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P Cohen

Publications and source records attributed to P Cohen.

At least 73 records · Page 4Linked to original sources
PubMed2001

Long-term followup of polyarteritis nodosa, microscopic polyangiitis, and Churg-Strauss syndrome: analysis of four prospective trials including 278 patients.

OBJECTIVE: To determine the long-term outcome of patients with polyarteritis nodosa (PAN), microscopic polyangiitis (MPA), and Churg-Strauss syndrome (CSS), to compare the long-term outcome with the overall French population, to evaluate the impact on outcome of the type of vasculitis, prognostic factors, and treatments administered at diagnosis, and to analyze treatment side effects and sequelae. METHODS: Data from PAN, MPA, and CSS patients (n = 278) who were enrolled between 1980 and 1993 were collected in 1996 and 1997 and analyzed. Two prognostic scoring systems, the Five-Factors Score (FFS) and the Birmingham Vasculitis Activity Score (BVAS), were used to evaluate all patients at the time of diagnosis. RESULTS: The mean (+/- SD) followup of the entire population was 88.3 +/- 51.9 months (range 3 days to 192 months). Of the 85 deaths recorded, at least 41 were due to progressive vasculitis or its consequences. Death rates reflected disease severity, as assessed by the FFS (P = 0.004) and the BVAS (P < 0.0002), and the 2 scores were correlated (r = 0.69). Relapses, rarer in hepatitis B virus (HBV)-related PAN (7.9%) than in MPA (34.5%) (P = 0.004), occurred in 56 patients (20.1%) and did not reflect disease severity. Survival curves were similar for the subpopulation of 215 patients with CSS, MPA, and non-HBV-related PAN who were given first-line corticosteroids (CS) with or without cyclophosphamide (CYC). However, CS with CYC therapy significantly prolonged survival for patients with FFS scores > or =2 (P = 0.041). Relapse rates were similar regardless of the treatment regimen; only patients treated with CS alone had uncontrolled disease. CYC was associated with a greater frequency of side effects (P < 0.00001). CONCLUSION: Rates of mortality due to PAN (related or unrelated to HBV), MPA, and CSS reflected disease severity and were higher than the mortality rate in the general population (P < 0.0004). Rates of relapse, more common in MPA than HBV-related PAN patients, did not reflect disease severity. Survival rates were better among the more severely ill patients who had received first-line CYC. Based on these findings, we recommend that the intensity of the initial treatment be consistent with the severity of the disease. The use of the FFS and BVAS scores improved the ability to evaluate the therapeutic response.

Adult↗
PubMed2001

Influence of HLA-DR phenotype on the risk of hepatitis C virus-associated mixed cryoglobulinemia.

OBJECTIVE: Circumstances predisposing hepatitis C virus (HCV)-infected patients to develop mixed cryoglobulinemia (MC), which may manifest as a small-vessel systemic vasculitis (MC vasculitis), remain unclear. Previous studies have failed to demonstrate a clear role of either viral factors (genotype, viral load) or host factors (lymphocytes or immunoglobulin subsets). This study was undertaken to examine a possible role of HLA class II alleles in HCV-associated MC. METHODS: One hundred fifty-eight HCV-infected patients, of whom 76 had MC (56 with type II MC and 20 with type III MC) and 82 did not have MC, were studied prospectively. MC vasculitis was noted in 35 HCV-infected patients with type II IgMkappa-containing cryoglobulins. HLA-DRB1 and HLA-DQB1 polymorphism was analyzed by hybridization using allele-specific oligonucleotides, after gene amplification. The odds ratio (OR) was calculated with Woolf's method. Then, using multivariate analysis, demographic, biologic, immunologic, virologic, and liver histologic factors associated with the presence of MC and MC vasculitis were investigated. RESULTS: HLA-DR11 was significantly more frequent in patients with type II MC than in those without MC (41.1% versus 17.1%; OR 3.4, corrected P [Pcorr] = 0.017), regardless of the presence of vasculitis accompanying the MC (37.1% of those with MC vasculitis, 34.1% of those with MC but no vasculitis). HLA-DR7 was less frequent in HCV-infected patients with MC than in those without MC (13.2% versus 30.5%; OR 0.34, P = 0.012, Pcorr not significant), with a particularly lower frequency in those with type II MC and those with MC vasculitis (12.5% and 8.6%, respectively). There was no significant difference in HLA-DQB1 distribution between the different patient groups. By univariate and multivariate analysis, HLA-DR11 was the only positive predictive factor, besides female sex and advanced age, for the presence of MC and HCV-associated MC vasculitis (OR 2.58). CONCLUSION: Our results indicate that the presence of the DR11 phenotype is associated with a significantly increased risk for the development of type II MC in patients with chronic HCV infection. In contrast, HLA-DR7 appears to protect against the production of type II MC. These results suggest that the host's immune response genes may play a role in the pathogenesis of HCV-associated MC.

