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Biomedical subjects

P Baron

Publications and source records attributed to P Baron.

At least 37 records · Page 2Linked to original sources
PubMed1999

Acute inflammatory intestinal vascular lesions and in situ abnormalities of the plasminogen activation system in Crohn's disease.

OBJECTIVES: The distribution of the intestinal vascular lesions and their relation with the fibrinolysis process are poorly known in Crohn's disease (CD). The mediators of the plasminogen activator system, namely urokinase-type plasminogen activator (u-PA), tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor type-1 (PAI-1), are a key complex involved in fibrinolysis. The aims of this study were: (1) to further define vascular lesions and their distribution in the intestine; and (2) to study concomitantly the qualitative in situ expression and the levels of u-PA, t-PA and PAI-1 in the ileum of patients with CD. PATIENTS AND METHODS: Histological, immunohistochemical and ultrastructural studies of vascular lesions in the resected ileum of 27 patients with CD were performed and compared with 36 control patients. Levels of u-PA, t-PA and PAI-1 measured by ELISA methods were compared in healthy and inflamed ileal tissues of 17 patients with CD. RESULTS: Acute vascular lesions involving mainly serosal venules and capillaries were present in 63% of patients with CD vs 3/36 controls and were associated with PAI-1 expression. They were prominent on the mesenteric border beneath macroscopically normal mucosa. In contrast, chronic vascular lesions were present in all layers beneath mucosal ulcerations, where a significant increase of PAI-1 levels was found. CONCLUSIONS: These results suggest that vascular involvement associated with abnormalities of PAI-1 expression is an early and widespread event in CD. Their prominence on the mesenteric border might explain the characteristic location of CD ulceration along the mesenteric margin.

Adolescent↗
PubMed1999

Critical role of glass fiber length in TNF-alpha production and transcription factor activation in macrophages.

Recent studies have demonstrated that dielectrophoresis is an efficient method for the separation of fibers according to fiber length. This method allows the investigation of fiber-cell interactions with fiber samples of the same composition but of different lengths. In the present study, we analyzed the effects of length on the interaction between glass fibers and macrophages by focusing on production of the inflammatory cytokine tumor necrosis factor (TNF)-alpha in a mouse macrophage cell line (RAW 264.7). The underlying molecular mechanisms controlling TNF-alpha production were investigated at the gene transcription level. The results show that glass fibers induced TNF-alpha production in macrophages and that this induction was associated with activation of the gene promoter. Activation of the transcription factor nuclear factor (NF)-kappaB was responsible for this induced promoter activity. The inhibition of both TNF-alpha production and NF-kappaB activation by N-acetyl-L-cysteine, an antioxidant, indicates that generation of oxidants may contribute to the induction of this cytokine and activation of this transcription factor by glass fibers. Long fibers (17 micrometer) were significantly more potent than short fibers (7 micrometer) in inducing NF-kappaB activation, the gene promoter activity, and the production of TNF-alpha. This fiber length-dependent difference in the stimulatory potency correlated with the fact that macrophages were able to completely engulf short glass fibers, whereas phagocytosis of long glass fibers was incomplete. These results suggest that fiber length plays a critical role in the potential pathogenicity of glass fibers.

Acetylcysteine↗
PubMed1999

Trends in indications and outcomes in the Whipple procedure over a 40-year period.

