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Biomedical subjects

M Humbert

Publications and source records attributed to M Humbert.

At least 145 records · Page 8Linked to original sources
PubMed1996

Distribution of ligand-occupied alpha IIb beta 3 in resting and activated human platelets determined by expression of a novel class of ligand-induced binding site recognized by monoclonal antibody AP6.

The sequence beta (3)203-228 is involved, in a yet undetermined manner, in alpha IIb beta 3 function. We now show that murine monoclonal antibody (MoAb) AP6, specific for beta (3)211-221, binds to alpha IIb beta 3 on adenosine diphosphate (ADP)-activated platelets only when the receptor is occupied by intact fibrinogen. The ligand-induced binding-site reported by AP6 is unique in that it is not expressed following occupancy by either RGD peptides or the gamma-chain carboxy-terminal dodecapeptide. Binding of AP6 to platelets coincides temporally with the binding of the MoAb 9F9, specific for a receptor-induced binding site on fibrinogen. Thus, AP6 reports the binding of fibrinogen to the recognition pocket of alpha IIb beta 3. Its binding to thrombin-stimulated washed platelets correlates with secretion as determined using an MoAb to P-selectin. When ultrathin sections of nonactivated platelets were examined by immunogold staining and electron microscopy, AP6 identified a pool of alpha IIb beta 3 colocalizing with P-selectin and suggesting the presence of alpha IIb beta 3-ligand complexes in the alpha-granule membrane. There was little binding of AP6 to surface alpha IIb beta 3 of unstimulated platelets. After ADP-induced activation, AP6 was abundantly distributed over the entire platelet surface, including pseudopods, but only when fibrinogen was present in the medium. ADP had little effect on AP6 reactivity within platelets. This contrasted with washed platelets and thrombin, where extensive AP6 binding was observed within internal membrane pools as early as 10 to 15 seconds after stimulation. Surface labeling with AP6 followed slower kinetics. Flow cytometry on Triton X-100 permeabilized fixed platelets confirmed AP6 binding to alpha IIb beta 3 within the platelet. Thus, our results provide evidence of (1) a pool of alpha-granule alpha IIb beta 3 occupied by ligand in nonactivated platelets; (2) thrombin-induced activation of alpha IIb beta 3 within the platelet, and (3) thrombin-induced mobilization of ligand-bound alpha IIb beta 3 to the surface.

Adenosine Diphosphate↗
PubMed1996

Intrapulmonary production of RANTES during rejection and CMV pneumonitis after lung transplantation.

RANTES (regulated upon activation, normally T expressed and secreted) is a chemoattractant for macrophages, memory T lymphocytes, and eosinophils. We investigated whether intrapulmonary production of the chemokine RANTES contributes to the recruitment of immune cells during lung transplantation complications. RANTES concentration was measured in bronchoalveolar lavage (BAL) fluids using an ELISA assay. It was significantly higher during CMV pneumonitis (36.2 +/- l6 pg/ml, n=12, P=0.031) and allograft rejection (31.1 +/- 8.5 pg/ml, n=27, P=0.013) than in patients without complications (9.1 +/- 2.3 pg/ml, n=22). At least some of the RANTES was produced by lung macrophages: BAL macrophages cultured for 24 hr spontaneously released larger amount of RANTES during CMV pneumonitis (140 +/- 53 pg/ml, n=8, P=0.002) and allograft rejection (84 +/- 44 pg/ml, n=11, P=0.037) than in control patients (15.2 +/- 6.5 pg/ml, n=21). Moreover, macrophages in transbronchial biopsies were labeled by an anti-RANTES mAb. RANTES production by BAL macrophages was followed in 2 patients with CMV pneumonitis. It remained high as long as CMV-induced cytopathic effects or clinical symptoms were present, but it returned to baseline as the infection was controlled. These results suggest that the intrapulmonary production of the chemokine RANTES by activated macrophages contributes to the intrapulmonary accumulation of immune cells during complications of lung transplantation.

Antiviral Agents↗
PubMed1996

Visualization of activation-dependent epitopes on glycoprotein IIb-IIIa complexes of platelets stimulated by thrombin: immunogold staining of ultrathin sections.