Adult↗
PubMed2001

Dual effect of chronic nicotine administration: augmentation of jejunitis and amelioration of colitis induced by iodoacetamide in rats.

Smoking has a dichotomous effect on inflammatory bowel disease, ameliorating disease activity in ulcerative colitis but having a deleterious effect on Crohn's disease. This effect is thought to be due to nicotine. We investigated the effect of chronic nicotine administration on the small and large bowel in iodoacetamide-induced jejunitis and colitis. Jejunitis was induced in Sprague-Dawley rats by intrajejunal administration of 0.1 ml 2% iodoacetamide and colitis by intrarectal administration of 0.1 ml 3% iodoacetamide. Nicotine was dissolved in drinking water (12.5 or 250 micrograms/ml), rats drinking ad libitum. Nicotine administration started 10 days prior to damage induction and throughout the experiment and had no effect on weight gain or daily food intake of rats. Rats were killed 5 days after iodoacetamide-induced colitis and 7 days after induction of jejunitis. The jejunum and colon were resected, rinsed, weighed, damage assessed macroscopically and microscopically and tissue processed for myeloperoxidase and nitric oxide synthase (NOS) activities and prostaglandin E2 (PGE2) generation. Effects of nicotine on gut microcirculation were also assessed. Nicotine by itself caused no damage to the colon. Nicotine had a dichotomous effect on jejunitis and colitis. At a dose of 12.5 micrograms/ml nicotine improved the macroscopic damage of colitis from 252 +/- 66 to 70 +/- 31 mm2, and segmental weight also declined significantly in the colon (from 1.7 +/- 0.2 to 1.2 +/- 0.1 g/10 cm). In contrast, the same dose of nicotine had a deleterious effect on iodoacetamide-induced jejunitis, increasing the macroscopic damage from 368 +/- 38 to 460 +/- 97 mm2 in rats treated with injury escalating to 970 +/- 147 in rats treated with 250 micrograms/ml nicotine. Nicotine treatment also significantly increased jejunal segmental weight. By itself nicotine did not change NOS activity or PGE2 generation compared to control rats, but it enhanced microcirculation in the colon, whereas in the jejunum nicotine decreased PGE2 generation and increased NOS activity but not jejunal microcirculation. Nicotine has opposite effects on iodoacetamide-induced colitis and jejunitis, which may be partly explained by decreased PGE2 generation and increased NOS activity in the jejunum and an increase in the colonic microcirculation.

Animals↗
PubMed2001

CD40 is not detected on human prostate cancer cells by immunohistologic techniques.

OBJECTIVES: The CD40 antigen is expressed by antigen-presenting cells, many kinds of epithelium, and carcinomas. As signaling through CD40 modulates the differentiation state of CD40-expressing cells, we wanted to investigate whether benign or malignant prostate epithelium expressed CD40. METHODS: Twenty-two paraffin-embedded and 10 snap-frozen human prostate tissue samples were analyzed by immunohistologic methods, using the basal cell-specific markers, high molecular weight cytokeratin (HMWCK) and keratin-14 (K14), and the luminal cell marker, low molecular weight cytokeratin (LMWCK), together with CD40. Fresh prostate tissue was cultured in vitro and analyzed by immunocytofluorescence. RESULTS: The pattern of CD40 expression was continuous on basal epithelial cells of normal and hyperplastic prostate glands but discontinuous in glands that featured prostatic intraepithelial neoplasia. Coexpression of CD40 with the basal cell-specific cytokeratins, HMWCK and K14, was confirmed by double labeling. In contrast, glandular epithelial cells in prostate adenocarcinoma did not express CD40 or these cytokeratins. A luminal cell phenotype defined as CAM5.2-positive and HMWCK-negative K14-negative was identified among primary epithelial cells cultured in vitro. Most of the cultured cells (more than 99%) were also CD40-negative. CONCLUSIONS: Together, our results support the hypothesis that CD40 expression correlates with the basal cell phenotype, which is lost upon malignant transformation of the prostate. Hence, CD40 may be useful diagnostically to distinguish benign from malignant prostate lesions in biopsy material.

Adenocarcinoma↗
PubMed2001

A common phosphate binding site explains the unique substrate specificity of GSK3 and its inactivation by phosphorylation.