There have been increasing changes in the role of pancreatoduodenectomy (PD) in the management of benign and malignant pancreatic disease. The aim of this paper was to compare the current role of PD with that of our earlier experience. The records of patients undergoing PD at our institution between 1983 and 1996 (Group A) were reviewed and compared with cases between 1956 and 1982 (Group B). Student's t test was used to analyze differences between groups. A total of 153 PDs were performed with 98 (64%) in Group A (88% of these in the last 6 years) and 55 (36%) in Group B. Carcinoma of the head of the pancreas was the most common indication for surgery in both periods (43% and 47% for Groups A and B, respectively). In Group A, the next most common indication was chronic pancreatitis, accounting for 28 per cent versus 13 per cent in Group B. Carcinoma of ampulla of Vater was also a common indication, making up 21 per cent of the cases in Group A and 20 per cent in Group B. Preoperative biliary drainage was performed in 62 per cent of Group A and 3 per cent of Group B patients (P < 0.001). Postoperative complications were comparable in both groups: delayed gastric emptying (22%), wound infection (17%), pancreatic fistula (13%), gastrointestinal bleeding (8%), and intestinal obstruction (3%). The perioperative mortality rate was significantly different between the two groups: 1 per cent in Group A versus 16 per cent in Group B (P < 0.001). Mean postoperative length of stay was 17 days in Group A (22 days for benign disease) and 25 days for Group B (P < 0.01). In the last 40 years, there has been a rise in the use of PD for chronic pancreatitis and a significant decrease in postoperative mortality and hospital length of stay. These data support the safety of PD in the management of patients with both benign and malignant periampullary disease.

Adult↗
PubMed1998

Cultured human monocytes release proinflammatory cytokines in response to myelin basic protein.

In human cultured monocytes we examined the ability of myelin basic protein (MBP) to induce the production of proinflammatory cytokines potentially involved in inflammatory demyelination. Northern blots and specific immunoassays demonstrated that monocytes incubated with optimal doses of MBP showed increased mRNA expression and release of tumor necrosis factor (TNF-alpha), interleukin-1beta (IL-1beta), interleukin-6 (IL-6), interleukin-8 (IL-8) but not of interleukin-12/p40 (IL-12/p40). We also showed that cytokine production by MBP-stimulated monocytes was abrogated by incubation with Dexamethasone. These data suggest that interaction of mononuclear phagocytes with MBP may participate in the regulatory process of cytokine production during inflammatory demyelination and support the beneficial role of corticosteroids therapy in aberrant immune responses to the myelin sheath.

Animals↗
PubMed1998

Effect of fiber length on glass microfiber cytotoxicity.

Fiber length has been implicated as a determinant of fiber toxicity. Fibers of narrowly defined length can be generated by dielectrophoretic classifiers. Since the quantities of fibers produced are very small, we developed a rat alveolar macrophage microculture system to study the toxicity of these samples. The objective of this study was to examine the role of fiber length on the cytotoxicity of Manville code 100 (JM-100) fibers. Rat alveolar macrophages were cultured with 0-500 microg/ml of 5 lengths of JM-100 fibers on 96-well plates. After 18 h, well supernatants were removed and lactate dehydrogenase (LDH) activity was measured to assess cell damage. Chemiluminescence (CL), an assessment of macrophage function, was measured by adding lucigenin with or without zymosan, a particulate stimulus, to appropriate wells. For each fiber length the effects were concentration dependent: CL declined and LDH rose with increasing fiber concentration. Comparing the effects of different lengths showed the greatest toxicity from a relatively long fiber sample (mean length = 17 microm). Microscopic examination of the interaction of fibers with macrophages revealed multiple macrophages attached along the length of the long fibers. This suggests that frustrated, or incomplete, phagocytosis may be a factor in the increased toxicity of longer fibers. Overall the results demonstrate that length is an important determinant of toxicity for JM-100 fibers.

Acridines↗
PubMed1998

Melanocortin peptides inhibit production of proinflammatory cytokines and nitric oxide by activated microglia.

Inflammatory processes contribute to neurodegenerative disease, stroke, encephalitis, and other central nervous system (CNS) disorders. Activated microglia are a source of cytokines and other inflammatory agents within the CNS and it is therefore important to control glial function in order to preserve neural cells. Melanocortin peptides are pro-opiomelanocortin-derived amino acid sequences that include alpha-melanocyte-stimulating hormone (alpha-MSH) and adrenocorticotropic hormone (ACTH). These peptides have potent and broad anti-inflammatory effects. We tested effects of alpha-MSH (1-13), alpha-MSH (11-13), and ACTH (1-24) on production of tumor necrosis factor alpha (TNF-alpha), interleukin-6 (IL-6), and nitric oxide (NO) in a cultured murine microglial cell line (N9) stimulated with lipopolysaccharide (LPS) plus interferon gamma (IFN-gamma). Melanocortin peptides inhibited production of these cytokines and NO in a concentration-related fashion, probably by increasing intracellular cAMP. When stimulated with LPS + IFN-gamma, microglia increased release of alpha-MSH. Production of TNF-alpha, IL-6, and NO was greater in activated microglia after innmunoneutralization of endogenous alpha-MSH. The results suggest that alpha-MSH is an autocrine factor in microglia. Because melanocortin peptides inhibit production of pro-inflammatory mediators by activated microglia they might be useful in treatment of inflammatory/degenerative brain disorders.

