in HR, systolic BP (SBP) and diastolic BP (DBP) during MST had half the rate of clinical events (10% in 3 years) as the quartile (20%) with the lowest changes in HR and BP (HR, P =.01; SBP, P =.07; DBP, P =.01)., Conclusions: Vigorous HR and BP responses to MST may be markers for a lower risk of incidence of clinical cardiovascular events among patients who have undergone recent CABG surgery.

4-aminopyridine (4AP) is a general blocker of voltage-dependent K+ channels. This pyridine derivative has also been shown to inhibit T cell proliferation, to modulate immune responses and to alleviate some of the symptoms associated with neurological disorders such as multiple sclerosis, myasthenia gravis and Alzheimer's disease. 4AP triggers a Ca2+ response in lymphocytes, astrocytes, neurons and muscle cells but little is known about the regulation of the 4AP response in these cells. We report that 4AP induced a non-capacitative transplasma membrane influx of Ca2+ in Jurkat T lymphocytes. The influx of Ca2+ was not affected by activation or inhibition of protein kinase A (PKA). In contrast, activation of protein kinase C (PKC) by phorbol myristyl acetate (PMA), mezerein or 1-oleoyl-2-acetyl-sn-glycerol (OAG) inhibited the influx of Ca2+ triggered by 4AP. The inhibitory effect of PKC could be prevented by prior exposure of the cells to the PKC inhibitor GF 109203X. Under these conditions, mezerein and OAG no longer inhibited the 4AP-dependent Ca2+ response. Inhibition of serine and threonine protein phosphatases PP1 and PP2A by treating the cells with calyculin A (CalA) reduced the Ca2+ response to 4AP. Okadaic acid (OA) had no effect, suggesting an involvement of PP1. A combination of CalA and OAG (or PMA) abolished the influx of Ca2+ induced by 4AP, adding further evidence to the importance of protein phosphorylation in the modulation of the 4AP response. Our data suggest that the transplasma membrane influx of Ca2+ triggered by 4AP in Jurkat T cells can be modulated by the opposite actions of PKC and protein serine and threonine phosphatase(s).

Objectives: We previously reported that 25% (108/441) of consecutive patients presenting to the emergency department (ED) of the Montreal Heart Institute with a chief complaint of chest pain suffered from panic disorder (PD). The purpose of the present study was to re-examine these patients (with and without PD) 2 years after their initial ED visit to determine their psychiatric and psychosocial status., Methods: An interviewer, who was kept blind to patients' initial medical and psychiatric diagnoses, attempted to contact all patients who participated in the initial study by phone. Patients who completed the phone interview were sent a battery of psychological questionnaires by mail., Results: A total of 301 (70%) patients completed the phone interview, and 228 (52%) patients completed the self-report questionnaires. Participants and non-participants did not differ with respect to age, gender, initial self-report scores, or initial cardiac or psychiatric diagnoses. At follow-up, significantly (p < 0.05) more PD+ than non-PD (PD-) patients reported: 1) chest pains in the last month (57% vs. 31%); 2) one or more ED consultations in the past year for chest pain (40% vs. 14%); 3) one or more hospitalizations in the past year (31% vs. 11%); and 4) perceiving their general health as "poor" (22% vs. 9%). PD+ patients displayed a significant (p < 0.05) worsening of their panic symptoms, agoraphobic avoidance, depression, and trait anxiety, and reported significantly (p < 0.05) greater suicidal ideation compared to PD- patients (32% vs. 9%). Of all PD+ patients, only 22% (18/82) reported receiving some form of mental health treatment for their symptoms., Conclusions: Unrecognized and untreated PD has a chronic and disabling course. Greater efforts should be made to screen for PD in patients complaining of chest pain in EDs.

Unlabelled: The association between a patient's illness representation and long-term changes in treatment adherence still needs to be clarified., Aim: to evaluate the association between the representation of hypercholesterolemia and dietary modifications over 1-year, controlling for biopsychosocial factors., Methods: 208 hypercholesterolemic Caucasian patients. Measures of dietary intake, illness representation, and biopsychosocial factors were collected at baseline, 3, 6, and 12 months., Results: Two multiple regressions were performed on the 1-year change in dietary habits; one with subjects with elevated fat consumption at baseline, another with individuals with low-moderate fat consumption. Higher scores on items reflecting an accurate illness representation at baseline were associated with greater dietary modification among patients of the first group. For patients with low-moderate total fat consumption, maintenance of dietary habits was associated to lower scores on the perception of stress and symptoms., Conclusion: To optimize adherence, intervention on illness representation should be adjusted according to initial dietary habits.