The inhibition of GSK3 is required for the stimulation of glycogen and protein synthesis by insulin and the specification of cell fate during development. Here, we demonstrate that the insulin-induced inhibition of GSK3 and its unique substrate specificity are explained by the existence of a phosphate binding site in which Arg-96 is critical. Thus, mutation of Arg-96 abolishes the phosphorylation of "primed" glycogen synthase as well as inhibition by PKB-mediated phosphorylation of Ser-9. Hence, the phosphorylated N terminus acts as a pseudosubstrate, occupying the same phosphate binding site used by primed substrates. Significantly, this mutation does not affect phosphorylation of "nonprimed" substrates in the Wnt-signaling pathway (Axin and beta-catenin), suggesting new approaches to design more selective GSK3 inhibitors for the treatment of diabetes.

Amino Acid Sequence↗
PubMed2001

Emotional reactivity and risk for psychopathology among adolescents.

Various aspects of personality or dispositional style predict risk for psychiatric disorders among adults. In particular, signs of neuroticism, emotional reactivity, or sensitivity to stress are strong predictors of later mood or anxiety disorders. The current report extends this literature to adolescents. An epidemiologic sample of 776 young people living in upstate New York received psychiatric assessments based on the Diagnostic and Statistical Manual of Mental Disorders, Third Edition-Revised, (DSM-III-R) and a self-report assessment of personality style in 1983 and 1985. Psychopathology was again assessed in 1992. The current study first examined demographic correlates of emotional reactivity. The study then considered the predictive relationship between emotionally reactive personality style at one study wave and psychopathology at later waves. In middle but not early adolescence, girls showed higher levels of emotional reactivity than boys. In turn, high levels of emotional reactivity predicted a range of psychiatric disorders at follow-up. The most consistent associations emerged for major depression and fearful spells, a term the authors use to describe a subclinical form of panic attacks. As in adults, midadolescent girls rate themselves as more emotionally reactive than midadolescent boys. Moreover, adolescents who rate themselves as emotionally reactive face a high risk for mood and anxiety disorders. High levels of emotional reactivity may represent a manifestation of underlying neurobiologic risk for mood and anxiety disorders.

Journal Article↗
PubMed2001

Relationship between specific adverse life events and psychiatric disorders.

This study examines whether certain psychiatric disorders are associated more closely with adverse life events than other disorders are, and whether some adverse life events are associated with a specific group of disorders (e.g., depressive disorders), but not with other disorders (e.g., anxiety disorders). A probability sample of youth aged 9-17 at 4 sites is used (N = 1,285). Univariate and multivariate logistic regressions identify specific relationships between 25 adverse life events and 9 common child and adolescent psychiatric disorders, measured by the Diagnostic Interview Schedule for Children. Conduct Disorder, Oppositional Defiant Disorder, Major Depressive Disorder, and Dysthymia are significantly associated with many of the adverse life events examined, whereas Attention Deficit/Hyperactivity Disorder, Agoraphobia, and Social Phobia are related to very few. This study suggests that certain psychiatric disorders may be more closely associated with adverse life events than other psychiatric disorders are, and that some adverse life events seem to be related to specific types of disorders.

Adolescent↗
PubMed2001

Ozone enema: a model of microscopic colitis in rats.

Ozone is one of the most powerful oxidants available, with many applications in industry and medicine. Medically relevant features of ozone include bacterial and virucidal properties, disinfection, sterilization, circulatory stimulation, and disruption of malignant cells. Ozone therapy is administered in various ways, including intravenously, intramuscularly, and intrarectally. The latter modality is used for the treatment of colitis and hepatitis. Our aim was to examine the effect of ozone water enema on normal and inflamed rat colonic mucosa. Ozone water (20 microg/ml) was prepared via ozone generator and administered intrarectally (0.5 ml) daily. Rats were killed one, three, and seven days after rectal ozone water administration, and their colons resected, rinsed, and weighed (grams per 10 cm). Damage was assessed macro- and microscopically and tissue processed for myeloperoxidase and nitric oxide synthase activity. Rats receiving saline served as controls. In an additional experiment colitis was induced by intrarectal iodoacetamide. Ozone therapy caused no macroscopic damage. Ozone therapy induced microscopic colitis, which lasted for at least a week and was accompanied by increase in segmental weight, myeloperoxidase and nitric oxide activity, and prostaglandin E2 generation. Ozone therapy had no protective effect on inflamed mucosa. In conclusion, ozone water therapy had a deleterious effect on normal colonic mucosa, suggesting intrarectal administration be reevaluated. Ozone water enema may serve as a model of microscopic colitis.

Administration, Rectal↗
PubMed2001

The renaissance of GSK3.