An immunoglobulin M monoclonal antibody (IgM MAb; AP-6) recognizing the sequence 211-221 of glycoprotein (GP) IIIa enabled a study of the distribution of this epitope on unstimulated or thrombin-activated platelets. Flow cytometry was used to evaluate the expression of this epitope on platelets and immunogold staining on ultrathin sections to analyze its distribution within the cell. There was little or no binding of AP-6 to unstimulated platelets, but immunogold staining showed labeling associated with the membranes of alpha-granules. The binding of AP-6 to thrombin-stimulated platelets was compared with that of anti-RIBS MAbs and antifibrinogen polyclonal antibodies. An increased expression of the AP6 epitope was observed on membranes of the surface-connected canalicular system and at the periphery of the cell as early as 10 to 15 seconds after platelet activation by thrombin. At the same time, binding of anti-RIBS MAbs confirmed that at least part of the endogenous fibrinogen had left the alpha-granules and was bound to platelet membranes. Staining with polyclonal antifibrinogen antibody also revealed fibrinogen in vesicles resulting from granule fusion. Rapidly, the pool of internal membranes with bound fibrinogen became exposed to the outside of the platelet, a process involving the unfolding of membranes and pseudopod formation. Our results provide evidence that activation of GP IIb-IIIa and binding of fibrinogen to platelet membranes can occur before their expression at the platelet surface. They also suggest the presence of an alpha-granule pool of GP IIb-IIIa linked to fibrinogen in unstimulated platelets.

Antigens, Human Platelet↗
PubMed1996

Contrasting effects of IL-4, IL-10 and corticosteroids on RANTES production by human monocytes.

RANTES is a chemokine produced in delayed-type hypersensitivity (DTH) and allergic reactions, in which it may contribute to the recruitment of immune cells. Macrophages participate in the cellular infiltration in both conditions and they represent a potent source of RANTES. To understand the regulation of RANTES production by human monocytes, we analyzed the effect of cytokines and of corticosteroids on this production. We showed that IFN-gamma and tumor necrosis factor (TNF)-alpha cooperated to induce RANTES production by monocytes. N-acetylcysteine inhibited this effect, indicating that reactive oxygen intermediates are required for RANTES production. Both IL-10 and corticosteroids antagonized the stimulating effect of IFN-gamma and TNF-alpha on RANTES production. In contrast, IL-4 had no effect on IFN-gamma-induced RANTES production and it potentiated the positive effect of TNF-alpha on this production. Thus, the deactivating properties of IL-10 and corticosteroids on macrophage functions include RANTES production, and this may contribute to the immunosuppressive effect of both compounds in DTH and allergic reactions. In contrast, IL-4 has an opposite effect on RANTES production and this property may contribute to cell recruitment in allergic reactions. Therefore, although IL-10 and IL-4 belong to the Th2 family of cytokines, they can display distinct functions in immune reactions.

Acetylcysteine↗
PubMed1996

Safety of fibreoptic bronchoscopy in asthmatic and control subjects and effect on asthma control over two weeks.

BACKGROUND: Concerns remain about the safety of bronchoscopy in asthma and there are few data on the effect of this procedure on asthma control in the days or weeks following bronchoscopy. METHODS: In an initial study of bronchoalveolar lavage and bronchial biopsies in asthmatic and control subjects, data on peak expiratory flow rates (PEFR) collected prospectively before and after the procedure were available from 21 of the 29 asthmatic subjects studied. These showed a median 23% fall in PEFR from baseline after bronchoscopy (range 3-58%). To determine whether this fall in PEFR following bronchoscopy reflected bronchospasm or the effect of sedation, PEFR and spirometric tests were performed during the two hours following bronchoscopy in a further study of 15 symptomatic asthmatic subjects and 20 non-asthmatic controls. To examine the effect on asthma control, asthmatic patients recorded PEFR, symptom scores, and medication use for two weeks before and after bronchoscopy. RESULTS: After bronchoscopy with bronchial biopsies there was no difference between the median maximal fall in either PEFR or arterial oxygen saturation between the 15 asthmatic patients (10.4% and 4%, respectively) and 20 controls (12% and 3%). Moreover, there were no significant changes in PEFR, symptom score, or medication use by the asthmatic subjects in the two weeks after bronchoscopy when compared with the two weeks before bronchoscopy. CONCLUSIONS: Fibreoptic bronchoscopy is well tolerated in asthmatic subjects. Falls in PEFR in both asthmatic and non-asthmatic subjects after bronchial biopsy may reflect the effects of sedation rather than bronchospasm. Additional bronchoalveolar lavage may cause bronchoconstriction. Careful monitoring is therefore essential. Peak flow monitoring up to two weeks after bronchoscopy with bronchial biopsy revealed no delayed effects on asthma control.