Objectives: To examine sex differences pertaining to pain characteristics in patients presenting to the ambulatory emergency department (ED) with nontraumatic chest pain and to the prediction of exercise-induced ischemia on a follow-up electrocardiogram., Methods: This was a prospective study of 131 women and 202 men (mean age 58 years) consulting the ED with a chief complaint of chest pain. Seventy-eight women and 116 men underwent exercise stress testing following the ED consultation. Chest pain location, extension, intensity and quality were measured. Chest pain was classified as nonspecific, or typical or atypical of angina., Results: Women received fewer 'typical' angina pain diagnoses (P<0.05), rated their pain as more intense (P<0.05) and used more affective words to describe their pain (P<0.05) compared with men. Pain in the posterior shoulder and middle back areas were more frequently reported by women (P<0.05). The presence of pain in the right anterior and posterior shoulder, as well as the absence of pain in the left anterior shoulder, predicted ischemia (P<0.05) in both men and women. Only in men, pain in the retrosternal and right middle back areas, as well as a classification of pain as typical or atypical, further contributed to the prediction of ischemia., Conclusions: Sex differences exist in the experience of chest pain and in the prediction of exercise-induced ischemia from pain variables. Further research on the unique symptomatology of men and women is needed to optimize their medical management.

Collagen type IV (CnIV) and fibronectin (Fn) were used as ligands to study the distribution of alpha(2)beta(1) and alpha(4)beta(1) integrins in low-density, detergent-resistant microdomains (DRM) of Jurkat lymphocytes. CnIV-coated microspheres induced (optical trapping) the redistribution of GM(1)-associated fluorescence from the cell periphery to the area of contact. This was not observed in cells treated with beta-methyl cyclodextrin (MCD). Fn- or bovine serum albumin-coated microspheres did not modify the peripheral distribution of fluorescence. These observations were confirmed by confocal microscopy. Western blot analysis of cells exposed to surfaces coated with CnIV revealed that the alpha(2)-subunit was initially present at low levels in DRM, became strongly associated after 40 min, and returned to basal levels after 75 min. Fn induced a slight recruitment of the beta(1)-integrin alpha(4)-subunit in DRM after 5 and 10 min, followed by a return to basal levels. Neither CnIV nor Fn triggered significant changes in the distribution of the beta(1)-subunit in DRM. Fn- and CnIV-coated microspheres or surfaces coated with these ligands triggered a MCD-sensitive mobilization of Ca(2)(+). MCD did not alter the state of the Ca(2)(+) reserves. The differential distributions of the alpha(2)beta(1) and alpha(4)beta(1) integrins in DRM may provide one additional step in the regulation of outside-in signaling involving these integrins.

It is widely accepted that cell-mediated immune functions decline with age, rendering an individual more susceptible to infection and possibly cancer, as well as to age-associated autoimmune diseases. The exact causes of T-cell functional decline are not known. One possible cause could be the development of defects in the transduction of mitogenic signals following TCR stimulation. This T-cell hyporesponsiveness due to defects of signalling through the TCR either from healthy elderly subjects or from individuals with autoimmune diseases such as rheumatoid arthritis or systemic lupus erythematosus results in an impaired ability to mount efficient immune responses and to maintain responsiveness to foreign antigens. This implies that a high proportion of autoreactive T cells might accumulate either intrathymically or in the periphery. T-cell anergy and differential TCR signalling could thus also be key players in the disruption of tolerance and the onset of autoimmune diseases. The increasing number of the elderly may lead to an increase of clinically important autoimmune diseases. We will review the signal transduction changes through the TCR-CD3 complex in T lymphocytes from healthy elderly subjects, which result in a modification of the activation of transcription factors involved in IL-2 gene expression leading to decreased IL-2 production. The putative contribution of altered T-cell signalling with ageing in the development of autoimmune diseases will be also discussed.

Previously, we have demonstrated age-associated alterations in transmembrane signaling. One of the most reproducible alterations found in the immune response with aging is the decrease of lymphocyte proliferation on stimulation with various different mitogens. Here, we confirm that proliferative responses to stimulation with phytohaemagglutin (PHA), recombinant human IL-2, or anti-CD3 monoclonal antibody are all greater in the young (20-25 years) than old (60-87 years) population. We attempted to modulate the proliferative response using various agents acting at different levels of transmembrane signaling (pertussis toxin, cholera toxin, isoproterenol, PMA, Ca ionophore A23187), as well as at the level of the lymphocyte plasma membrane (methyl-beta-cyclodextrin, MBCD), or by using antioxidant vitamins (Vitamin E or C). None of these agents was able to restore effectively the proliferative response of lymphocytes from the aged to the level of young subjects. Even the combination of A23187 and PMA acting directly on calcium metabolism and protein kinase C activity was insufficient to restore the decreased mitogenic capacity of T cells from elderly subjects. Cyclodextrin, which decreases the cholesterol content of the membrane, increased the proliferative response of lymphocytes of elderly subjects, but not to the level of the young. Vitamin E had a very strong inhibitory effect on lymphocyte stimulation in both the age groups, except in combination with MBCD in T cells of the elderly, while Vitamin C had no significant modulatory effect. MAPK ERK and p38 activation was found to be decreased with aging in T cells after anti-CD3 mAb stimulation. Vitamin E but not Vitamin C strongly inhibited MAPK ERK or p38 activation. The direct activation of certain molecules or the modulation of the cholesterol content of the membrane seems to be effective immunomodulatory interventions with aging.

