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N Blank

Publications and source records attributed to N Blank.

At least 19 recordsLinked to original sources
PubMed2006

The role of DMARDs in systemic sclerosis therapy.

The aim of this review is to evaluate the evidence for disease-modifying anti-rheumatic drugs (DMARDs) for treatment of systemic sclerosis (SSc). In the previously published trials, DMARD therapy was usually initiated for severe skin thickening, organ involvement and alveolitis. These studies suggest beneficial effects of methotrexate, azathioprine, ciclosporine A and cyclophosphamide therapy in SSc patients. However, many of these data were derived from retrospective analyses with low numbers of patients, short-term follow-up and often without an appropriate control group. Finally, some of these studies led to inconsistent results. At the present time there is no DMARD therapy of proven efficacy in SSc. Immunosuppressive therapy should only be considered in patients with early diffuse disease, overlap syndromes or pulmonary fibrosis. Current expert recommendations suggest a therapy with methotrexate for skin thickening or cyclophosphamide for acute alveolitis. However, more clinical trials with larger numbers of patients with recent onset SSc are needed.

Antirheumatic Agents↗
PubMed2006

An epidemiological study of headache in Florianopolis, Brazil.

The aim of this study was to estimate the 1-year prevalence of headache, migraine, tension-type headache (TTH) and chronic daily headache (CDH), and the degree of association of migraine with some sociodemographic characteristics of the population of Florianopolis, Brazil. This is a cross-sectional, door-to-door, population-based study. In 300 randomly selected households, 625 subjects, aged 15-64 years, responded to a structured questionnaire. The 1-year prevalence of headache was 80.8%, of migraine 22.1%, of TTH 22.9%, and of CDH 6.4%. Migraine and CDH were significantly more prevalent in females than in males. Migraine was significantly associated with the following variables: low household income, low electricity consumption, and divorced or widowed marital status. We have shown high prevalences of migraine and CDH in Florianopolis, close to the higher rates of previous studies. There was a preponderance of migraine in females, divorced or widowed, with a low socioeconomic level.

Adolescent↗
PubMed2005

Induction of apoptosis by spermine-metabolites in primary human blood cells and various tumor cell lines.

Polyamines are involved in the regulation of cellular growth and survival by interacting with processes like translation, transcription or ion transport. The aim of our study was to analyze whether polyamines induce apoptosis in hematopoetic cells and to investigate the molecular mechanisms involved. We found an induction of apoptosis by spermine in primary human cells and malignant tumor cell lines. Spermine-treatment resulted in an intracellular increase of reactive oxygen species. Apoptosis was mediated by a collapse of mitochondrial membrane potential, a decrease in Bcl-2 expression and a release of apoptosis mediating molecules from mitochondrial intermembrane space (cytochrome C, Smac/DIABLO). Spermine-mediated apoptosis was caspase-dependent. To test whether spermine mediates apoptosis through metabolites we analyzed the effects of several molecules that interfere with its catabolism. Aminoguanidine, an inhibitor of serum amine oxidase, aldehyde-dehydrogenase, which degrades aldehydes to less reactive molecules or N-acetyl-cysteine, a glutathion precursor, significantly inhibited spermine-mediated apoptosis. From these data we conclude that spermine-derived aldehydes and intracellular accumulation of reactive oxygen species result in mitochondria mediated apoptosis.

Acetylcysteine↗
PubMed2004

Extranuclear detection of histones and nucleosomes in activated human lymphoblasts as an early event in apoptosis.

OBJECTIVE: To evaluate the presence of histones and nucleosomes in cell lysates of freshly isolated peripheral blood mononuclear cells (PBMC), fully activated lymphoblasts, or lymphoblasts after induction of apoptosis. METHODS: Each histone class (H1, H2A, H2B, H3, and H4) was detected by western blot analysis with specific antibodies. Annexin V/propidium iodide (PI) staining was performed for each treatment to distinguish viable, early, and late apoptotic, and necrotic cells. DNA degradation was evaluated by PI staining in a hypotonic buffer. RESULTS: All five histones were detected in cell lysates of activated lymphoblasts in higher concentrations than in lysates of PBMC. An additional significant increase of H2A, H2B, H3, H4, and complete nucleosomes in cell lysates of lymphoblasts was found during interleukin (IL)2 deprivation for 8 or 24 hours. The content of these histones or nucleosomes in cell lysates decreased after delayed IL2 readdition. H1 content in cell lysates was not affected by IL2 deprivation or addition. Quantities of H2A, H2B, H3, and H4 in cell lysates correlated significantly with signs of early apoptosis. UV-B light exposure or etoposide treatment of lymphoblasts resulted in a distinct increase for each histone class in cell lysates compared with standard curves. No bands for post-translationally modified histones were detected in cell lysates in contrast with signals in nuclear preparations. CONCLUSION: Extranuclear accumulation of histones and nucleosomes is an early event of apoptosis in human lymphoblasts. Dysregulation of early apoptosis might support the induction of autoimmunity against nuclear components.