Adolescent↗
PubMed1996

Ultrastructural studies of platelet aggregates from human subjects receiving clopidogrel and from a patient with an inherited defect of an ADP-dependent pathway of platelet activation.

Our study investigated the effect of the antithrombotic drug clopidogrel (75 mg/d for 7 days) on the ultrastructure of platelet aggregates induced by ADP or 2-methylthio-ADP (2-MeS-ADP) in citrated platelet-rich plasma and examined the activation state of the GP IIb/IIIa complexes. Results were compared with those obtained for patient M.L., who has a congenital disorder characterized by a reduced and reversible platelet response to ADP. When untreated normal platelets were stimulated with high-dose ADP, electron microscopy revealed large and stable aggregates often surrounded by a layer of what appeared to be degranulated platelets. The reversible aggregates of platelets from subjects receiving clopidogrel or from patient M.L. did not show this layer. Electron microscopy showed that in both situations, the aggregates were composed of loosely bound platelets with few contact points. Immunogold labeling of ultrathin sections of Lowicryl-embedded aggregates formed by ADP or 2-MeS-ADP showed a much decreased platelet surface staining by (1) a polyclonal anti-fibrinogen antibody and (2) AP-6, a murine anti-ligand-induced binding site monoclonal antibody specific for GP IIb/IIIa complexes occupied with fibrinogen. Similar findings were seen after disaggregation, when many single platelets were present that showed no signs of secretion. Flow cytometry confirmed that the number of ligand-occupied GP IIb/IIIa complexes was much lower on platelets stimulated with ADP or 2-MeS-ADP after clopidogrel treatment. As expected from previous studies, ADP-induced platelet shape change and Ca2+ influx were unaffected by clopidogrel. These results agree with the hypothesis that platelet activation by ADP is biphasic and highlight a receptor-induced activation pathway affected by clopidogrel (or congenitally impaired in patient M.L.) that is necessary for the full activation of GP IIb/IIIa and the formation of stable macroaggregates.

Adenosine Diphosphate↗
PubMed1996

High-affinity IgE receptor (FcepsilonRI)-bearing cells in bronchial biopsies from atopic and nonatopic asthma.

Asthma is characterized by bronchial mucosal inflammation. Although allergen-induced activation of cells binding allergen-specific immunoglobulin E (IgE) through high-affinity receptors (Fc(epsilon)RI) is believed to play some role in asthma, inappropriate synthesis of total or allergen-specific IgE cannot be demonstrated in some ("intrinsic") patients despite the fact that the nature of the bronchial inflammation is similar to that in atopic ("extrinsic") asthmatics. We have studied the numbers and phenotype of Fc(epsilon)RI-bearing cells in bronchial biopsies from 12 atopic and 10 nonatopic asthmatic patients and compared our findings with 10 atopic and 12 nonatopic control subjects using single and double immunohistochemistry. Significantly increased numbers of Fc(epsilon)RI-bearing cells were identified in bronchial biopsies from atopic and nonatopic asthmatics and atopic control subjects when compared with normal controls (p = 0.001, 0.006, and 0.0006, respectively). In asthmatics and atopics the majority of Fc(epsilon)RI-bearing cells were identified as mast cells and macrophages; a much smaller percentage were eosinophils. We conclude that elevated numbers of high-affinity IgE receptor-bearing cells are a feature of bronchial biopsies of asthmatic subjects, irrespective of their atopic status.

Adult↗
PubMed1996

IL-4 and IL-5 mRNA and protein in bronchial biopsies from patients with atopic and nonatopic asthma: evidence against "intrinsic" asthma being a distinct immunopathologic entity.