Adrenocorticotropic Hormone↗
PubMed1997

Immunocytochemical expression of human muscle cell p75 neurotrophin receptor is down-regulated by cyclic adenosine 3',5'-monophosphate.

To investigate whether the immunocytochemical expression of low affinity neurotrophin receptor (p75) in human muscle is modulated by increased levels of intracellular cyclic adenosine 3',5'-monophosphate (cAMP), human cultured myogenic cells were treated with cAMP analogues dibutyryl cAMP (dbcAMP 0.5-1 mM) and 8-bromo cAMP (1 mM) or the adenylate cyclase activator forskolin (10-100 microM). Cultures were processed for indirect immunofluorescence microscopy using an anti-human p75 mAb. The treatment of cultured muscle cells with cAMP analogues or forskolin for two days induced a decrease of immunoreactivity for p75 and a reduction of both myotube formation and morphological cell differentiation. Removal of cAMP derivatives from the medium resulted in a return of immunoreactive cells to the levels of untreated controls. These data indicate that adenylate cyclase is involved in the regulation of human muscle p75.

Adenylyl Cyclases↗
PubMed1997

Effect of acetyl-L-carnitine in the treatment of painful peripheral neuropathies in HIV+ patients.

We studied the effects of acetyl-L-carnitine on pain in 16 HIV+ patients affected by painful distal symmetrical neuropathy. Patients were treated with 0.5-1 gr per day of acetyl-L-carnitine either i.m. or i.v. for 3 weeks. Pain intensity was measured before and after the treatment by the Huskisson's analogic scale. Ten patients (62.5%) reported an improvement of symptoms, five patients (31.25%) were unchanged, one patient worsened. The results of this open study show that acetyl-L-carnitine can have a role in the treatment of pain in distal symmetrical polyneuropathy related to HIV infection. However, further double-blind, placebo-controlled studies are needed to confirm these preliminary results.

Acetylcarnitine↗
PubMed1997

Impact of surgery on quality of life in Crohn's disease.

OBJECTIVE: Health-related quality of life (HRQOL) status is an important component in assessing the impact of disease and its treatments in patients with chronic disorders. We recently validated a HRQOL questionnaire in French patients with inflammatory bowel disease. The aim of this study was to evaluate prospectively the impact of surgery on HRQOL in patients operated on for Crohn's disease (CD). METHODS: Twenty-six patients (14 women, 12 men; median age 28.5 yr) undergoing an elective ileocolonic resection for CD were studied. The HRQOL questionnaire comprised a general questionnaire of 36 items (Medical Outcomes Study-Short Form 36), to which was added a sleep module, and a specific questionnaire of 28 items (Rating Form of Inflammatory Bowel Disease Patient Concerns), to which were added three independent items because of their pertinence in the French population. HRQOL was assessed immediately preoperatively and 3 months postoperatively. RESULTS: HRQOL was improved postoperatively compared with the immediate preoperative status in almost all scales. Patient concerns and worries decreased after surgery. However, ranking was unchanged for the five most intense concerns: having an ostomy bag, having surgery, energy level, uncertainty of the disease, and pain or suffering. CONCLUSIONS: HRQOL is greatly improved after surgery for CD, and this reassuring message might be delivered to our patients. In addition, the questionnaire showed the ability to detect clinical changes over time. This attests to its potential use in research.

Adult↗
PubMed1996

Priming of monocyte respiratory burst by beta-amyloid fragment (25-35).

