[The interesting anti-H1 effects in maintenance insomnia: A reflection on the comparative advantages of doxylamine and doxepin]. / Les effets anti-H1 intéressants dans les insomnies de maintien : réflexion sur les intérêts comparés de la doxylamine et de la doxépine.

Doxylamine (Donormyl®, Lidene®, Generics) is commonly proposed by pharmacists as a sleeping pill which does not require a prescription. In France, today it is only prescribed for occasional insomnia in adults. In light of knowledge about the role of the histamine H1 inverse agonist drugs in the treatment of insomnia, and specifically the low dose doxepin (3 mg and 6 mg) marketed in the US and Canada (Silenor®), we suggest that the use of doxylamine may be appropriate for treating insomnia in the last third of the night. Better information to the pharmacist on the prescription of this anti-H1 hypnotic would be beneficial to the patient.

Dementia-specific quality of life instruments: a conceptual analysis.

BACKGROUND: Over the past 20 years, many researchers have worked in developing various methods for measuring quality of life (QoL) of people with dementia. The aim of this review is to develop the conceptual frameworks of the dementia-specific QoL instruments, to identify their evolution over time and to provide elements of reflection on the QoL concept in dementia and its evaluation. METHODS: An electronic search was conducted on PsycINFO and MEDLINE databases, from January 1985 to June 2015 using a combination of key words that include QoL, dementia, and review. RESULTS: The analysis of the conceptual frameworks of the 18 selected dementia-specific QoL tools shows a great diversity in: (1) the QoL definitions (e.g. health-related QoL definitions, QoL definitions based on Lawton's work, or similar to this latter); (2) the theoretical QoL models (e.g. Lawton' work and modified Lawton, adaptation, personhood); (3) the domains and dimensions; (4) the way to construct the instrument (e.g. development based on literature, opinion of the experts), and (5) the items' formulation (e.g. use of criterion of intensity or frequency). CONCLUSIONS: There are different conceptual frameworks in the dementia-specific QoL measures with improvements over time (e.g. inclusion of interesting concepts such as adaptation, taking into account the views of patients themselves). Each of the conceptual parameters (definitions, models, domains, and dimensions) is discussed to identify the scales that are conceptually the strongest. Through their review, recommendations for future instrument refinement and development are discussed and a new QoL definition is proposed.

From inflamm-aging to immune-paralysis: a slippery slope during aging for immune-adaptation.

Aging is accompanied by many physiological changes including those in the immune system. These changes are designated as immunosenescence indicating that age induces a decrease in immune functions. However, since many years we know that some aspects are not decreasing but instead are increasing like the pro-inflammatory activity by the innate immune cells, especially by monocytes/macrophages. Recently it became evident that these cells may possess a sort of memory called trained memory sustained by epigenetic changes occurring long after even in the absence of the initiator aggressor. In this review we are reviewing evidences that such changes may occur in aging and describe the relationship between inflamm-aging and immunosenescence as an adaptation/remodelling process leading on one hand to increased inflammation and on the other to decreased immune response (immune-paralysis) mastered by the innate immune system. These changes may collectively induce a state of alertness which assure an immune response even if ultimately resulting in age-related deleterious inflammatory diseases.

Quality of work life in doctors working with cancer patients.

BACKGROUND: Although studies have shown that medical residents experience poor psychological health and poor organizational conditions, their quality of work life (QWL) had not been measured. A new tool, the Quality of Work Life Systemic Inventory (QWLSI), proposes to fill the gap in the definition and assessment of this concept. AIMS: To confirm the convergent validity of the QWLSI, analyse Belgian medical residents' QWL with the QWLSI and discuss an intervention methodology based on the analysis of the QWLSI. METHODS: One hundred and thirteen medical residents participated between 2002 and 2006. They completed the QWLSI, the Maslach Burnout Inventory and the Job Stress Survey to confirm the correspondence between these three tools. RESULTS: Residents' low QWL predicted high emotional exhaustion (ß = 0.282; P < 0.01) and job stress (ß = 0.370; P < 0.001) levels, confirming the convergent validity. This sample of medical residents had an average QWL (µ = 5.8; SD = 3.1). However, their QWL was very low for three subscales: arrangement of work schedule (µ = 9; SD = 6.3), support offered to employee (µ = 7.6; SD = 6.1) and working relationship with superiors (µ = 6.9; SD = 5.3). CONCLUSIONS: The results confirm that the QWLSI can provide an indication of workers' health well-being and of organizational performance in different areas of work life. The problem factors found among Belgian medical residents suggest that prevention should focus on reduction of work hours, development of support and change in leadership style.

