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Biomedical subjects

M Joseph

Publications and source records attributed to M Joseph.

At least 37 records · Page 2Linked to original sources
PubMed2001

Effects of mechanical ventilation of isolated mouse lungs on surfactant and inflammatory cytokines.

Mechanical ventilation of the lung is an essential but potentially harmful therapeutic intervention for patients with acute respiratory distress syndrome. The objective of the current study was to establish and characterize an isolated mouse lung model to study the harmful effects of mechanical ventilation. Lungs were isolated from BalbC mice and randomized to either a nonventilated group, a conventionally ventilated group (tidal volume 7 mL x kg(-1), 4 cm positive endexpiratory pressure (PEEP)) or an injuriously ventilated group (20 mL x kg(-1), 0 cm PEEP). Lungs were subsequently analysed for lung compliance, morphology, surfactant composition and inflammatory cytokines. Injurious ventilation resulted in significant lung dysfunction, which was associated with a significant increase in pulmonary surfactant, and surfactant small aggregates compared to the other two groups. Injurious ventilation also led to a significantly increased concentration of interleukin-6 and tumour necrosis factor-a in the lavage. It was concluded that the injurious effects of mechanical ventilation can effectively be studied in isolated mouse lung, which offers the potential of studying genetically altered animals. It was also concluded that in this model, the lung injury is, in part, mediated by the surfactant system and the release of inflammatory mediators.

Animals↗
PubMed2000

[Study of the behavior of the vegetative meristem of alfa (Stipa tenacissima L.). Cytological and histological approaches].

The biological and cytological studies of the vegetative meristem of Stipa tenacissima L. gave clear indication about its structure. It was similar to what was previously described in several species. This meristem showed an axial apical zone constituted by sommital cells of both tunica and corpus, a sub-apical lateral zone, very chromophilous, representing the initial ring and a medullar meristem. The cytofluorimetric determination of DNA in interphasic nuclei of these three zones revealed that the nuclei of the apical and lateral zones were in S phase, announcing the beginning of mitosis and meaning that these zones were the centers of the foliar initiation. The medullar meristem was in dormancy: all the nuclei were in G1 phase.

DNA, Plant↗
PubMed1999

Comparison of IgE and IgG antibody-dependent cytotoxicity in vitro and in a SCID mouse xenograft model of ovarian carcinoma.

Allergic reactions are mediated by IgE antibodies bound to high-affinity receptors on mast cells in peripheral tissues and are characterized by their immediacy and hypersensitivity. These properties could also be advantageous in immunotherapy against cancer growth in peripheral tissues. We have constructed chimeric IgE and IgG1 antibodies with murine V regions and human C regions corresponding to the MOv18 monoclonal antibody against the human ovarian tumor-associated antigen, folate binding protein. The antibodies exhibited the expected binding affinities for antigen and Fc receptors, and effector activities with human basophils and platelets in vitro. The protective activities of MOv18-IgE and MOv18-IgG1 were compared in a SCID mouse xenograft model of ovarian carcinoma. The beneficial effects of MOv18-IgE were greater and of longer duration than those of MOv18-IgG1. Our results suggest that the allergic reaction could be harnessed for the suppression of ovarian tumors.

Animals↗
PubMed1999

Production of chemokines and proinflammatory and antiinflammatory cytokines by human alveolar macrophages activated by IgE receptors.

BACKGROUND: The alveolar macrophage (AM) expresses the low affinity IgE receptor and has the ability to produce not only several proinflammatory cytokines (TNF-alpha, IL-1, IL-6) but also antiinflammatory cytokines (IL-1 receptor antagonist [IL-lra], IL-10), chemokines (IL-8, monocyte chemotactic protein-1 [MCP-1]), and macrophage inflammatory protein-1alpha (MIP-1alpha). OBJECTIVE: The aim of this study was to evaluate the capacity of the AM from patients with allergic asthma and control subjects to produce chemokines and antiinflammatory versus proinflammatory cytokines after activation by IgE receptors and to define the role of CD23 in this activation. METHODS: AMs were collected by bronchoalveolar lavage from 13 patients with allergic asthma and 14 healthy subjects. Adherent AMs were activated either by the successive addition of IgE and anti-IgE or by monoclonal mouse IgG anti-CD23 or by a control monoclonal mouse antibody. TNF, IL-1beta, IL-1ra, IL-10, IL-8, MCP-1, and MIP-1alpha levels were evaluated in supernatants of AMs incubated for 18 hours and in some cases after 4 hours of incubation. RESULTS: Activation by IgE and anti-IgE antibodies significantly increased the production of TNF, IL-1beta, IL-8, MCP-1, MIP-lalpha, and IL-10 in both control subjects and patients with asthma, whereas the increase for IL-1ra was only significant for the control subjects. Whereas F(ab) fragments of anti-CD23 antibodies inhibited IgE plus anti-IgE-induced cytokine production, activation by monoclonal IgG anti-CD23 antibodies reproduced the effect of IgE immune complexes. At 4 hours, the secretion of proinflammatory cytokines was increased by activation by IgE receptors, in contrast to antiinflammatory cytokines. In addition, analysis of the balance between proinflammatory and antiinflammatory cytokines showed that IgE-dependent activation largely favored the proinflammatory cytokines, particularly in patients with asthma. CONCLUSION: IgE-dependent activation by the FcepsilonRII receptor upregulates the synthesis of both chemokines and antiinflammatory cytokines in addition to proinflammatory cytokines. However, AMs from patients with allergic asthma may promote airway inflammation after activation by IgE receptors through its preferential effect on proinflammatory cytokines.

