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M Stern

Publications and source records attributed to M Stern.

At least 163 records · Page 9Linked to original sources

[Cytomegalovirus pneumopathies. What role should be given to cytomegaloviruses isolated from blood and bronchoalveolar lavage fluid in AIDS and from organ and bone marrow grafts?].

Cytomegalovirus (CMV) is often suspected as the causal agent in lung disease occurring in various immunodepressive states: AIDS, organ transplantation, bone marrow graft. The mechanisms involved in these three situations is however quite different. The role played by the cytopathogenic effect of the virus and the immune reaction of the host vary considerably depending on the underlying immunodepression. Thus, the criteria allowing to distinguish between CMV infection (presence of the virus or anti-CMV antibodies, no clinical signs) and CMV disease (generalized or organ specific disease resulting from the pathogenic effect of CMV replication) lack precision. The aim of this review of the literature is to assess the implicated immunovirology mechanism and thus the diagnostic (and thus therapeutic) criteria of CMV lung diseases. There is a graduation scale from AIDS, to organ transplantation and bone marrow allograft in the degree of immune reaction implicated in the lung disease and thus the need and timing of antiviral treatment. In AIDS, an interstitial pneumonia, associated with an isolation of CMV (whatever the sample origin, blood, bronchoalveolar lavage or the isolation technique) does not usually implicate treatment. Treatment may be indicated in rare cases (advanced stage immunodepression, high virus titre, endothelial involvement) or in cases in which the infection is also located in other organs. For organ transplantation, observation of CMV in blood or lavage samples in a patient with clinical or radiological signs would justify treatment. For lung transplantation, more so than for any other organ, treatment should be started early whenever respiratory signs are associated with evidence of CMV infection. Finally, in bone marrow allografts, the high rate of failure when pneumonitis has become patent implicates starting treatment immediately upon diagnosis of CMV infection. The strategy proposed here is based on a certain rationale but can be open to discussion. Controlled clinical trials are required to determine the most rigorous and coherent attitude. Finally, within the framework of the diseases examined here, search for lung disease caused by cytomegalovirus should not mask other organ localizations in, for example, the retina, the digestive tract.

AIDS-Related Opportunistic Infections↗

Quantitative fluorescence measurements of chloride secretion in native airway epithelium from CF and non-CF subjects.

Functional assessment of the efficacy of CFTR gene transfer protocols in humans has previously involved measurement of in vivo potential difference. We have studied whether freshly obtained airway epithelial cells may provide suitable tissue for studies of in vivo gene transfer using fluorescent digital imaging microscopy. Nasal epithelial cells from non-cystic fibrosis subjects (n = 6) and from cystic fibrosis (CF) patients (delta F508: delta F508, n = 5) were obtained by brushing and loaded with 6-methoxy-N-(3-sulfopropyl)quinolinium (SPQ). Addition of the cAMP-agonists forskolin (20 microM) and 3-isobutyl-1-methylxanthine (IBMX, 100 microM) produced an increased efflux of iodide from the cells which was significantly (P < 0.05) greater in non-CF than in CF cells. Efflux following addition of the calcium ionophore, ionomycin (100 microM) was similar in both non-CF and CF cells. Liposome-mediated transfection of CF nasal epithelial cells in vitro with CFTR-cDNA restored the cAMP-stimulated efflux to non-CF values. Bronchial epithelial cells from non-CF subjects showed responses to forskolin and ionomycin that were not different to those in non-CF nasal epithelia. These data demonstrate that the assay provides a useful method for assessing correction of abnormal ion transport in non-cultured CF epithelium and is likely to provide a further assay for assessment of in vivo gene transfer efficiency in protocols of gene therapy for CF.

Adult↗

Molecular cloning of a mammalian hyaluronidase reveals identity with hemopexin, a serum heme-binding protein.