Intrinsic (nonatopic) asthma is considered to be a distinct pathogenetic variant of asthma since, unlike extrinsic (atopic) asthma, patients with the disease are skin test-negative to common aeroallergens, and have total serum IgE concentrations within the normal range. Nevertheless, the recent demonstration of increased numbers of cells expressing the high-affinity IgE receptor in bronchial biopsies from atopic and nonatopic asthmatic subjects, together with epidemiologic evidence indicating that serum IgE concentrations relate closely to asthma prevalence regardless of atopic status, suggests that IgE-mediated mechanisms may participate in the pathogenesis of both atopic and nonatopic asthma. Furthermore both variants of the disease are associated with bronchial mucosal eosinophilic inflammation. Interleukin-4 (IL-4) is an essential cofactor for IgE synthesis, and there is strong evidence that IL-5 plays a major role in eosinophil accumulation in asthmatic inflammation. For these reasons we compared the expression of IL-4 and IL-5 mRNA and protein product using a semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR) amplification, in situ hybridization, and immunohistochemistry in bronchial biopsies from symptomatic atopic and nonatopic asthmatic subjects and atopic and nonatopic controls. The results showed that as compared with controls, biopsies from both groups of asthmatic subjects had increased numbers of IL-4 and IL-5 mRNA copies relative to beta-actin mRNA as detected by RT-PCR. Similarly, in situ hybridization and immunohistochemistry demonstrated increased numbers of cells expressing IL-4 and IL-5 mRNA and protein in asthmatic subjects, irrespective of their atopic status. We conclude that individuals with either atopic or nonatopic asthma show infiltration of the bronchial mucosa with cells expressing Th2-type cytokines, providing further evidence for similarities in the immunopathogenesis of these clinically distinct forms of asthma.

Adult↗
PubMed1996

Increased expression of mRNA encoding RANTES and MCP-3 in the bronchial mucosa in atopic asthma.

The selective recruitment of eosinophils into the mucosal lining of the airways is a prominent feature of atopic asthma, and is believed to be an important component in the disease pathogenesis. The precise stimuli responsible for the influx of eosinophils remain unclear. Using a semiquantitative reverse transcriptase polymerase chain reaction (RT-PCR) technique, the numbers of copies (relative to the "housekeeping" gene beta-actin) of messenger ribonucleic acid (mRNA) encoding the eosinophil-active chemotactic cytokines, the factor regulated upon activation in normal T-cells expressed and secreted (RANTES) and monocyte chemotactic protein-3 (MCP-3), was measured in bronchial biopsies from atopic asthmatic patients (n = 9), and compared with atopic nonasthmatic (n = 8) and nonatopic nonasthmatic (n = 8) control subjects. In addition, further biopsies from each subject were prepared for immunohistochemistry and the numbers of activated (EG2+) eosinophils measured. The expression of RANTES mRNA was significantly elevated in the atopic asthmatic group as compared to the atopic nonasthmatic controls (p = 0.013) and the nonatopic nonasthmatic controls (p = 0.007). Similarly, the expression of mRNA encoding MCP-3 was significantly elevated in the atopic asthmatic group, relative to the atopic nonasthmatic controls (p = 0.014) and the nonatopic nonasthmatic control group (p = 0.011). Elevated RANTES and MCP-3 mRNA expression was associated with significantly increased numbers of bronchial mucosal eosinophils in the atopic asthmatic patients as compared to the atopic nonasthmatic (p = 0.03) and nonatopic nonasthmatic (p = 0.006) control subjects. In conclusion, we have identified elevated expression of messenger ribonucleic acid encoding RANTES and monocyte chemotactic protein-3 in the bronchial mucosa of atopic asthmatic patients relative to controls. These findings are compatible with the hypothesis that eosinophil-active beta-chemokines play a role in the mechanism of eosinophil recruitment to the asthmatic bronchial mucosa.

Actins↗
PubMed1996

[Cytomegalovirus infection and allograft rejection].

Allograft rejection and human cytomegalovirus (HCMV) infections are two major complications of allotransplantation. HCMV infection could promote allograft rejection through different mechanisms including the production of several proinflammatory cytokines, increased expression of major histocompatibility complex and adhesion molecules, and molecular mimicry. Similarly immune activation occurring during allograft rejection, its treatment and its prevention budget increases rates of HCMV disease. A better understanding of the links between allograft rejection and HCMV infection is necessary to develop new preventative or curative therapeutic approaches which could improve allotransplantation results in humans.

Cell Adhesion Molecules↗
PubMed1995

The kinetics of allergen-induced transcription of messenger RNA for monocyte chemotactic protein-3 and RANTES in the skin of human atopic subjects: relationship to eosinophil, T cell, and macrophage recruitment.