Unlabelled: This article presents an overview of the clinical use of Benzodiazepines (BZD) for anxiety problems. It presents a synthesis of the literature on potentially problematic aspects associated with long-term use and presents alternatives to BZD use in the management of anxiety. Medline searches from 1980 to 2001 were conducted. Relevant articles anterior to these dates, located through reference sections of more recent articles, were also reviewed., Conclusions: Risks and benefits of these drugs for the long-term management of anxiety problems are still not clearly established. Nevertheless, despite recommendations that BZDs should be used on a short-term basis only, an important proportion of patients continue using them on a long-term basis. It would be useful to assess how alternative anxiety management strategies are presented to patients and, if relevant, how to make them more accessible and appealing to anxious patients.

This study compared mood changes in 212 patients treated for hypercholesterolemia, as a function of their level of adherence to dietary recommendations. Assessments of mood (anxiety, depression, and hostility), measured by the Profile of Mood States, were obtained at baseline and 3-, 6-, and 12-month follow-up. Adherence to diet was categorized as low, medium, or high based on the Food Record Rating. Repeated-measures ANOVAs showed a significant decrease over time for anxiety, total cholesterol (TC), and low-density lipoproteins (LDL). A multiple regression was performed to determine if reductions in TC or LDL were associated with the anxiety decrease. The model for anxiety change was highly significant and included gender, baseline anxiety, number of stressful events, psychological stress, baseline level of adherence to diet, gender x adherence interaction, and change in TC x adherence interaction. In conclusion, cholesterol lowering did not negatively affect patients' moods. However, those who adhered poorly but nonetheless showed stable or reduced TC exhibited a greater decrease in anxiety.

Purpose: To develop an instrument to measure patients' perceptions of the services provided by anesthesiologists, an important indicator of quality for which little information is available., Methods: The scale of patients' perceptions of cardiac anesthesia services (SOPPCAS) is composed of 17 Likert-type and sociodemographic questions. Data collection was conducted on T-1 (fourth postoperative day) and T-2 (15 days postoperatively). In addition, we employed the Marlow-Crowne scale and a short form of the Psychological Symptoms Index to verify the influence of social desirability and psychological distress respectively. Data analysis included a principal component analysis (PCA)., Results: One hundred seventy patients answered the questionnaires at T-1 and 133 patients at T-2. Cronbach alpha of the SOPPCAS was 0.58. PCA revealed four perioperative factors: patient/anesthesiologist interactions, preoccupations related to anesthesia, experience with anesthesia and pain management. Global mean satisfaction was 4.45 +/- 0.64 (maximum score 6.0). Main items related to satisfaction were: satisfaction with premedication, empathy from anesthesiologists, pain management. Main items related to dissatisfaction were: lack of information on blood transfusion and recall of endotracheal intubation. A score of 14/20 was obtained for social desirability. Social desirability did not influence the construct of the SOPPCAS., Conclusion: We developed, using rigorous methods, an instrument to measure patients' perceptions of the quality of cardiac anesthesia services. Global mean satisfaction with anesthesia services was moderately high contrary to previous studies where it was high. Finally, the SOPPCAS should allow anesthesiologists to improve the quality of the care they provide.

Endothelial cells derived from the human umbilical vein (HUVEC) are used to study the mechanisms involved in EC response to various stimuli as well as to investigate the basis of pathological conditions of the vascular system such as altered endothelium permeability, tumor-induced angiogenesis, atherosclerosis and leukocyte extravasation in chronic inflammatory responses. However, investigations of gene involvement related to these conditions have progressed slowly because of the difficulty of transfecting HUVEC with high efficiency. Whereas several technical approaches have been described, they usually result in low levels of transfected cells or they require several steps or sophisticated instrumentation. We describe here a straightforward protocol of transfection of freshly isolated HUVEC that is based on the simple technique of electroporation. Efficiencies of gene transfection greater than 40% were routinely obtained by using a combination of optimized conditions of HUVEC isolation, composition of the electroporation medium and homogeneity of the plasmids. The protocol has been applied to the functional transient transfection of functional genes in HUVEC as illustrated in the case of the cDNA encoding GFP, protein kinase C (alpha and epsilon isotypes) and beta-galactosidase.