Hyaluronan is the most abundant glycosaminoglycan of the extracellular matrix and is a critical substrate for cellular attachment and locomotion. Little is known about the class of enzymes, termed hyaluronidases, that are responsible for hyaluronan catabolism in mammals. We have determined a partial amino acid sequence from a purified preparation of porcine liver hyaluronidase and have used this information as the basis for cloning complementary DNA that encodes the corresponding protein. When expressed in a recombinant baculovirus system, the protein exhibited hyaluronidase activity in a substrate-gel assay. The deduced sequence of this mammalian hyaluronidase is that of a 459-amino-acid polypeptide bearing four potential N-glycosylation sites as well as a copy of a proposed hyaluronan binding motif. Remarkably, amino acid sequence comparisons and immunologic cross-reactivities strongly suggest that the cloned protein is identical to hemopexin, an abundant, heme-binding serum protein. Although hemopexin has not previously been reported to possess any enzymatic activity, it includes a conserved domain found in collagenases, stromelysins, and other enzymes that metabolize the extracellular matrix. We conclude that hemopexin is the predominant hyaluronidase expressed in mammalian liver.

Amino Acid Sequence↗

Calcium dependence of neurotransmitter release and rate of spontaneous vesicle fusions are altered in Drosophila synaptotagmin mutants.

Since the demonstration that Ca2+ influx into the presynaptic terminal is essential for neurotransmitter release, there has been much speculation about the Ca2+ receptor responsible for initiating exocytosis. Numerous experiments have shown that the protein, or protein complex, binds multiple Ca2+ ions, resides near the site of Ca2+ influx, and has a relatively low affinity for Ca2+. Synaptotagmin is an integral membrane protein of synaptic vesicles that contains two copies of a domain known to be involved in Ca(2+)-dependent membrane interactions. Synaptotagmin has been shown to bind Ca2+ in vitro with a relatively low affinity. In addition, synaptotagmin has been shown to bind indirectly to Ca2+ channels, positioning the protein close to the site of Ca2+ influx. Recently, a negative regulatory role for synaptotagmin has been proposed, in which it functions as a clamp to prevent fusion of synaptic vesicles with the presynaptic membrane. Release of the clamp would allow exocytosis. Here we present genetic and electrophysiological evidence that synaptotagmin forms a multimeric complex that can function as a clamp in vivo. However, upon nerve stimulation and Ca2+ influx, all synaptotagmin mutations dramatically decrease the ability of Ca2+ to promote release, suggesting that synaptotagmin probably plays a key role in activation of synaptic vesicle fusion. This activity cannot simply be attributed to the removal of a barrier to secretion, as we can electrophysiologically separate the increase in rate of spontaneous vesicle fusion from the decrease in evoked response. We also find that some syt mutations, including those that lack the second Ca(2+)-binding domain, decrease the fourth-order dependence of release on Ca2+ by approximately half, consistent with the hypothesis that a synaptotagmin complex functions as a Ca2+ receptor for initiating exocytosis.

Animals↗

Granulocyte apoptosis and the control of inflammation.

We have described a novel pathway available for the clearance of extravasated granulocytes from inflamed tissues whereby aging granulocytes undergo apoptosis, a process which leads to their phagocytosis by inflammatory macrophages. By contrast with necrosis, which may also be seen at inflamed sites, apoptosis represents a granulocyte fate which by a number of mechanisms would tend to limit inflammatory tissue injury and promote resolution rather than progression of inflammation: (i) apoptosis is responsible for macrophage recognition of senescent neutrophils with intact cell membranes which exclude vital dyes and retain their potentially histotoxic granule contents; (ii) the apoptotic neutrophil loses its ability to secrete granule enzymes on deliberate external stimulation; (iii) the macrophage possesses a huge phagocytic capacity for apoptotic neutrophils which it rapidly ingests and degrades without disgorging neutrophil contents; and (iv) the macrophage utilizes a novel phagocytic recognition mechanism which fails to trigger the release of pro-inflammatory macrophage mediators during the phagocytosis of apoptotic neutrophils. Preliminary characterization of the recognition mechanism implicates the integrin alpha v beta 3 (vitronectin receptor) and CD36 (thrombospondin receptor) on the macrophage surface. Macrophage phagocytosis of apoptotic neutrophils is greatly influenced by the microenvironmental pH and by the presence of cationic molecules. Moreover, it can be specifically modulated by external cytokines and intracellular second messenger systems. By controlling the functional longevity of neutrophil and eosinophil granulocytes and their subsequent removal by macrophages, granulocyte apoptosis, with its potential for modulation by external mediators, is likely to play a key dynamic role in the control of the 'tissue load' of granulocytes at inflamed sites.(ABSTRACT TRUNCATED AT 250 WORDS)