Apoptosis↗
PubMed2001

Herpesvirus saimiri replaces ZAP-70 for CD3- and CD2-mediated T cell activation.

The protein tyrosine kinase ZAP-70 plays a pivotal role involved in signal transduction through the T cell receptor and CD2. Defects in ZAP-70 result in severe combined immunodeficiency. We report that Herpesvirus saimiri, which does not code for a ZAP-70 homologue, can replace this tyrosine kinase. H. saimiri is an oncogenic virus that transforms human T cells to stable growth based on mutual CD2-mediated activation. Although CD2-mediated proliferation of ZAP-70-deficient uninfected T cells was absent, we could establish H. saimiri-transformed T cell lines from two unrelated patients presenting with ZAP-70 deficiencies. In these cell lines, CD2 and CD3 activation were restored in terms of [Ca(2+)](i), MAPK activation, cytokine production, and proliferation. Activation-induced tyrosine phosphorylation of zeta remained defective. The transformed cells expressed very high levels of the ZAP-70-related kinase Syk. This increased expression was not observed in the primary T cells from the patients and was not due to the transformation by the virus because transformed cell lines established from control T cells did not present this particularity. In conclusion, wild type H. saimiri can restore CD2- and CD3-mediated activation in signaling-deficient human T cells. It extends our understanding of interactions between the oncogenic H. saimiri and the infected host cells.

Autocrine Communication↗
PubMed2001

CD45 tyrosine phosphatase controls common gamma-chain cytokine-mediated STAT and extracellular signal-related kinase phosphorylation in activated human lymphoblasts: inhibition of proliferation without induction of apoptosis.

The objective of this study was to test whether CD45 signals can influence signaling processes in activated human lymphoblasts. To this end, we generated lymphoblasts which proliferate in response to common gamma-chain cytokines, but readily undergo apoptosis after cytokine withdrawal. In experiments with the CD45R0 mAb UCHL-1, but not control CD45 mAbs, we found significant inhibition of proliferation. Interestingly, the pan-CD45 mAb GAP8.3, which is most effective in inhibition of OKT-3-mediated proliferation in quiescent lymphocytes, was ineffective in lymphoblasts. Addition of CD3 mAb OKT-3 had no influence on IL-2-mediated proliferation (with or without UCHL-1). In contrast, after addition of OKT-3 to IL-4- and IL-7-stimulated proliferation assays, UCHL-1 signals could not significantly alter cellular proliferation. We did not find induction of apoptosis following CD45R0 signaling. In Western blots using mAbs detecting phosphorylated STAT-3, STAT-5, STAT-6, or extracellular signal-related kinase 1/2, we found that CD45R0 signaling could effectively diminish phosphorylation of these intracellular signaling components. Using RT-PCR, we found that CD45R0 signaling inhibited IL-2 mRNA production without major influence on IL-13, IL-5, or IFN-gamma mRNA levels. Costimulation with OKT-3 and IL-2 optimally induced secretion of IFN-gamma, TNF-alpha, and IL-5, which was not decreased by CD45 signals. In conclusion, we illustrate that CD45R0 signals control early cytokine receptor-associated signaling processes and mRNA and DNA synthesis in activated human lymphoblasts. Furthermore, we show the existence of CD45 epitopes (GAP8.3), which are active and critical for signaling in quiescent lymphocytes, but are nonfunctional in activated human lymphoblasts.

Apoptosis↗
PubMed2000

Differential requirement of ZAP-70 for CD2-mediated activation pathways of mature human T cells.