There is an alteration of the immune response in aging that leads to the increased incidence of infections, cancers and autoimmune disorders. The aim of the present study was to investigate whether there exists changes in signal transduction under the IL-2 receptor stimulation and the role of plasma membrane cholesterol in the activation of T cells with aging. We report age-related changes in the JAK-STAT signalling pathway that results in decreased tyrosine phosphorylation of STAT5. We present evidence for the importance of cholesterol content in regulating signalling pathways in T cells and in modulating their proliferation by using the plasma membrane cholesterol-depleting agent methyl-beta-cyclodexrin (MBCD). MBCD treatment (0.5 mM) induced a significant decrease in the cholesterol content of T cells of elderly subjects whereas it was increased in T cells of young subjects. MBCD induced changes in the phosphorylation of p56(lck), especially in T cells of elderly subjects. The proliferation of MBCD-treated T cells decreased in lymphocytes of young subjects but did not change in T cells of elderly subjects. These results suggest a role for plasma membrane cholesterol in the regulation of the TcR signalling pathways with differential effects related to aging. However, the data suggest that modulation of the plasma membrane cholesterol content alone may not be enough to restore signal transduction changes with aging.

Background: A lack of resources has created waiting lists for many elective surgical procedures within Canada's universal health care system. Coronary artery bypass grafting (CABG) for the treatment of atherosclerotic ischemic heart disease is one of these affected surgical procedures. We studied the impact of waiting times on the quality of life of patients awaiting CABG., Methods: A prospective cohort of 266 patients from 3 hospitals in Montreal was used. Patients who gave informed consent were followed from the time they were registered for CABG until 6 months after surgery; recruitment began in November 1993, and the last follow-up was completed in July 1995. Patient groups were classified according to the duration of the wait for CABG (< or = 97 days or > 97 days). We measured the following outcomes: quality of life (using the Medical Outcomes Study 36-item Short Form [SF-36]), incidence of chest pain (using the New York Heart Association angina classification), frequency of symptoms (using the Cardiac Symptom Inventory) and rates of complications and death before and after surgery., Results: There were no differences in quality of life at baseline between the 2 groups. Immediately before surgery, compared with patients who waited 97 days or less, those who waited longer had significantly reduced physical functioning (change from baseline SF-36 score 0 v. -4 respectively, p = 0.001), vitality (change from baseline score -0.1 v. -1.3, p = 0.01), social functioning (change from baseline score 0.4 v. -0.4, p = 0.03) and general health (change from baseline score 1.1 v. -1.7, p = 0.001). At 6 months after surgery, compared with patients who waited 97 days or less for CABG, those who waited longer had reduced physical functioning (change from baseline SF-36 score 4.0 v. -0.1 respectively, p = 0.001), physical role (change from baseline score 0.8 v. 0.0, p = 0.001), vitality (change from baseline score 2.2 v. 0.9, p = 0.001), mental health (change from baseline score 1.2 v. 0.0, p = 0.001) and general health (change from baseline score 1.8 v. -0.3, p = 0.001). The incidence of postoperative adverse events was significantly greater among the patients with longer waits for CABG than among those with shorter waits (32 v. 14 events respectively, p = 0.005). Longer waits before CABG were associated with an increased likelihood of not returning to work after surgery (p = 0.08): 10 (53%) of the 19 patients with longer waiting times remained employed after CABG, as compared with 17 (85%) of the 20 with shorter waiting times., Interpretation: The significant decrease in physical and social functioning, both before and after surgery, for patients waiting more than 3 months for CABG is an important observation. Longer waiting times were also associated with increased postoperative adverse events. By decreasing waiting times for CABG, we may improve patients' quality of life and decrease the psychological morbidity associated with CABG.