The C-C chemokines RANTES and monocyte chemotactic protein-3 (MCP-3) are potent chemoattractants in vitro for eosinophils and other cell types associated with allergic reactions. We tested the hypothesis that the allergen-induced infiltration of eosinophils, T cells, and macrophages in the skin of atopic subjects is accompanied by the appearance of mRNA+ cells for RANTES and MCP-3. Cryostat sections were obtained from skin biopsies from six subjects 6, 24, and 48 h after allergen challenge. Tissue was processed for immunocytochemistry (ICC) and for in situ hybridization using 35S-labeled riboprobes for RANTES and MCP-3. In contrast to diluent controls, allergen provoked a significant increase in mRNA+ cells for MCP-3, which peaked at 6 h and progressively declined at 24 and 48 h. This paralleled the kinetics of total (major basic protein positive [MBP]+) and activated (cleaved form of eosinophil cationic protein [EG2]+) eosinophil infiltration. The allergen-induced expression of cells mRNA+ for RANTES was also clearly demonstrable at 6 h. However, the numbers were maximal at 24 h and declined slightly at the 48-h time point. The number of mRNA+ cells for RANTES paralleled the kinetics of infiltration of CD3+, CD4+, and CD8+ T cells whereas the number of CD68+ macrophages was still increasing at 48 h. These data support the view that MCP-3 is involved in the regulation of the early eosinophil response to specific allergen, whereas RANTES may have more relevance to the later accumulation of T cells and macrophages.

Adult↗
PubMed1995

Secretion of the eosinophil-active cytokines interleukin-5, granulocyte/macrophage colony-stimulating factor and interleukin-3 by bronchoalveolar lavage CD4+ and CD8+ T cell lines in atopic asthmatics, and atopic and non-atopic controls.

Specific eosinophil accumulation and activation within the asthmatic bronchial mucosa are thought to occur at least partly through the actions of cytokines, including interleukin (IL)-5, IL-3 and granulocyte/macrophage colony-stimulating factor (GM-CSF). Although mRNA encoding some of these cytokines has been demonstrated in bronchoalveolar lavage (BAL) fluid cells and bronchial biopsies from asthmatics, it has yet to be established whether these cells produce the translated products and whether expression is associated with CD4+ T helper or CD8+ cytotoxic T cells. We addressed this problem by raising polyclonal CD4+ and CD8+ T cell lines from the BAL fluid of six atopic asthmatics, five atopic non-asthmatics and seven non-atopic non-asthmatic controls. BAL fluid cells obtained at fiberoptic bronchoscopy were depleted of adherent cells, and then T lymphocytes expanded by stimulation with monoclonal anti-CD3 antibody and recombinant human IL-2. When lymphocytes had expanded to sufficient numbers, CD4+ and CD8+ cells were separated by positive selection with magnetic beads coated with anti-CD4 or anti-CD8 monoclonal antibodies and further expanded. Cytokine secretion by standardized cell numbers was measured by enzyme-linked immunosorbent assays. BAL CD4+ T cell lines from the asthmatics secreted significantly elevated quantities of both IL-5 and GM-CSF as compared with lines from the atopic and non-atopic controls (p = 0.023-0.003). In contrast, IL-3 secretion did not significantly differ between the groups. In some subjects, CD8+ T cell lines also secreted significant quantities of these cytokines and there was a trend for IL-5 secretion by these cells to be higher in asthmatics than non-atopic controls (p = 0.035). These data are consistent with the hypothesis that activated T lymphocytes from asthmatics, particularly of the CD4+ subset, are predisposed to release elevated quantities of cytokines relevant to the accumulation and activation of eosinophils.

Adult↗
PubMed1995

Confirmation that GP Ib-IX complexes have a reduced surface distribution on platelets activated by thrombin and TRAP-14-mer peptide.