[Catatonia in a 14 year-old girl: treatment with clorazepam and carbamazepine, a 10-year follow-up]. / Catatonie chez une adolescente de 14 ans: traitement par clorazépam et carbamazépine et évolution à dix ans.

INTRODUCTION: Child and adolescent catatonia has been poorly investigated. Moreover, diagnosis criteria only exist for adult psychiatry, and there are no therapeutic guidelines. The aim of this paper is to describe the case of a 14-year-old girl presenting an overlap between psychogenic and neuroleptic induced catatonia, acute treatment and ten year's follow-up. CASE REPORT: A 14-year-old Caucasian French girl, Elsa, was admitted in February 1998 to a University adolescent mental health center with an acute psychotic disorder. She showed agitation, impulsivity (sudden engagement in inappropriate behaviour), paranoid delusions, visual and auditory hallucinations, diurnal and nocturnal urinary incontinence, lack of self-care, inadequate food intake because of fear of poisoning, and vomiting after meals leading to rapid weight loss of 5 kg. Clinical examination, laboratory tests, EEG and RMI were normal. Toxicological tests were negative. Her IQ, assessed six months before admission, was in the dull average range (70-75). Elsa was treated with loxapine 150 mg per day for one week without improvement and this was then replaced by haloperidol 30 mg per day. One week after the start of haloperidol her agitation, impulsivity, and hallucinatory symptoms decreased. Twenty four days after loxapine introduction and 17 days after the haloperidol, her condition deteriorated rapidly over less than 48 hours. She exhibited immobility, minimal response to stimuli, staring and catalepsy with waxy flexibility. The diagnosis of catatonia was established. Examination revealed tremulous extremities, tachychardia (110 pm) and apyrexia. Creatine phosphokinase levels were 106 UI/l (normal range 0-250). Human immunodeficiency virus, hepatitis, listeria and Lyme serology were negative. Cerebrospinal fluid analysis was normal. Haloperidol was stopped and intravenous clonazepam 5mg/kg was begun. It was not possible to obtain signed consent from the two parents for Electroconvulsive therapy. The patient was transferred to a pediatric intensive care unit. The treatment was standard parenteral nutrition, nursing, intravenous clonazepam 0.05 mg/kg, with regular attendance by a child psychiatrist. Elsa stayed three weeks in this condition. She then began to notice the child psychiatrist, and a few days later she was able to carry out simple requests. Elsa was transferred to an adolescent psychiatric unit. As soon as she could eat by herself again, carbamazepine 400mg per day was begun. Her agitation reduced at a carbamazepine level of 7 mg/l. One month later her condition was stable. However, language difficulties persisted for a further six months. One year after the episode she scored 66 on a repeat IQ test and her RMI was normal. She exhibited no significant residual symptoms except some cognitive impairment. She integrated into a special education facility. These attempts to stop the carbamazepine were followed by depressed mood, aggressiveness and impulsivity; carbamazepine was finally stopped successfully after seven years. Ten years later, Elsa is the mother of two young children and is able to take care of them. She has never had a relapse of her psychotic disorder or catatonic state. DISCUSSION: The etiopathogenic diagnosis is problematic. Some indices in the familial history may suggest a traumatic event. But one to the total residual amnesia it was never confirmed, and traumatic catatonia are extremely rare. Normal CPK levels, with autonomic disturbance limited to tachycardia and the lack of resolution after discontinuance of medication, argues against a diagnosis of neuroleptic malignant syndrome (NMS). But CPK levels are non specific, and NMS without pyrexia has been described. The occurrence of the catatonic syndrome 21 days after the first dose of a neuroleptic could be diagnostic. This case involved a non organic catatonic psychosis followed by neuroleptic induced catatonia. Catatonia is described as a risk factor for the development of NMS and some consider NMS to be a variant of malignant catatonia. The interest of this report is (1) it reinforces the need to be cautious before prescribing neuroleptics in adolescents presenting with symptoms of catatonia; (2) the complete recovery from catatonia after treatment with intensive care and more than three weeks of intravenous clonazepam without the use of ECT and (3) the effectiveness of carbamazepine over a long period of follow-up. Although trials on carbamazepine in catatonia are published, there are no data available for the control of residual symptoms or the long term prognosis, especially in child and adolescent psychiatry.