Atherosclerosis has been implicated in myocardial infarction, stroke and a host of cardiovascular diseases. The presence of activated T lymphocytes and macrophages, and the increased expression of HLA-DR antigen are consistent with the notion of immune activity in the atherosclerotic plaque. The nature of the causative antigen has not been established although oxidised low density lipoproteins (oxLDL) that accumulate in atherosclerotic plaques could fulfil this role. Here, we report that monocytes play a key role in influencing the fate of purified peripheral human T lymphocytes from healthy donors when the cells are exposed to LDL oxidised under the controlled conditions of water radiolysis. Our data showed that oxLDL generated under these conditions were chemoattractants for T cells. However, they induced a state of apoptosis in T lymphocytes cultured in the absence of monocytes. The extent of apoptosis was related to the degree of oxidation of LDL and the time of T cell exposure to oxLDL. OxLDL-dependent apoptosis did not involve a scavenger-like receptor. CD4(+) cells were more sensitive to the apoptotic effect of oxLDL than CD8(+) cells. OxLDL-primed (12 h) autologous monocytes triggered a robust proliferation of T lymphocytes cultured in the absence of oxLDL. The strength of T cell stimulation was related to the degree of oxidation of the LDL used in priming. Heterologous monocytes exposed to oxLDL under similar conditions induced a response that was not different than monocytes exposed to untreated LDL (natLDL) which did not induce T cell proliferation. Fucoidan did not modify the oxLDL-, monocyte-dependent T cell response to proliferation, suggesting that a scavenger-like receptor was not involved. The expression of the HLA-DR marker and the B7.2 protein were up-regulated in monocytes exposed to oxLDL but not to natLDL. The levels of B7.1 were unchanged. Our data are consistent with the notion that monocytes are critical for T cell survival in the presence of oxLDL and MHC-restricted T cell proliferative response to oxLDL.

We reported previously that the protein kinase C (PKC) inhibitor GF109203X stimulated the hamster CYP11B2 promoter activity in transfected NCI-H295 cells. PKCalpha, -epsilon, and -zeta were detected in hamster adrenal zona glomerulosa and NCI-H295 cells, and PKCtheta in NCI-H295 cells. 12-O-Tetradecanoylphorbol-13-acetate (TPA) inhibited basal and stimulated cytochrome P450 aldosterone synthase mRNA expression by angiotensin (AII), dibutyryl cyclic adenosine 3':5'-monophosphate (Bt2cAMP), or KCl in NCI-H295 cells. Basal CYP11B2 promoter activity was inhibited in cells cotransfected with constitutively active (CA) PKCalpha, -epsilon, and -theta mutants, whereas it was increased with CA-PKCzeta. Dominant negative (DN) PKCalpha, -theta, -epsilon, and -zeta mutants stimulated the promoter activity. AII-, KCl-, and Bt2cAMP-stimulatory effects were abolished in cells cotransfected with CA-PKCalpha, -epsilon, or -theta. The effect of Bt2cAMP was abolished by CA-PKCzeta but AII and KCl were still able to enhance the promoter activity. DN-PKCalpha, -epsilon, -theta, or -zeta did not inhibit these effects. Gö6976 enhanced promoter activity, providing further evidence that PKCalpha was involved. Various CYP11B2 promoter constructs were used to identify the area associated with TPA and PKC inhibition. TPA and CA-PKCalpha, -epsilon, or -theta abolished the effects of AII, KCl, and Bt2cAMP on the activity of -102 and longer constructs. In summary, our findings suggest that the hamster CYP11B2 gene is under differential control by conventional (alpha) and atypical (zeta) PKC.

Purpose: The evaluation of services by patients is an essential component of continuous quality improvement in anesthesiology. Little is known, however, about how to achieve this objective. Our goal was to conduct a systematic review of all available studies on patient satisfaction with anesthesia services, thereby ascertaining the present level of knowledge in this field and suggesting ways of improving current measurement methodologies., Source: We reviewed relevant major data banks--Medline, Dissertation Abstract, Psyclit and Cochrane--between 1980 and 2000 and bibliographies from primary sources. We used the following keywords for our search: quality improvement, anesthesia, quality, patient perceptions, consumer satisfaction, continuous quality improvement, outcome measures., Principal Findings: The review yielded 14 pertinent studies. Studies were divided into two groups (A & B), according to the quality of the psychometric evaluation (tests performed to verify the reliability and validity of an instrument). While all studies reported high levels of patient satisfaction with anesthesia services, many used methods of questionable value. None of the 14 studies controlled for any confounding variables, such as social desirability. Four studies had seriously biased their data collection and the majority of the studies lacked rigour in the development of the instrument used to measure patient satisfaction. Only one study presented a definition of the concept measured, and none provided a conceptual model of patients' satisfaction with anesthesia services., Conclusion: The currently available studies of patient satisfaction are of questionable value. Only rigorous methods and reliable instruments will yield valid and clinically relevant findings of this important issue in anesthesiology.

Bisindolylmaleimide, a protein kinase C (PKC) inhibitor, was shown to stimulate the hamster CYP11B2 promoter activity in transfected NCI-H295 cells. In this study we have found that TPA, an activator of PKC, also inhibited the hamster CYP11B2 promoter activity. DAG-dependent PKC alpha and PKC epsilon, and atypical PKC zeta were detected in hamster adrenal zona glomerulosa, whereas the isoforms alpha, epsilon, zeta and theta were found in NCI-H295 cells. CYP11B2 promoter activity was inhibited in cells co-transfected with constitutively active PKC alpha and epsilon mutants, whereas it was increased with the constitutively active PKC zeta mutant. Dominant negative PKC alpha, epsilon and zeta mutants stimulated the promoter activity. Gö6976, a specific inhibitor of classical PKCs, enhanced promoter activity, providing further evidence that PKC alpha, the only classical PKC revealed in hamster adrenal and NCI-H295 cells, was involved in the promoter inhibition.