Animals↗
PubMed1998

p300/MDM2 complexes participate in MDM2-mediated p53 degradation.

Control of p53 turnover is critical to p53 function. E1A binding to p300/CBP translates into enhanced p53 stability, implying that these coactivator proteins normally operate in p53 turnover control. In this regard, the p300 C/H1 region serves as a specific in vivo binding site for both p53 and MDM2, a naturally occurring p53 destabilizer. Moreover, most of the endogenous MDM2 is bound to p300, and genetic analysis implies that specific interactions of p53 and MDM2 with p300 C/H1 are important steps in the MDM2-directed turnover of p53. A specific role for p300 in endogenous p53 degradation is underscored by the p53-stabilizing effect of overproducing the p300 C/H1 domain. Taken together, the data indicate that specific interactions between p300/CBP C/H1, p53, and MDM2 are intimately involved in the MDM2-mediated control of p53 abundance.

Cell Line↗
PubMed1998

Characterizing alterations in the pulmonary surfactant system in a rat model of Pseudomonas aeruginosa pneumonia.

Bacterial pneumonia remains a significant cause of patient morbidity and mortality worldwide. Pulmonary surfactant serves to maintain homeostasis in the lung through the maintenance of alveolar stability and the regulation of the alveolar immune response. The purpose of this study was to characterize the lung injury and associated surfactant alterations in a rat model of acute Pseudomonas aeruginosa pneumonia. Pneumonia was induced in male Sprague-Dawley rats via intratracheal injection of 0.2 ml, phosphate-buffered saline (PBS) containing P. aeruginosa (6x10(8) colony-forming units x mL(-1)). Control animals received 0.2 mL sterile PBS. Twenty-four hours after inoculation, the pneumonia group (PN) exhibited clinical signs of pneumonia including deficits in gas exchange, leukopenia and elevated arterial lactate levels. Morphological assessment confirmed the presence of pneumonia with airspaces filled with polymorphonuclear cells. Lung homogenate analysis demonstrated evidence of bacterial colonization of pneumonic lung tissue. Lung compliance was also significantly lower in the PN group. Lung lavage analysis of PN rats revealed the pooled surfactant levels to be lower and the surfactant function reduced compared to control rats. Surfactant composition was also found to be altered in PN rats. These results demonstrate that in Pseudomonas aeruginosa pneumonia, the pulmonary surfactant system is both poorly functioning and reduced in quantity. These alterations may contribute to the lung dysfunction characteristic of this disorder.

Acute Disease↗
PubMed1998

Insight into the environment of tryptophan in a hydrophobic model peptide upon aggregation and interaction with lipid vesicles: a steady state and time resolved fluorescence study.

Fluorescence spectroscopy is extensively used to monitor binding of peptides to lipid vesicles as well as orientation in the lipid bilayer. In steady-state fluorescence, the emission characteristics of intrinsic and extrinsic fluorophores, which are sensitive to environment are monitored. Life time measurements should yield useful information about the location and flexibility of fluorophores, as these factors have a significant effect on the life times. However, studies on protein structure and dynamics indicate that interpretation of life-time data is complicated (Beechem. J.M. and Brand, L. (1985) Annu. Rev. Biochem. 54, 43-71). Hence, simple well-defined systems should help in interpretation of life time data, especially in lipid-peptide interactions. In order to examine how fluorescence characteristics of tryptophan and anthroyl group would reflect molecular details of peptide aggregation and lipid-peptide interaction, studies have been carried out on a model hydrophobic peptide and its fatty acylated derivative. Steady-state fluorescence measurements suggest that: (1) the fatty acyl chain attached to an amino acid associates with the peptide chain in aqueous environment. (2) In the lipid bilayer, the acyl chain is oriented perpendicular to the lipid bilayer surface with the peptide chain at an angle to it. Analysis of the fluorescence decay of tryptophan indicates the predominance of a very short life-time component (<1ns) in aqueous environment and lipid-vesicles. Since the preexponentials were not negative, it is unlikely that this is due to extensive deactivation process. We attribute the observation of the low life time component to predominance of one rotamer around (C alpha-C beta)bond of tryptophan in aqueous and lipid environments. Our investigations suggest that fluorescence life time data need to be complemented with steady state measurements to get an insight into details of lipid-peptide interaction.