This study addresses the role of the tyrosine kinase ZAP-70 in CD2-mediated T cell activation. Patients lacking ZAP-70 have few mature CD8+ T cells and high numbers of CD4+ T cells that are nonfunctional upon TCR triggering. Such a patient with a homozygous deletion in the zap-70 gene that resulted in the complete absence of ZAP-70 protein expression has been identified. Expression of the tyrosine kinases Lck, Fyn, and Syk was normal. The patient's T cells were activated with two different pairs of mitogenic mAbs. CD2-induced phosphorylation of the zeta-chain and influx of Ca2+ was defective in the ZAP-70-deficient T cells, whereas CD2-induced phosphorylation of several other proteins, including Syk, was not affected. CD2-induced proliferation as well as production of TNF-alpha and IFN-gamma was abrogated in ZAP-70-deficient T cells, whereas PMA plus ionomycin induced normal activation of these cells. Together, this study shows that CD2-activation triggers ZAP-70-dependent and -independent pathways. Deletion of ZAP-70 affected CD2- and CD3-mediated proliferation and cytokine production in a similar way, suggesting that one of the different CD2 pathways converges with a CD3 pathway at or upstream of the activation of ZAP-70.

CD2 Antigens↗
PubMed2000

Chlorpromazine induces apoptosis in activated human lymphoblasts: a mechanism supporting the induction of drug-induced lupus erythematosus?

OBJECTIVE: Drug-induced lupus erythematosus is a serious side effect of certain medications, such as procainamide, quinidine, hydralazine, chlorpromazine, and isoniazid, the underlying pathogenesis of which is unresolved. In this study, we examined the influence of these drugs on the regulation of apoptosis, or programmed cell death, in quiescent and activated human lymphocytes. We also discuss the dysregulation of apoptosis as a pathogenetic factor in systemic lupus erythematosus. METHODS: Peripheral blood mononuclear cells or activated lymphoblasts from normal donors were incubated with different concentrations of each of the above-mentioned drugs. RESULTS: We did not find induction of apoptosis in quiescent cells over a broad concentration range. In contrast, lymphoblasts readily underwent apoptosis when cultured with chlorpromazine, but not any of the other drugs, after stimulation with interleukin-2 (IL-2) in a dose-, time- and cell cycle-dependent manner. By several lines of evidence, toxicity was ruled out. Characteristic features of apoptosis-like incorporation of propidium iodide (PI), such as increased annexin V binding, changes in mitochondrial membrane potential, and induction of DNA breaks (as evidenced by TUNEL techniques), could be induced in lymphoblasts after chlorpromazine treatment. Chlorpromazine did not cause apoptosis by inhibition of cytokine binding or blockade of early intracellular signaling. The protease inhibitor Z-VAD and the ceramide inhibitor sphingosine 1-phosphate effectively blocked chlorpromazine-induced apoptosis (by PI staining and by externalization of phosphatidylserine), in contrast to the caspase 3/CPP32 inhibitor DEVD, which had only minor effects. Western blot analysis revealed IL-2-mediated phosphorylation of extracellular signal-regulated kinase, which was sensitive to chlorpromazine. Using lymphoblasts from a patient with Canale-Smith syndrome, we found that chlorpromazine-mediated apoptosis is Fas/ APO-1 independent. CONCLUSION: These data suggest that chlorpromazine mediates apoptosis in human lymphoblasts through specific activation of intracellular proapoptotic signaling cascades. This mechanism might lead to an unsynchronized inflow of apoptotic break-down products and thereby to the induction of (auto)immunity against nuclear components.

Apoptosis↗
PubMed2000

CD 95-independent mechanisms of IL-2 deprivation-induced apoptosis in activated human lymphocytes.

Growth factor deprivation-induced apoptosis plays an important role in several cellular systems. However, knowledge of the molecular mechanisms involved are restricted to a few murine models or tumor cell lines. Therefore, we aimed studying signaling pathways leading to apoptosis in activated human peripheral T cells after IL-2 withdrawal. Lymphoblasts from patients with CD 95 (Fas/APO-1)-deficiency revealed that functional CD95 was not required to induce apoptosis after IL-2 withdrawal. Moreover, apoptosis induction in response to various cytotoxic stimuli was found to be mediated in the absence of functional CD95 but was affirmatorily influenced by IL-2 signaling. Immunoblots showed no downregulation of Bcl-2 or Bcl-xL and no upregulation of Bax, whereas decreased mitochondrial membrane potential was readily measurable 24 h after cytokine deprivation. Tetrapeptide inhibitors showed limited efficacy in preventing apoptosis whereas the caspase inhibitor zVAD-FMK potently blocked induction of apoptosis. Cleavage of different fluorogenic substrates revealed multiple caspase enzyme activities in lymphoblasts, which were not negatively affected by the fas mutation. Starting at 8 h after IL-2 withdrawal, upregulation of active caspase-3 but not of caspase-8 could be detected. Taken together, our data argue for molecular mechanisms of cytokine deprivation-induced apoptosis in activated human lymphocytes independent of CD95.