We have treated Jurkat T lymphocytes with a concentration (160 nM) of phorbol myristyl acetate (PMA) that down-regulates conventional and novel protein kinase C (PKC) isozymes and we have investigated the effects on Ca2+ signaling and protein tyrosine phosphorylation using mAb (C305) directed against the beta-subunit of the Ti heterodimer or the epsilon/delta-component of the CD3 complex (mAb Leu 4 or OKT 3). The levels of expression of PKC alpha, betaI, betaII, and delta were reduced by 90% or more in PMA-treated cells, whereas the expression of PKCtheta decreased by approximately 30%. In contrast, the chronic treatment with PMA increased the expression of PKCepsilon and PKCzeta. There was a lack of Ca2+ response and myo-inositol trisphosphate (IP3) production in PMA-treated cells when they were exposed to mAb Leu 4 but the cells responded to mAb C305. The treatment with PMA did not affect the surface expression of Ti or CD3. The overall levels of tyrosine-phosphorylated proteins were markedly reduced in PMA-treated cells. We investigated whether these observations were related to defects in signal transduction related to protein tyrosine kinase (PTK) of the src and syk families. The electrophoretic mobilities of p59(fyn) or ZAP-70 were not changed in PMA-treated cells but p56(Ick) migrated as a large band of M(r) 60-62 kDa. The decreased mobility of p56(Ick) was related to a state of hyperphosphorylation. The activity of modified p56(Ick) was not up-regulated in activated Jurkat cells. Our data suggest that clonotypic Ti can trigger Ca2+ mobilization independently of conventional PKC isoforms. Our observations further suggest that conventional PKC isoforms are involved early in the cascade of events associated with Jurkat T lymphocyte activation.

Is it possible to have panic attacks without fear? Beitman et al. reported that 32%-41% of panic disorder (PD) patients seeking treatment for chest pain have non-fearful panic disorder (NFPD). To replicate and extend this work on NFPD, the authors compared NFPD patients (N = 48), PD patients (N = 60), and No-PD patients (N = 333) at the time of an emergency department visit and follow-up approximately 2 years later. The authors compared comorbid Axis I diagnoses, panic attack symptoms, and scores on self-report measures. A significantly greater proportion of PD patients had comorbid generalized anxiety disorder and agoraphobia than NFPD patients. NFPD patients had self-report scores that were between no-PD and PD patients or similar to no-PD patients, with the exception of the Beck Depression Inventory. At follow-up, NFPD patients, like PD patients, were still symptomatic and had either not improved or had worsened according to scores on all self-report measures. NFPD should be recognized as a variant of PD, both because of its high prevalence in medical settings and its poor prognosis.

Objective: To evaluate the range of long term vascular manifestations of Coxiella burnetii infection., Design: Cohort study in Switzerland of people affected in 1983 by the largest reported outbreak of Q fever and who were followed up 12 years later. Follow up information about possible vascular disease and endocarditis was obtained through a mailed questionnaire and death certificates., Setting: Val de Bagnes, a rural Alpine valley in Switzerland., Participants: 2044 (87%) of 2355 people who had serum testing for Coxiella burnetii infection in 1983: 1247 were classed as not having been infected, 411 were classed as having been acutely infected, and 386 were classed as having been infected before 1983., Main Outcome Measures: Relative risk controlled for age and sex and 12 year risk of vascular diseases and endocarditis among infected participants as compared with those who had never been infected., Results: The 12 year risk of endocarditis or venous thromboembolic disease was not increased among those who had been acutely infected. The 12 year risk of arterial disease was significantly higher among those who had been acutely infected (7%) as compared with those who had never been infected (4%) (relative risk 2.2, 95% confidence interval 1.4 to 3.6). Specifically, there was an increased risk of developing a cerebrovascular accident (relative risk 3.7, 1.6 to 8.4) and cardiac ischaemia (relative risk 1.9, 1.04 to 3.4). 12 year mortality was significantly higher among the 411 people who had been acutely infected in 1983 (9.7%; age adjusted relative risk 1.8, 1.2 to 2.6) when compared with the 1247 participants who had remained serologically negative in 1983 (7.0%)., Conclusions: Coxiella burnetii infection may cause long term complications including vascular disease.