In the present study we have examined the ability of the beta-amyloid peptide (A beta(25-35)) to modulate the respiratory burst activity of human monocytes in vitro. Incubation of the cells for 24 h with A beta(25-35) as well as with A beta(1-42) resulted in an enhanced production of reactive oxygen radicals (ROI) in response to phorbol 12-myristate 13-acetate (PMA). Such effect was additively increased by coincubation with interferon-gamma (IFN gamma), and was paralleled by modulation of gene and protein expression of some components of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase system. Since the effects of A beta(25-35) were also reproduced in primary rat microglia, our findings indicate that A beta(25-35) can potentiate the ability of mononuclear phagocytes to produce ROI, and add further insights into its biological effects.

Amyloid beta-Peptides↗
PubMed1996

In situ hybridization study of myelin protein mRNA in rats with an experimental diabetic neuropathy.

Distribution of protein zero (P0) and myelin basic protein (MBP) mRNAs in the sciatic nerve from rats with alloxan-induced diabetes was analyzed at two different time points using in situ hybridization. Some animals of each diabetic group were treated with insulin. Densitometric quantitation of silver clusters revealed that 5 weeks after diabetes induction P0 mRNA only is significantly increased, while at 14 weeks both P0 and MBP mRNA contents are markedly higher than controls. Insulin treatment normalizes glycemia levels and slightly counteracts increased P0 mRNA at both stages of diabetes. An increase in MBP mRNA is observed in chronic diabetic animals only, and is unaltered by the normoglycemic effect of insulin. The increased transcript levels of P0 and MBP suggest that Schwann cells can modulate gene expression of myelin-specific proteins in response to diabetic-induced metabolic derangement. Such a change may represent a higher turnover of myelin proteins as an attempt by the Schwann cells to repair the diabetes-induced nerve damage. The observed pattern of transcript amount is only slightly influenced by insulin treatment.

Animals↗
PubMed1996

Induction of p75NGFR in human diabetic neuropathy.

In this immunohistochemical study we investigated the expression of low-affinity NGF receptor (p75NGFR) in peripheral nerves from 16 patients with type I or type II diabetes mellitus. Fourteen nerves from age- and sex-matched normal individuals and nine nerves from non-diabetic patients with ischemic neuropathy served as controls. All nerve samples were preliminarily examined by standard histology, fiber teasing and electron microscopy. Increased p75NGFR immunoreactivity was detectable within the endoneurium of cross-sections from ischemic and particularly from diabetic nerves. Immuno-teasing demonstrated that p75NGFR immunostaining was distributed along the entire length of isolated nerve fibers undergoing axonal degeneration. Quantitative assessment of p75NGFR immunoreactivity, performed by histospectrophotometry and expressed as percentage of adsorbance, was 21.20 +/- 3.50 in nerves from diabetic patients, 13.35 +/- 3.62 in nerves from non-diabetic patients with ischemic neuropathy and 9.02 +/- 2.75 in normal controls. The increased expression of p75NGFR in diabetic nerves is consistent with an axonopathic defect and further suggests involvement of NGF and other neurotrophins in the pathogenesis of human diabetic neuropathy.

Adult↗
PubMed1996

Measuring depression for Swedish nonclinical adolescents: factorial validity and equivalence of the Beck Depression Inventory across gender.

Building upon earlier confirmatory factor analytic research that validated a 2nd-order 4-factor structure of the Beck Depression Inventory for Canadian and Swedish nonclinical adolescents, the purposes of the present study were twofold: (a) to test the factorial structure of the Swedish version of the instrument separately for males (n = 559) and females (n = 537), and (b) to test for its measurement and structural equivalence across gender. Except for three minor discrepancies involving correlated errors, the hypothesized model best described the data for both males and females. Nonetheless, the imposition of equality constraints across sex revealed differences bearing on the measurement of six items, and latent construct relations involving the Somatic Elements factors. Four gender differences in factorial structure replicated findings for Canadian adolescents. Results have important implications for researchers, clinicians, and others whose interests focus on nonclinical adolescent depression.

Adolescent↗
PubMed1996

L-carnitine and acetyl-L-carnitine in human nerves from normal and diabetic subjects.