In 1990 we reported that GP Ib-IX complexes accumulated within the surface-connected canalicular system (SCCS) of thrombin-stimulated platelets. This conclusion was reached following investigations using monoclonal antibodies (MAbs) in flow cytometry and a polyclonal antibody to GP Ib alpha in electron microscopy with immunogold staining performed on ultrathin sections of resin-embedded platelets. Recent controversy concerning these results has prompted us to perform further studies using 14 anti-GP Ib-IX MAbs obtained from the 1993 Boston Workshop on Leukocyte Antigens. Features were the use of the MAbs in mixtures and the fact that immunogold staining was performed on frozen thin sections. Platelets were stimulated with either alpha-thrombin or TRAP-14-mer peptide. In all cases a decreased density of GP Ib-IX complexes on exposed areas of the activated platelet surface was accompanied by an increased expression within the SCCS. At the same time we noted that when platelets were stimulated with TRAP-14-mer they progressively exhibited a different internal morphology in comparison to that seen with thrombin. In particular, the dense central mass disappeared and large vacuoles were present throughout the cytoplasm. Overall, these studies confirm that changes in the distribution of GP Ib-IX complexes which follow thrombin-induced platelet activation (i) are indeed observed when antibody mixtures are used to detect them, and (ii) are mediated through the receptor recognized by the TRAP-14-mer peptide.

Blood Platelets↗
PubMed1995

Increased interleukin-1 and interleukin-6 serum concentrations in severe primary pulmonary hypertension.

Primary pulmonary hypertension (PPH) is characterized by the proliferation of smooth-muscle cells, fibroblasts, and endothelial cells in the walls of small pulmonary arteries. In order to evaluate a role for proinflammatory cytokines in this process, we studied the concentration of interleukin-1 beta (IL-1 beta), IL-6, and tumor necrosis factor-alpha (TNF alpha) in the serum of 29 patients with severe PPH referred to our center for lung transplantation. Results were compared with those obtained in 15 normal controls and nine patients with pulmonary hypertension secondary to chronic obstructive pulmonary disease (COPD-PH). TNF alpha serum levels were within the normal range in each group. This contrasted with increased IL-1 beta serum levels in severe PPH (118 +/- 36 pg/ml, mean +/- SEM) as compared with controls (3 +/- 1 pg/ml, p < 0.001) or COPD-PH patients (3 +/- 1 pg/ml, p < 0.001). IL-6 serum concentrations were also higher in severe PPH (66 +/- 20 pg/ml) than in controls (14 +/- 6 pg/ml, p < 0.01). This study demonstrates increased serum levels of IL-1 beta and IL-6 in severe PPH, and suggests a role for proinflammatory cytokines in PPH.

Adult↗
PubMed1994

Soluble TNF receptors (TNF-sR55 and TNF-sR75) in lung allograft recipients displaying cytomegalovirus pneumonitis.

Two distinct types of tumor necrosis factor receptors (TNF-R) have been identified (TNF-R55 and TNF-R75). Both TNF-R also exist in soluble forms (TNF-sR), resulting from the release of the extracellular domains (TNF-sR55 and TNF-sR75). TNF-sR may play an important role in vivo as they can bind to TNF alpha and prevent ligand binding to the cellular TNF-R, thus acting as naturally occurring inhibitors of TNF alpha. Sera from lung allograft recipients with cytomegalovirus (CMV) pneumonitis (12 patients) were assayed for TNF-sR55 and TNF-sR75. The concentrations were compared with those from either control lung recipients displaying neither rejection nor infection (12 patients), or lung recipients with allograft rejection (12 patients). Serum TNF-sR55 and TNF-sR75 concentrations were measured by enzyme-linked immunologic binding assay. Serum TNF-sR55 and TNF-sR75 concentrations were significantly higher during CMV pneumonitis (mean +/- SEM: 13.7 +/- 4.7 ng/ml, and 11.7 +/- 2.7 ng/ml, respectively) than during allograft rejection (3.7 +/- 0.3 ng/ml, p < 0.001, and 2.6 +/- 0.6 ng/ml, p < 0.001, respectively). They were also higher than in control subjects (3.6 +/- 0.3 ng/ml, p < 0.001, and 1.9 +/- 0.5 ng/ml, p < 0.001, respectively). Serum TNF alpha concentration was low in case of rejection or in control subjects (< 20 pg/ml). Conversely increased levels of TNF alpha were detected in the serum of six out of the 12 patients with CMV pneumonitis (p < 0.03 versus rejection and control subjects). Ganciclovir treatment of CMV pneumonitis led to a dramatic decrease of TNF alpha, TNF-sR55, and TNF-sR75 serum levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