Amino Acid Sequence↗
PubMed1997

Expression and functions of the high-affinity IgE receptor on human platelets and megakaryocyte precursors.

Platelets can be activated by IgE and are therefore involved in IgE-mediated effector mechanisms against parasites and in allergic disorders. Here we show that, besides the low-affinity IgE receptor (Fc epsilon RII/CD23), platelets express the high-affinity receptor for IgE (Fc epsilon RI). Flow cytometry analysis revealed the existence of surface Fc epsilon RI on platelets with a large heterogeneity among individual donors, and a low proportion of platelets co-expressing Fc epsilon RI and FC epsilon RII/CD23. Northern hybridization and reverse transcription polymerase chain reaction confirmed the presence of mRNA encoding the alpha, beta and gamma chains of Fc epsilon RI in platelets and in their megakaryocytic precursors. Cross-linking of Fc epsilon RI with monoclonal antibody (mAb) to alpha chain using either the whole molecule or F(ab')2 triggered platelet cytotoxicity for Schistosoma mansoni larvae. Anti-Fc epsilon RII/CD23 mAb significantly inhibited IgE- or Fc epsilon RI-mediated cytotoxicity, indicating down-regulatory effects of Fc epsilon RII/CD23 on Fc epsilon RI-dependent functions. These results demonstrate functional properties for Fc epsilon RI on platelets and indicate unsuspected interactions between the low- and the high-affinity IgE receptors.

Adult↗
PubMed1997

A new X linked recessive syndrome of mental retardation and mild dysmorphism maps to Xq28.

Efforts to understand the genetic basis of mental retardation are greatly assisted by the identification of families with multiple relatives with mental retardation that clinical geneticists encounter in the routine practice of their profession. Here we describe a linkage study of a four generation family in which X linked recessive mental retardation (XLMR) is associated with minor dysmorphism and premature death of the affected males. Microsatellite based polymorphic loci evenly spaced over the entire X chromosome were used initially to detect linkage to Xq28. Further analysis identified a haplotype of Xq28 markers bounded proximally by locus DXS1113 and distally by DXS1108 that cosegregated with XLMR in this family. Two point lod scores > 3.0 provided strong evidence that the gene locus responsible for XLMR in this family is within this 7 Mb region of Xq28. The minor anomalies noted in some affected males were not distinctive enough to suggest a unique syndrome. None of our patients had features of the Waisman-Laxova syndrome or the PPM-X syndrome. The possibility of allelism with any of the five other non-specific XLMR syndromes (MRX3, MRX16, MRX25, MRX28, and MRX41) mapped to Xq28 could not be excluded. While the recognition of a gene responsible for this disorder needs much additional work, multiple female relatives at risk in this family benefit immediately from knowing their genotype and heterozygotes will have the opportunity to undergo prenatal diagnosis.

Adult↗
PubMed1997

Alterations of the endogenous surfactant system in septic adult rats.

Sepsis is the most common factor leading to the acute respiratory distress syndrome (ARDS) and is associated with the highest mortality rate. It has been suggested that the pulmonary surfactant system is altered and contributes to the lung dysfunction associated with ARDS. The objective of this study was to characterize the lung injury, specifically the endogenous surfactant system in septic adult rats. Sepsis was induced in male Sprague-Dawley rats by cecal ligation and perforation and resulted in significant increases in heart rates, respiratory rates, and lactate levels along with positive blood cultures in septic animals compared with a sham control group. Two distinct septic groups were developed, a septic group and a sepsis with lung injury (septic+LI) group. The septic group had no significant differences in oxygenation compared with the sham group, whereas the septic+LI group had significantly lower PaO2 and higher A-a gradient values compared to both the sham and septic groups. The total surfactant pool size was significantly lower in the septic+LI group compared with the sham group. The small surfactant aggregate to large surfactant aggregate ratio was significantly lower in the septic group and was further reduced in the septic+LI group. There were also significantly higher levels of surfactant protein A (SP-A) in both septic and septic+LI groups compared to the sham group. These results demonstrated that the endogenous surfactant system was altered in systemic sepsis without lung dysfunction and is further altered when a lung injury is present.

Analysis of Variance↗
PubMed1996

Interactions between endothelial cells and effector cells in allergic inflammation.