Apoptosis↗

AZT-induction of micronuclei in human lymphocyte subpopulations.

Micronucleus (MN) induction by azidothymidine (AZT) in B and T lymphocytes was analyzed by a recently developed MAC (morphology-antibody-chromosome) method which allows the immunologic identification of different cell lineages. An increased frequency of MN in AZT-treated cultures compared with controls was observed. CD4 cells were found to be more sensitive to AZT damage. AZT-treated cultures showed a significant decrease in the proportion of CD4 interphasic cells. Furthermore, higher MN frequencies in isolated lymphocytes than in whole blood in both control and AZT-treated cultures were observed.

Adult↗

A multicenter double-blind placebo-controlled trial of pergolide as an adjunct to Sinemet in Parkinson's disease.

Three hundred and seventy-six subjects with advanced Parkinson's disease participated in a prospective, double-blind placebo-controlled study of the dopamine agonist pergolide mesylate as an adjunct to Sinemet. At 6 months, patients randomized to pergolide had a statistically significant improvement in total Parkinson's score, scores of activities of daily living, motor function, number of "off" hours, Hoehn and Yahr stage, and numerous parameters of parkinsonian function including bradykinesia, rigidity, gait, and dexterity. This benefit was obtained with the addition of a mean dose of 2.94 mg of pergolide, which permitted a 24.7% reduction in dose of levodopa. Adverse reactions were, for the most part, mild, reversible, and not of major clinical significance. No significant cardiac or electrocardiographic abnormalities were detected. This study demonstrates that pergolide mesylate, as an adjunct to levodopa, is an effective antiparkinsonian agent that provides clinical improvement while permitting a reduction in levodopa dose.

Activities of Daily Living↗

rop, a Drosophila homolog of yeast Sec1 and vertebrate n-Sec1/Munc-18 proteins, is a negative regulator of neurotransmitter release in vivo.

The mammalian homolog of the yeast Sec1p, n-Sec1/Munc-18 has been demonstrated to bind the presynaptic membrane protein syntaxin, a putative synaptic vesicle docking protein. To determine the role of n-Sec1/Munc-18 in neurotransmitter release in vivo, we have overexpressed the Drosophila homolog, rop, in third instar larvae and measured the electrophysiological consequences at the neuromuscular junction. A 3- to 5-fold induction of the rop protein causes a dramatic decrease in neurotransmitter release, suggesting rop may restrict the ability of vesicles to dock or of docked vesicles to fuse. Consistent with this hypothesis, rop overexpression also reduces the number of spontaneous vesicle fusions by more than 50%, and repetitive stimulation results in significant decreases in evoked responses similar to those observed in rab3a mutant mice. However, rop overexpression does not alter significantly the Ca2+ dependence of neurotransmitter release. We propose that the Drosophila n-Sec1/Munc-18 homolog plays a negative role in neurotransmitter release in vivo, in addition to its previously identified positive function, possibly by modulation of docking of synaptic vesicles or activation of a pre-fusion complex at the active zone.

Animals↗

Prevalence of hypertension in Mexico City and San Antonio, Texas.