Apoptosis↗
PubMed1996

Inequalities in health: the interaction between socio-economic and personal circumstances.

This longitudinal study utilizes a data set from the Survey of Living Conditions conducted by Statistics Sweden (SCB) during the years 1980-1981 and 1988-1989. It comprises a representative sample of the employed Swedish population (2,861 individuals) between the ages of 20 and 65. The objective of the study is to analyse the interaction between socio-economic and personal circumstances in explaining inequalities in health. It is based on a theoretical framework which presupposes that inequalities in health are likely to be explained by a complicated process involving a multitude of factors. At the same time, differential exposures and differential responses to risk factors between socio-economic classes for certain health outcomes are determined. The joint effect on general health status, seven years later, of being a manual worker and having reported psychosomatic symptoms is 113% greater than would have been expected on the assumption of additivity of the singular effects of these variables. It is suggested that it is necessary to highlight in further research the complex interactions and pathways between factors associated with health outcomes to improve our understanding of the causal processes involved and determine appropriate preventive measures.

Adult↗
PubMed1996

The prediction of different experiences of longterm illness: a longitudinal approach in Sweden.

STUDY OBJECTIVE: To analyse the role played by socioeconomic factors and self rated general health in the prediction of the reporting of severe longterm illness, and the extent to which these factors explain social class differences in the reporting of such illness. DESIGN: Analysis of panel data from the survey of living conditions, conducted by Statistics Sweden over the years 1979-81 and 1986-89. SETTING: A random sample of the Swedish population, interviewed in 1979-81 and then re-interviewed in 1986-89. PARTICIPANTS: A representative sample of 3889 employed Swedish people, aged 16-65 years. MAIN RESULTS: Socioeconomic and individual factors predict severe longterm illness regardless of the kind of reported disorder from which the subject suffers. The main predictive factor involved is health self rated as fair/poor, but exposure to high physical job demands proved to be the main explanation of the role played by socioeconomic class. There was a significant interaction effect between self rated general health and physical job demands with regard to the experience of severe illness. CONCLUSIONS: The results of the study strengthen the hypothesis that manual workers are not only more exposed to causes of illness that have important individual and social consequences, but also to the personal factors that determine different experiences of illness. Interaction between these two kinds of factors (job demands and self rated health) suggests that socioeconomic and individual factors play different but complementary roles in the causal process leading to the experience of severe longterm illness.

Adult↗
PubMed1996

Social inequalities in the experience of illness in Sweden: a "double suffering".

This paper analyses the factors involved in differences in the experience of long-term illness (severe and non-severe illness), as measured in terms of self-reported frequency and intensity of symptoms. The study has a cross-sectional design. It uses a database from the Survey of Living Conditions of Statistics Sweden, and treats a representative sample of the employed Swedish population (n = 13,501), aged between 16 and 65, interviewed over the period 1986-89. The results show that male manual workers report more non-severe and severe illness than non-manual workers, and that manual and lower-level non-manual female workers report more severe illness, but not non-severe illness, than intermediate/higher-level non-manual working females. The observed class differences in experience of severity of illness are partly explained by the factors investigated (job demands, personal economic difficulties, smoking daily, weak social network) in the case of men, and virtually entirely in the case of women. Other ill-health dimensions, such as self-rated general health and impaired working capacity, prove to be related to severity of illness, the latter being more strongly associated with experience of severe illness than the former irrespective of social class. The results lend support to the hypothesis that manual classes are subjected to what might be called "double suffering"; they have more long-term illnesses and also experience these illnesses with greater intensity and frequency.

Adolescent↗
PubMed1995

Short-term and long-term sick-leave in Sweden: relationships with social circumstances, working conditions and gender.

The primary aim of the study was to analyse similarities and differences between repeated spells of short-term sick-leave (more than 3 spells of less than 7 days' duration in a 12-month period) and long-term absence through sickness (at least 1 spell of more than 59 days' duration in a 12-month period) in relation to variables representing certain social circumstances and aspects of the work situation. Particular attention was paid to gender differences. The study, which had a cross-sectional design, employed data from the surveys of living conditions (ULF) conducted by Statistics Sweden over the period 1986-89. The study group comprised 13,828 employed persons between the ages of 16 and 65. The results suggested the existence of a common mechanism by which a variety of factors are related to the taking of both repeated short spells and long-term sick-leave; gender differences with regard to the effect of working conditions on the taking of sick-leave may be incorrectly estimated if factors related to occupational structure are not taken into consideration; a less than additive effect of physical job demands and repeated short spells of sick-leave on subjective health was found.