The local inflammatory response that occurs after repeated exposure to allergens or during the late-phase reaction results from a complex network of interactions between inflammatory cells (mast cells, eosinophils, macrophages) and resident cells belonging to the lung structure itself like EC, fibroblasts, or bronchial epithelial cells. Among structural cells, EC represent critical elements: they control leukocyte traffic through the expression of adhesion molecules; they are also able to amplify leukocyte activation through the production of proinflammatory cytokines like IL-1, IL-6, or of chemokines like IL-8. Three cell models have been successively considered. When supernatants of alveolar macrophages, recovered from patients exhibiting a late asthmatic response after allergen exposure, were tested on HUVEC cultures, a TNF alpha-dependent ICAM-1 and E-selectin overexpression was observed. Among mast-cell mediators, histamine was already known to induce a rapid and transient expression of P-selectin; we demonstrated that histamine also induced an IL-6 and IL-8 secretion by HUVEC, which was concentration-dependent and inhibited by H1 or H2 receptor antagonists. Finally purified eosinophils obtained from donors with hypereosinophilia similarly increased adhesion molecule expression and chemokine production. The precise nature of the eosinophil product(s) involved in this process is currently under investigation.

Asthma↗
PubMed1996

Venom immunotherapy modulates interleukin-4 and interferon-gamma messenger RNA expression of peripheral T lymphocytes.

The mechanism by which specific immunotherapy exerts its beneficial effect remains unclear. In order to evaluate the influence of venom immunotherapy on the T-cell cytokine pattern of allergic reactions, we studied interleukin-4 (IL-4) and interferon-gamma (IFN-gamma) mRNA expression of peripheral T lymphocytes from 12 patients undergoing rush venom desensitization, before treatment at Day 0 (D0), at Day 15 (D15) and Day 90 (D90) after treatment, and from seven controls. Antigen-specific T-cell proliferation was also determined. Cytokine mRNA expression was evaluated using in situ hybridization, 24 hr after culture of peripheral T cells with medium, venom, or an unrelated allergen. Allergen-induced T-cell proliferation decreased at D15 and D90 of rush immunotherapy (P < or = 0.02). In venom-stimulated cultures of the patient group, there was a decrease in IL-4 mRNA-positive cells at D15 and D90 (P < or = 0.001). Before desensitization, IFN-gamma mRNA expression was lower in patients than in controls and did not increase after in vitro allergen stimulation. In contrast, after immunotherapy, spontaneous IFN-gamma mRNA expression increased, but only at D90 (P < or = 0.001). The cytokine pattern observed at D90 after immunotherapy was similar to that observed in control subjects. In conclusion, venom immunotherapy induced an altered cytokine mRNA pattern in allergen-stimulated T cells which was dissociated from the early changes of allergen-induced T-cell responsiveness.

Adolescent↗
PubMed1996

Xp pseudoautosomal gene haploinsufficiency and linear growth deficiency in three girls with chromosome Xp22;Yq11 translocation.

Colony stimulating factor-2 receptor alpha (CSF2RA) and interleukin-3 receptor alpha (IL3RA), two genes from the chromosome Xp and Yp pseudoautosomal region (PAR), have been suggested as candidate genes for short stature in Turner syndrome. We report three girls with X;Y translocation (46,X,der(X)t(X;Y)(p22;q11) initially detected by amniocentesis. The terminal portion of the X chromosome distal to the translocation breakpoint at Xp22 was deleted on the derivative X chromosome in all three patients. Each had normal stature at birth, with greater than expected deceleration of growth velocity by the second year. Using fluorescence in situ hybridisation (FISH), we have shown deletion of the CSF2RA and IL3RA loci on the derivative X chromosomes of all three patients. The role of CSF2RA and IL3RA haploinsufficiency in linear growth and final adult stature is discussed. Additional studies, particularly of molecular deletions within the PAR, are needed to improve our understanding of the role of these and other PAR loci in the genetic control of adult stature.

Adolescent↗
PubMed1996

Timing of exogenous surfactant administration in a rabbit model of acute lung injury.

The purpose of this study was to evaluate early vs. late administration of exogenous surfactant in an adult rabbit model of acute lung injury. Lung injury was induced by repetitive whole lung saline lavage and subsequent mechanical ventilation. Bovine lipid extract surfactant was instilled either 1 (Early) or 4 h (Late) after the last lavage. Animals were monitored for 7 h after the last lavage. Although arterial PO2 values increased significantly immediately after treatment in both the Early and Late groups, this improvement was not sustained in the Late group. There was also a higher incidence of pneumothoraxes in the Late group vs. both the Early group and a nontreated control group. The ratio of poorly functioning small surfactant aggregates to superior functioning large aggregates was higher in the Late group compared with the Early group. Morphological analysis revealed that early surfactant treatment prevented the progression of lung injury over time. We conclude that administration of exogenous surfactant at an early time point in lung injury resulted in superior responses compared with later treatments.

Animals↗