This study compared subjects who had received standard tapered withdrawal of benzodiazepine (BZD) (group 1) with a group with comparable diagnosis still receiving BZD (group 2) and a control group of comparable diagnosis not yet receiving treatment (group 3). Sixty subjects aged 21-65 years with a diagnosis of nonpsychotic anxiety or insomnia were included. The assessment of psychological distress and quality of life was timed to coincide with the maximum immediate effect of BZD discontinuation, as calculated according to drug half-life. Subjects diagnosed with insomnia reported lower distress in all three groups. The pattern of distress experienced by group 1 was closer to group 3 than to group 2, indicating the potential importance of re-emergence of anxiety. High neuroticism, lower education level, and lower quality of life were associated with higher levels of distress during withdrawal.

Cellular immune responses decrease with aging. Lymphocytes of aged individuals do not perform as well as cells from young subjects in a number of in vitro assays including cell proliferation, cytokine production, and protection against apoptosis. Here, we have tested the hypothesis that a decrease in T cell responses in tymphocytes from elderly subjects could parallel a decrease in the activity of protein tyrosine kinases (PTK) associated with signal transduction in T lymphocytes. We report that anti-CD3-triggered T lymphocyte proliferation was significantly decreased in T lymphocytes from elderly subjects, but the decrease was not due to an alteration of the percentage or mean fluorescence intensities of CD3, CD4, and CD45. Of significance, the activities of p56lck and ZAP-70 in vitro were significantly decreased in T lymphocytes from elderly subjects compared to young individuals. However, the level of expression of the two kinases did not change with aging. The activity of p59fyn did not show changes with aging, suggesting that p59fyn did not compensate for the decreased activity of p56lck. We also found that the extent of tyrosine phosphorylation of the adaptor protein p95vav was similar in activated T lymphocytes from elderly and young subjects. Our results suggest that the altered cellular immune responses observed in T lymphocytes with aging may be the result, at least in part, of an alteration in early events associated with signal transduction through the TcR/CD3 complex that translates into decreased activities of p56lck and ZAP-70. Impairment in the activities of these twokey components of T cell signaling may contribute to reduced immune functions associated with aging.

This study compared 96 women and 58 men suffering from panic disorder with agoraphobia. Participants completed questionnaires assessing various clinical features associated with panic disorder with agoraphobia (PDA), general adjustment, and drug/alcohol use. Results showed that PDA is a more severe condition in women. Women reported more severe agoraphobic avoidance when facing situations or places alone, more catastrophic thoughts, more body sensations, and higher scores on the Fear Survey Schedule. Also, women more often had a comorbid social phobia or posttraumatic stress disorder. The lower agoraphobic avoidance of men was associated with their alcohol use. However, there were no differences between genders in other dimensions, including depression, situational and trait anxiety, stressful life events, social self-esteem, marital adjustment, and drug use.

In a recent study, the authors reported that 25% (108/441) of consecutive emergency department (ED) chest pain patients had panic disorder (PD). As part of this study, the authors sought to answer the question: How do ED patients with PD compare with patients with PD who seek treatment in a psychiatric setting? PD patients from an ED (n = 108) and psychiatric clinic (n = 137) were compared with respect to comorbid Axis I diagnoses, self-report scores, and recent suicidal ideation. The group of psychiatric patients was younger (36.5 vs. 52.3 years) (P < 0.0001) and consisted of proportionally more women (63% vs. 39%) (P = 0.0001) than the ED patients. The psychiatric patients had significantly higher rates of comorbid agoraphobia (100% vs. 15%) (P < 0.0001), social phobia (23% vs. 3%) (P = 0.0001), specific phobia (12.3% vs. 4.6%) (P = 0.03), and posttraumatic stress disorder (16.9% vs. 5.6%) (P = 0.006), compared with the ED patients, and displayed significantly higher scores on all of the self-report panic measures. However, the patients in both groups had similar rates of comorbid generalized anxiety disorder (41.2% vs. 33.3%) (P = 0.17), major depression (8.8% vs. 11.1%) (P = 0.54), and obsessive-compulsive disorder (1.5% vs. 2.8%) (P = 0.7). Both groups also did not differ on the Beck Depression Inventory and in their rate of report of recent suicidal ideation (32% vs. 25%) (P = 0.23). Both psychiatric and ED patients with PD appear to be highly distressed patients who require treatment. Early intervention for ED patients may prevent both chronic patient distress and development of the significant phobic avoidance observed in psychiatric patients.