Glycogen synthase kinase 3 (GSK3) was initially described as a key enzyme involved in glycogen metabolism, but is now known to regulate a diverse array of cell functions. The study of the substrate specificity and regulation of GSK3 activity has been important in the quest for therapeutic intervention.

Animals↗
PubMed2001

The role of protein phosphorylation in human health and disease. The Sir Hans Krebs Medal Lecture.

The reversible phosphorylation of proteins regulates almost all aspects of cell life, while abnormal phosphorylation is a cause or consequence of many diseases. Mutations in particular protein kinases and phosphatases gives rise to a number of disorders and many naturally occurring toxins and pathogens exert their effects by altering the phosphorylation states of intracellular proteins. In this lecture, I present an overview of the progress that is being made in developing specific inhibitors of protein kinases for the treatment of cancer and chronic inflammatory diseases and describe how recent advances in our understanding of the specificity and regulation of one particular protein kinase (GSK3) may facilitate the development of drugs to treat diabetes that would not have the potential to be oncogenic. I also discuss the exploitation of specific protein kinase inhibitors for the study of cell signalling and make recommendations for their effective use in cell-based assays.

Calcium-Calmodulin-Dependent Protein Kinases↗
PubMed2001

Seeking consumer views: what use are results of hospital patient satisfaction surveys?

There has been increasing emphasis on the use of patient satisfaction surveys in publicly funded health services to assess elements of quality of care. However, how these surveys are used to change policy and services has received less attention. This paper reports on two different surveys conducted in Victoria, Australia and how these have developed and been used at a policy level. One is a survey of recent mothers, repeated three times over the course of the decade. The other is an inpatient survey developed over the past 5 years. The results of the surveys are publicly available and arc one means of obtaining consumer views, influencing health care quality and reporting to the public.

Data Collection↗
PubMed2001

Prospective, longitudinal study of tic, obsessive-compulsive, and attention-deficit/hyperactivity disorders in an epidemiological sample.

OBJECTIVE: Understanding the interrelatedness of tics, obsessive-compulsive disorder (OCD), and attention-deficit/hyperactivity disorder (ADHD) has been complicated by studying only cross-sectional samples of clinically referred subjects. The authors report the cross-sectional and longitudinal associations of these disorders in an epidemiological sample of children followed prospectively into early adulthood. METHOD: Structured diagnostic interview information was acquired on 976 children, aged 1 to 10 years, who were randomly selected from families living in upstate New York in 1975. Reassessments were acquired in 776 of these subjects 8, 10, and 15 years later. Diagnostic prevalences were estimated at each time point. The associations among tics, OCD, and ADHD were assessed within and across time points, as were their associations with comorbid illnesses and demographic risk factors. RESULTS: In temporal cross-section, tics and ADHD symptoms were associated with OCD symptoms in late adolescence and early adulthood after demographic features and comorbid psychiatric symptoms were controlled. In prospective analyses, tics in childhood and early adolescence predicted an increase in OCD symptoms in late adolescence and early adulthood. ADHD symptoms in adolescence predicted more OCD symptoms in early adulthood, and OCD in adolescence predicted more ADHD symptoms in adulthood. The associations of tics with ADHD were unimpressive in temporal cross-section and were not significant in prospective analyses. Tics, OCD, and ADHD shared numerous complex associations with demographic and psychopathological risk factors. ADHD was associated with lower IQ and lower social status, whereas OCD was associated with higher IQ. CONCLUSIONS: Tics and OCD were significantly associated in this sample, as were OCD and ADHD. These findings are in general consistent with those from family studies, and they help to define the natural history, comorbid illnesses, and interrelatedness of these conditions.

Age Distribution↗
PubMed2001

Longitudinal relationships between childhood, adolescent, and adult eating disorders.

OBJECTIVE: This study investigates the longitudinal course of eating problems from childhood though adulthood. The following questions are answered: (1) How stable are eating disorder symptoms and diagnoses over a 17-year interval from childhood to adulthood? (2) Do early childhood eating problems predict the occurrence of eating disorders in adulthood? METHOD: An epidemiologically selected sample of approximately 800 children and their mothers received DSM-based structured psychiatric assessments in 1975, 1983, 1985, and 1992. The stability of full DSM diagnostic criteria for anorexia nervosa and bulimia nervosa, symptom scales derived from DSM criteria, and individual symptoms such as binge eating or dieting between early adolescence, late adolescence, and young adulthood was examined. RESULTS: Early adolescent bulimia nervosa is associated with a 9-fold increase in risk for late adolescent bulimia nervosa and a 20-fold increase in risk for adult bulimia nervosa. Late adolescent bulimia nervosa is associated with a 35-fold increase in risk for adult bulimia nervosa. Symptom scale scores for anorexia nervosa and bulimia nervosa correlate in the 0.3 to 0.5 range from early to late adolescence and young adulthood. For both anorexia nervosa and bulimia nervosa, gender, as well as eating symptoms at early and late adolescence, all predict young-adult eating disorder symptoms. Risk factors for the later development of eating disorders comprise eating conflicts, struggles with food, and unpleasant meals in early childhood. CONCLUSION: The presence of eating problems in early childhood or an eating disorder in adolescence confers a strong risk for an eating disorder in young adulthood.