Absenteeism↗
PubMed1994

Specificity of high-resolution CT findings in pulmonary asbestosis: do patients scanned for other indications have similar findings?

OBJECTIVE: High-resolution CT findings in patients with asbestosis include subpleural curvilinear densities, subpleural density in dependent portions of the lung, parenchymal bands, thickened septal lines, and honeycomb lung. Our objective was to examine the prevalence of these CT findings in a random group of patients scanned for a variety of clinical reasons not specifically related to occupational exposure. MATERIALS AND METHODS: One hundred sixty-eight CT studies of the thorax were performed at six levels in 168 patients examined for a variety of clinical indications. The scans were evaluated by two radiologists for the presence of subpleural curvilinear densities, subpleural density in dependent locations, parenchymal bands, thickened septal lines, and honeycomb lung. RESULTS: CT scans of 11 patients showed pleural plaques suggesting previous exposure to asbestos. Among the 157 studies showing no evidence of pleural plaques, CT scans showed subpleural curvilinear densities in dependent areas in 32 (20%); subpleural curvilinear densities in nondependent areas in 19 (12%); parenchymal bands in 47 (30%); thickened septal lines in dependent areas in 93 (59%), and septal lines in nondependent areas in 67 (43%); subpleural density in dependent areas in 66 (42%); and honeycomb lung in five (3%). CONCLUSION: Subpleural curvilinear densities, subpleural density in dependent locations, parenchymal bands, and thickened septal lines occur as isolated and as combined CT findings in patients with a variety of underlying diseases or conditions unrelated to asbestosis and by themselves are nonspecific findings. Their occurrence, even in patients with CT evidence of pleural plaques, does not necessarily indicate the presence of asbestosis.

Asbestosis↗
PubMed1990

Acute lung rejection after heart-lung transplantation: correlation of findings on chest radiographs with lung biopsy results.

This retrospective study was performed to determine if the chest radiograph could serve as a predictor for acute lung rejection in heart-lung transplantation patients. The findings on chest radiographs were correlated with the results of transbronchial biopsies in 16 heart-lung transplantation patients. The chest radiographs immediately preceding 83 biopsies were evaluated for a variety of findings. The histopathologic results of the lung biopsies were divided into five categories: (1) acute lung rejection (n = 25); (2) suggestive, but not diagnostic, of acute lung rejection (n = 8); (3) nonspecific (n = 26); (4) infection (n = 17); and (5) normal lung (n = 9). Biopsies from two patients showed both acute lung rejection and cytomegalovirus infection and were included in both categories. These histopathologic results were then correlated with the radiologic observations. We found that the combination of septal lines and new or increasing pleural effusions, without concomitant increase in cardiac size or vascular pedicle width, or evidence of vascular redistribution, indicated acute lung rejection with a sensitivity of 68% (17/25), specificity of 90% (52/58), and overall accuracy of 83% (69/83). We conclude that the chest radiograph is a useful indicator of acute lung rejection.

Adult↗
PubMed1987

The mediastinum in Hodgkin's and non-Hodgkin's lymphomas.

The mediastinum is commonly involved with disease in patients with Hodgkin's and non-Hodgkin's lymphomas. The involvement may be permeative, or individual groups of nodes may be enlarged. The parietal nodes of the mediastinum may also be abnormal with either type. Precise mapping of all disease is important when radiation therapy is to be a major component of treatment planning. Detection of relapse following mantle irradiation is frequently dependent on having a new comparative baseline after the distortions of mediastinal contours consequent to radiation treatment have stabilized.

Adult↗
PubMed1986

Hodgkin disease: contributions of chest CT in the initial staging evaluation.

Chest radiographs and chest computed tomography (CT) scans were compared in 203 patients with newly diagnosed Hodgkin disease. The incidence of positive findings was tabulated from six intrathoracic lymph node groups, lung parenchyma, pericardium, pleura, and chest wall. The discordant cases were assessed to determine impact on clinical management. The CT scans provided additional evidence of disease involvement, ranging from 0% to 15% at each of the designated anatomic sites. Treatment was altered in 9.4% of all patients (19 of 203), including 13.8% (nine of 65) of those undergoing radiation therapy alone and 8.2% (ten of 122) of those undergoing combined-modality treatment. We conclude that routine chest CT examinations are valuable in the clinical management of those patients for whom radiation therapy is planned.

Adolescent↗