'I'm cured but....': perceptions of illness following treatment.

The current qualitative research studied representations of illness posttreatment from a heart transplant group, a panic disorder group, and a tic disorder group. All three groups were preoccupied with perceptions about the impact of the illness, perception of self and the perception of how others view the ill person. The heart transplant group seem to adopt an active style of coping compared to the panic disorder group who presented a more passive, anticipatory mode of coping, and the tic group who were preoccupied with control over the perceptions of others. This qualitative information could help optimize adaptation strategies.

Colonic drug delivery: influence of cross-linking agent on pectin beads properties and role of the shell capsule type.

For colonic delivery, pectin beads obtained by ionotropic gelation method have been already reported as an interesting approach. This study investigated the influence of the cross-linking agent (calcium or zinc) and the type of shell capsule used (classical or enteric capsules) on pectin beads properties and on their performance to target the colon (in vitro dissolution studies with subsequent pH change to mimic overall gastro-intestinal tract). Zinc pectinate beads seemed to be relatively similar to calcium's ones in morphological point, except on the surface aspect. When beads were introduced in classical hard capsules, ketoprofen release was not significantly different between CPG and ZPG beads, and it was too premature and too quick due to a chemical erosion of the pectinate matrix (acid + basic attacks). However, zinc pectinate beads showed slower ketoprofen release compared with calcium pectinate beads when enteric hard capsules were used. This interesting finding could be due to the strength of the network formed during the process between the zinc cations and the LM-pectin following the "egg-box" model. This network was stronger and induced a reduction of swelling and hydration when contact with dissolution medium, then subsequently a decrease of drug release. Thus, the zinc pectinate beads could protect sufficiently drug entrapped from the upper gastro-intestinal conditions and drug release will be controlled by pectin degradation with colonic microflora. Finally, these zinc pectinate beads in enteric hard capsules are promising as a carrier for specific colonic delivery of drugs after oral administration.

Colon-specific drug delivery: Influence of solution reticulation properties upon pectin beads performance.

In this study, pectinate gel beads were produced by ionotropic gelation method with different solutions of cross-linking agents and ketoprofen was entrapped as model drug. The influence of these formulation parameters was investigated upon bead properties and upon their performance to target the colon. Zinc pectinate beads obtained with 10% of counter-ions solution at pH 1.6 exhibited the strongest gel network due to "egg-box" dimmer formation helped by hydrogen bonding. Furthermore the gel network formed at low pH was arranged in a compact three-fold conformation. Thus, this matrix structure in enteric capsules induced the lowest drug release in the upper gastro-intestinal tract (pH 1.2 following by pH 7.4). However ketoprofen release occurred specifically in the colon thanks to the presence of pectinolytic enzymes and the release rate can be modulated by the counter-ion concentration during the reticulation process. Therefore this approach using pectinate beads is very promising as efficient carrier for specific delivery of drug into the colon, after oral administration.

Measurement properties of a new quality of life measure for patients with work disability associated with musculoskeletal pain.

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.

Patients' perceptions of cardiac anesthesia services: a pilot study.

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.

High efficiency transient transfection of genes in human umbilical vein endothelial cells by electroporation.

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.

Impact of waiting time on the quality of life of patients awaiting coronary artery bypass grafting.

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.

Cyclodextrin modulation of T lymphocyte signal transduction with aging.

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.

Monocytes influence the fate of T cells challenged with oxidised low density lipoproteins towards apoptosis or MHC-restricted proliferation.

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.

Patient satisfaction with anesthesia services.

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.

The impact of cholesterol lowering on patients' mood.

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.

Control of CYP11B2 gene expression through differential regulation of its promoter by atypical and conventional protein kinase C isoforms.

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.

Chronic PMA treatment of Jurkat T lymphocytes results in decreased protein tyrosine phosphorylation and inhibition of CD3- but not Ti-dependent antibody-triggered Ca2+ signaling.

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.