Lymphocyte extravasation involves a step(s) of de-adhesion to allow trans- and subendothelial migration in response to inflammatory signals. We show here that ligated VCAM-1 was rapidly internalized (t1/2 14.5 min) in ECV 304 endothelial cells and in TNF-alpha-primed human umbilical vein-derived endothelial cells (t1/2 11.2 min). The process required energy (ATP), intracellular Ca2+, an intact cytoskeletal network and active protein kinases. The internalization of VCAM-1 involved a clathrin-dependent pathway based on the observations that 1) it was inhibited in cells treated with lysosomotropic agents or with a hypertonic concentration of sucrose, and 2) internalized VCAM-1 colocalized with clathrin. In contrast, the cross-linked alpha 4 beta 1 integrin counter-receptor of VCAM-1 remained associated with the plasma membrane of purified peripheral T and Jurkat cells. Our results suggest a model where VCAM-1 would initially participate in the retention of T cells to the endothelium by binding alpha 4 beta 1 integrin. Lymphocyte de-adhesion would be facilitated as a result of the internalization of VCAM-1. The persistent cell surface expression of alpha 4 beta 1 integrin would allow the migrating T cells to interact with and receive signal(s) from its fibronectin ligand of the extracellular matrix.

cDNA encoding the full-length hKv1.3 lymphocyte channel and a C-terminal truncated (delta 459-523) form that lacks the putative PKA Ser468 phosphorylation site were stably transfected in human embryonic kidney (HEK) 293 cells. Immunostaining of the transfected cells revealed a distribution at the plasma membrane that was uniform in the case of the full-length channel whereas clustering was observed in the case of the truncated channel. Some straining within the cell cytoplasm was found in both instances, suggesting an active process of biosynthesis. Analyses of the K+ current by the patch-clamp technique in the whole cell configuration showed that depolarizing steps to 40 mV from a holding potential (HP) of -80 mV elicited an outward current of 2 to 10 nA. The current threshold was positive to -40 mV and the current amplitude increased in a voltage-dependent manner. The parameters of activation were -5.7 and -9.9 mV (slope factor) and -35 mV (half activation, V0.5) in the case of the full-length and truncated channels, respectively. The characteristics of the inactivation were 14.2 and 24.6 mV (slope factor) and -17.3 and -39.0 mV (V0.5) for the full-length and truncated channels, respectively. The activation time constant of the full-length channel for potentials ranging from -30 to 40 mV decreased from 18 to 12 msec whereas the inactivation time constant decreased from 6600 msec at -30 mV to 1800 msec at 40 mV. The unit current amplitude measured in cells bathing in 140 mM KCl was 1.3 +/- 0.1 pA at 40 mV, the unit conductance, 34.5 pS and the zero current voltage, 0 mV. Both forms of the channels were inhibited by TEA, 4-AP, Ni2+ and charybdotoxin. In contrast to the native (Jurkat) lymphocyte Kv1.3 channel that is fully inhibited by PKA and PKC, the addition of TPA resulted in 34.6 +/- 7.3% and 38.7 +/- 9.4% inhibition of the full-length and the truncated channels, respectively, 8-BrcAMP induced a 39.4 +/- 5.4% inhibition of the full-length channel but had no effect (8.6 +/- 8.3%) on the truncated channel. Cell dialysis with alkaline phosphatase had no effects, suggesting that the decreased sensitivity of the transfected channels to PKA and PKC was not due to an already phosphorylated channel. Patch extract experiments suggested that the hKv1.3 channel was partially sensitive to PKA and PKC. Cotransfecting the Kv beta 1.2 subunit resulted in a decrease in the value of the time constant of inactivation of the full-length channel but did not modify its sensitivity to PKA and PKC. The cotransfected Kv beta 2 subunit had no effects. Our results indicate that the hKv1.3 lymphocyte channel retains its electrophysiological characteristics when transfected in the Kv beta-negative HEK 293 cell line but its sensitivity to modulation by PKA and PKC is significantly reduced.

In this study we address the following questions: (1) What percentage of coronary artery disease (CAD) patients that present with chest pain, but whose symptoms cannot be fully explained by their cardiac status, suffer from panic disorder (PD)? (2) How do patients with both CAD and PD compare to patients without CAD and to patients without either PD or CAD in terms of psychological distress? Four hundred forty-one consecutive walk-in emergency department patients with chest pain underwent a structured psychiatric interview (ADIS-R) and completed psychological scales. Fifty-seven percent (250 of 441) of these patients were diagnosed as having noncardiac chest pain and constituted this study's sample. A total of 30% (74 of 250) of noncardiac chest pain patients had a documented history of CAD. Thirty-four percent (25 of 74) of CAD patients met criteria for PD. Patients with both PD and CAD displayed significantly more psychological distress than CAD patients without PD and patients with neither CAD nor PD. However, they did not differ from non-CAD patients with PD. PD is highly prevalent in patients with CAD that are discharged with noncardiac diagnoses. The psychological distress in these patients appears to be related to the panic syndrome and not to the presence of the cardiac condition.