Adolescent↗
PubMed2001

Polyarteritis nodosa and mixed cryoglobulinaemia related to hepatitis B and C virus coinfection.

OBJECTIVE: To determine the responsibility of hepatitis B virus (HBV) and hepatitis C virus (HCV) and therapeutic implications in a patient who developed systemic vasculitis. CASE REPORT: The case of a 38 year old woman who had a past history of addiction to intravenous drugs and developed systemic vasculitis after infection by HBV and HCV is described. The clinical and laboratory findings substantiated not only the diagnosis of polyarteritis nodosa (PAN) but also that of mixed cryoglobulinaemia with a monoclonal IgMkappa component. CONCLUSION: Because cryoglobulins are rarely found in HBV related PAN but often associated with HCV infection, and in light of the histological findings, cryoglobulinaemia was interpreted as being secondary to HCV infection. This example of a highly complex situation emphasises the need to gather all relevant clinical, biological, histological, and complementary data so that the best treatment for overlapping of distinct vasculitides can be selected.

Adult↗
PubMed2001

Risk factors and prognostic influence of infection in a single cohort of 87 adults with systemic lupus erythematosus.

OBJECTIVES: To describe infectious complications and analyse their risk factors and prognostic role in adults with systemic lupus erythematosus (SLE). METHODS: A monocentric cohort of 87 adults with SLE (1960-1997) was studied to determine the risk factors for infection (disease activity evaluated by SLAM and SLEDAI scores, type of organ(s) involved or any biological abnormality, specific treatments) by comparing patients who had suffered at least one infectious episode (n=35; 40%) with non-infected patients (n=52; 60%). Prognostic indicators were assessed by comparing survivors at 10 years with non-survivors. RESULTS: Of the 57 infectious episodes, 47 (82%) were of bacterial origin, 16 (28%) were pneumonia, and 46 (81%) were community acquired. According to univariate analysis, significant risk factors for infection were: severe flares, lupus glomerulonephritis, oral or intravenous corticosteroids, pulse cyclophosphamide, and/or plasmapheresis. No predictors were identified at the time of SLE diagnosis. Multivariate analyses retained intravenous corticosteroids (p<0.001) and/or immunosuppressants (p<0.01) as independent risk factors for infection, which was the only factor for death after 10 years of evolution (p<0.001). CONCLUSION: In adults with SLE, infections are common and most often caused by community acquired bacteria. Intravenous corticosteroids and immunosuppressants are independent risk factors for infection, which is the only independent risk factor for death after 10 years of SLE evolution.

Adolescent↗
PubMed2001

Individualizing growth hormone dosing in children.

Much has been learned over the last three decades regarding the management of growth hormone (GH) treatment in children and adolescents. Current GH therapy enables most GH-treated children to attain a final height within the normal range and close to their target height. However, an optimal outcome is not always achieved and the approach to GH dosing differs among physicians and between countries. Furthermore, the individual response to GH varies dramatically between children, depending on age, the primary disease for which GH is prescribed and its severity, and other factors. Thus, the necessity to individualize treatment according to the specific needs of each child is being recognized. Consensus does not currently exist as to how to formulate individualized treatment plans. Nonetheless, a clear role for biochemical as well as auxological monitoring approaches has been established. Accurate determination of height velocity and interval height increase (expressed as the change in height z-score) continue to be the most important parameters in monitoring response to treatment. The importance of routinely monitoring serum insulin-like growth factor (IGF)-I and IGF binding protein-3 is an emerging paradigm. Roles have been firmly established for this approach in the assurance of compliance and safety (particularly to avoid long-term theoretical risks). IGF monitoring also has important potential utility as a tool to assess and optimize response to GH therapy through dose adjustment. In the years to come, we expect multiple optimization strategies including approaches such as prediction modeling as well as serum IGF monitoring and dose adjustment to evolve and improve. Currently, trials evaluating the utility of GH dose titration aiming to maintain the IGF-I level within a narrow range are being evaluated. The results of such large prospective randomized trials will surely help identify the value of individualizing GH dosing.

Child, Preschool↗