Marked reduction in the contents of L-carnitine and acetyl-L-carnitine has been reported in peripheral nerves of rats with experimental diabetes. Since these substances have been claimed to improve a number of signs and symptoms of peripheral neuropathy in controlled clinical trials, this study was aimed at assessing whether nerves from diabetic subjects would also reveal similar decrease in the concentration of L-carnitine and acetyl-L-caritine. To this end, these substances were measured in nerves obtained from 11 patients with diabetic neuropathy, 13 patients with ischemic non-diabetic neuropathy, and 12 normal controls. Nerves from patients with either diabetic neuropathy and ischemic non-diabetic neuropathy showed levels of both carnitines lower than those from normal controls. However, differences among the three groups were not statistically significant, indicating that a reduction in these amino acids probably represents only a co-factor in the development of the variegated clinical picture of human diabetic neuropathy.

Acetylcarnitine↗
PubMed1995

Activation of microglial cells by beta-amyloid protein and interferon-gamma.

Alzheimer's disease is the most common cause of progressive intellectual failure. The lesions that develop, called senile plaques, are extracellular deposits principally composed of insoluble aggregates of beta-amyloid protein (A beta), infiltrated by reactive microglia and astrocytes. Although A beta, and a portion of it, the fragment 25-35 (A beta (25-35)), have been shown to exert a direct toxic effect on neurons, the role of microglia in such neuronal injury remains unclear. Here we report a synergistic effect between A beta and interferon-gamma (IFN-gamma) in triggering the production of reactive nitrogen intermediates and tumour-necrosis factor-alpha (TNF-alpha) from microglia. Furthermore, using co-culture experiments, we show that activation of microglia with IFN-gamma and A beta leads to neuronal cell injury in vitro. These findings suggest that A beta and IFN-gamma activate microglia to produce reactive nitrogen intermediates and TNF-alpha, and this may have a role in the pathogenesis of neuronal degeneration observed in ageing and Alzheimer's disease.

Aging↗
PubMed1995

Oltipraz, a novel inhibitor of human immunodeficiency virus type 1 (HIV-1) replication.

Glutathione (GSH) levels are markedly depleted in patients infected with human immunodeficiency virus type 1 (HIV-1) and supplementation of media with high concentrations (5-20 mM) of low-molecular weight thiols prevents HIV-1 replication in cultured cells. We were intrigued whether chemopreventive enzyme inducers might represent a more pharmacologically feasible method to inhibit HIV-1 replication since these compounds elevate intracellular concentrations of GSH at nontoxic doses in vivo. After establishing that all inducers surveyed were able to elevate GSH levels in human T-cell and monocytoid cell lines, we were surprised to find that oltipraz (5-pyrazinyl-4-methyl-1,2-dithiole-3-thione) was uniquely able to inhibit HIV-1 replication (IC50 = 5-15 microM). Oltipraz and other antiviral 1,2-dithiole-3-thiones (DTTs) appear to inhibit acute HIV-1 replication by inactivating reverse transcriptase (RT). However, among DTTs that inhibit HIV-1 replication in acutely infected cells, only oltipraz was able to inhibit HIV-1 replication in a chronic infection model. Thus, in addition to inactivating RT, oltipraz appears to have an additional antiviral mechanism distal to viral integration. Our laboratories are attempting to determine the mechanism by which oltipraz inhibits HIV-1 replication in chronically infected cells; we are also attempting to determine the bioorganic mechanism for the inactivation of RT. Since the covalent modification of schistosomal proteins and transcription factor(s) are thought to be responsible for the antiparasitic and chemopreventive activities of DTTs, respectively, our studies should be relevant to understanding the diverse medicinal properties of DTTs. Oltipraz, an antischistosomal drug undergoing clinical evaluation as an anticarcinogen, inhibits HIV-1 replication at concentrations achievable in human serum. It is intriguing to consider oltipraz as a therapeutic agent not only for its antiretroviral activity, but also for the prevention of HIV-1 associated neoplasms.

Acquired Immunodeficiency Syndrome↗