BACKGROUND: Few data are available on the prevalence of hypertension in Mexico. METHODS AND RESULTS: We compared the prevalence of mild hypertension (systolic blood pressure > or = 140 mm Hg and/or diastolic blood pressure > or = 90 mm Hg and/or use of antihypertensive medications) in 1500 low-income Mexican Americans who participated in the San Antonio Heart Study and 2280 low-income Mexicans who participated in the Mexico City Diabetes Study. The crude prevalence of mild hypertension was 17.1% in Mexican men versus 24.4% in Mexican American men (P = .001) and 17.4% in Mexican women versus 22.0% in Mexican American women (P = .005). After adjustment for age, body mass index (BMI), waist-to-hip ratio (WHR), non-insulin dependent diabetes mellitus (NIDDM), educational attainment, and percent native American genetic admixture (Caucasian and native American), the odds ratio (Mexico City/San Antonio) was 0.55 (95% CI, 0.39, 0.77; P < .001) in men and 0.81 (CI, 0.54, 1.12; P = .201) in women. In a pooled model including both men and women, the odds ratio was 0.67 (95%, CI, 0.53, 0.84; P < .001). In the pooled model, city, age, female sex, NIDDM, BMI, WHR, and low educational attainment were significantly related to the prevalence of hypertension. CONCLUSIONS: The causes for these differences in hypertension prevalence are not known but may reflect a less modernized lifestyle in Mexico City, including greater physical activity, less obesity, and the consumption of a high-carbohydrate, low-fat diet.

Adult↗

Treatment of organic bipolar mood disorders in Parkinson's disease.

Two patients with long-standing idiopathic Parkinson's disease (PD), without individual or family histories of affective disorders, developed bipolar mood disorders. Both were treated with lithium and clozapine, and one responded favorably. These may be the first reported cases in which mania was treated with clozapine in PD patients.

Bipolar Disorder↗

A highly unusual combination of pulmonary pathogens in an HIV infected patient.

We report on a case with an unusual combination of pulmonary pathogens including Pneumocystis carinii, Rhodococcus equi and Toxoplasma gondii in an HIV infected patient. The multiple microbiological procedures required to ascertain the etiological diagnoses of pneumonitis in HIV-seropositive subjects are discussed.

AIDS-Related Opportunistic Infections↗

Subchronic 10 day immunotoxicity of polydimethylsiloxane (silicone) fluid, gel and elastomer and polyurethane disks in female B6C3F1 mice.

Millions of people have been exposed to silicones because of the widespread use in consumer products such as cosmetics and toiletries, food products, household products and paints. Silicones have wide use in medical practice, including lubricants in tubing and syringes, and as implantable devices. The most prevalent silicone in medical use is polydimethylsiloxane. This study was undertaken to determine the subchronic immunotoxicologic potential of the principal constituents of breast implants: silicone fluid, silicone gel and silicone elastomer. An alternative covering for devices containing silicone gels, polyurethane, was also included in the study. Silicone fluid and gel were injected subcutaneously into female B6C3F1 mice (1 ml/mouse) and 6 mm disks of silicone elastomer or polyurethane were implanted subcutaneously. There were no treatment-related deaths or overt signs of toxicity. None of the tested materials had notable effects on body or organ weights, erythrocytes or leukocytes in the blood, blood chemistries such as alanine aminotransferase, urea nitrogen, glucose, albumin or total protein. The cellularity of the bone marrow and responses to CSF-GM and CSF-M were normal. The tested silicones did not alter the distribution of B cells and T cells in the spleen, but polyurethane perturbed the distribution of CD4+CD8+ and CD4-CD8- T cells. The antibody response to sheep erythrocytes was not markedly altered, nor were proliferative responses to concanavalin A, phytohemagglutinin, lipopolysaccharide or allogeneic cells. Reticuloendothelial function was normal, but polyurethane evoked an enhanced phagocytosis of Covaspheres by adherent peritoneal cells. Natural killer cell activity and serum complement were not altered. All silicone materials afforded modest protection to a challenge with Listeria monocytogenes that killed 40 to 58% of control mice. Host resistance to Streptococcus pneumoniae or the B16F10 tumor was not affected by any of the treatments. There is a pattern indicative of some perturbation of T cell differentiation in mice implanted with a polyurethane disk.

Animals↗

Immunotoxicity of 180 day exposure to polydimethylsiloxane (silicone) fluid, gel and elastomer and polyurethane disks in female B6C3F1 mice.

Millions of people have been exposed to silicones which are present in consumer goods such as cosmetics and toiletries, processed foods and household products. In addition, silicones have been used extensively in medical practice as a lubricant in tubing and syringes, and as implantable devices. A silicone widely used in medical practice is polydimethylsiloxane. This study was undertaken to determine the immunotoxicologic potential of long term exposure to the principal constituents of breast implants: silicone fluid, silicone gel and silicone elastomer. An alternative covering for devices containing silicone gels, polyurethane, was also included in the study. Silicone fluid and gel were injected subcutaneously into female B6C3F1 mice (1 ml/mouse) and 6 mm disks of silicone elastomer or polyurethane were implanted subcutaneously. There were no treatment-related deaths or overt signs of toxicity during the 180 day exposure. None of the tested materials had notable effects on body or organ weights, erythrocytes or leukocytes in the blood, blood chemistries such as alanine aminotransferase, urea nitrogen, glucose, albumin or total protein, or serum CH 50 or C3 levels. The cellularity of the bone marrow and responses to CSF-GM and CSF-M were normal. The tested silicones and polyurethane marginally reduced the level of Ig+ cells in the spleen but did not consistently alter the distribution of T cell surface markers. The antibody response to sheep erythrocytes was not markedly altered, nor were proliferative responses to concanavalin A, phytohemagglutinin, lipopolysaccharide or allogeneic cells. Reticuloendothelial function was normal, as was phagocytosis of chicken erythrocytes and Covaspheres by adherent peritoneal cells. Natural killer cell activity was depressed in all silicone treatment groups and in mice implanted with polyurethane. No silicone or polyurethane treatment group displayed altered susceptibility to a challenge with Listeria monocytogenes, Streptococcus pneumoniae or the B16F10 tumor. The only consistent effect of 180 day exposure to silicone materials or polyurethane was a modest depression of natural killer cell activity.

Animals↗

Immunotoxicity of nitrobenzene in female B6C3F1 mice.

Nitrobenzene (NBZ) is primarily employed as an oxidizing agent in the synthesis of analine and benzene compounds. It produces myelotoxic effects and effects on erythrocytes in both animal models and man. Reported hepatosplenomegaly and effects on the bone marrow are indicators that NBZ may be immunotoxic. In these studies, female B6C3F1 mice were exposed to 30, 100 and 300 mg/kg of NBZ in corn oil by gavage for 14 consecutive days. To assess the immunotoxic potential of NBZ, body and organ weights were determined and selected immunologic and host resistance responses were studied. In these studies, the liver and spleen appeared to be the primary target organs. Both liver and spleen weights were dose dependently increased. Gross histopathologic examinations revealed significant changes in the spleen, consisting of severe congestion of the red pulp areas with erythrocytes and reticulocytes. Serum chemistry profiles showed increases in alanine aminotransferase and aspartate aminotransferase activities, indicating liver toxicity. Hematologic studies showed a decrease in erythrocyte number and a concomitant increase in mean corpuscular hemoglobin and mean corpuscular volume. A dose-dependent increase in peripheral reticulocytes was also seen. DNA synthesis was enhanced, as was the number of formed elements and the number of monocyte/granulocyte stem cells in the bone marrow of treated mice. IgM responses were decreased and the phagocytic activity of macrophages in the liver was dose dependently increased with a concomitant decrease in the activities in the spleen and lung. Other immunological parameters examined were unchanged. Host resistance to microbial or viral infection was not markedly altered by NBZ; however, there were trends towards increased susceptibility where T-cell function contributes to host defense. These data indicate that NBZ-induced hemolysis and liver injury are linked to the observed alterations in bone marrow activity.

Administration, Oral↗

Immunotoxicity of mono-nitrotoluenes in female B6C3F1 mice: I. Para-nitrotoluene.

para-Nitrotoluene (p-nitrotoluene) is used primarily as an intermediate in the production of various dyes, explosives, pharmaceuticals, and in the production of rubber and agricultural products. Previous investigations indicated that p-nitrotoluene was mutagenic in the Ames Test and that other mono-substituted nitrotoluenes bound covalently to hepatic macromolecules. The objective of these studies was to evaluate the potential immunotoxicity of p-nitrotoluene in mice exposed by the oral route. Mice exposed to p-nitrotoluene (200-600 mg/kg) daily for 14 days showed modest dose-dependent increases in liver and spleen weights. The livers of mice exposed subchronically to 400 and 600 mg/kg showed a mild to moderate swelling of the hepatocytes adjacent to the central veins; this swelling appeared to be reversible and there was no evidence of necrosis. The proportion of monocytes in blood was decreased in mice treated with p-nitrotoluene or toluene. Serum chemistries, bone marrow cellularity and the number of CFU-M and CFU-GM were unaffected. Immunologic investigations showed p-nitrotoluene suppressed the IgM response to sRBC and the DHR response to KLH. There was a 24% decrease in the percentage of CD4+ T lymphocytes in the spleen. There was no dose-dependent alteration of peritoneal macrophage numbers or differential count, unstimulated natural killer cell activity, response to B cell mitogen LPS, C3 activity or interferon levels. Exposure of mice to p-nitrotoluene decreased resistance to Listeria monocytogenes but not to Streptococcus pneumoniae, Plasmodium yoelii or the B16F10 melanoma, and increased resistance to the PYB6 tumor. These studies indicated that the immune system is an important target for toxicity of p-nitrotoluene. The decreased host resistance to L. monocytogenes can be attributed to the decrease in T lymphocytes and to a decreased delayed hypersensitivity response to KLH.

Administration, Oral↗

Immunotoxicity of mono-nitrotoluenes in female B6C3F1 mice: II. Meta-nitrotoluene.

The nitrotoluenes are chemicals used in dyes, agricultural products, pharmaceuticals and explosives. In the present studies, the toxicology and immunotoxicity of meta-nitrotoluene (m-nitrotoluene) were evaluated. Mice, exposed to m-nitrotoluene at dose levels of 200, 400 and 600 mg/kg/body weight for 2 weeks by gastric gavage, gained body weight over the treatment period to a slightly greater extent than the control groups. Of the selected organs weighed, the liver and kidney of mice exposed to m-nitrotoluene were increased in weight while the thymus weight was decreased. The liver of mice exposed to m-nitrotoluene, but not ortho-nitrotoluene, showed slight to moderate swelling of the hepatocytes adjacent to the central veins. The hepatocyte swelling appeared to be reversible and there was no evidence of necrosis. The hematology and serum chemistries examined were unaffected by m-nitrotoluene exposure although there were modest decreases in the percentage of polymorphonuclear leukocytes and eosinophils in differential blood counts. Bone marrow cellularity and the number of CFU/M and CFU/GM were unaffected by m-nitrotoluene exposure. m-Nitrotoluene suppressed the IgM response to sRBC and the DHR response to KLH. There was a slight (8%) decrease in the percentage of B lymphocytes in the spleen. The response to the T cell mitogens was suppressed by as much as 39%. Fc-mediated adherence and phagocytosis of chicken erythrocytes and NK cell activity were increased dose dependently in mice exposed to m-nitrotoluene. Several immune parameters were unaffected by exposure to m-nitrotoluene, including the IgG response to sRBC, responses to the B cell mitogen LPS and to allogeneic cells, and serum interferon levels. Resistance to Streptococcus pneumoniae and Plasmodium yoelii were unaffected also. Resistance to the tumor model PYB6 was increased. Exposure of mice to m-nitrotoluene decreased resistance to Listeria monocytogenes. The decreased resistance to L. monocytogenes may be related to an effect on T cells, evidenced by a decrease in T cell numbers and in the DHR.

Administration, Oral↗