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Biomedical subjects

J Lederer

Publications and source records attributed to J Lederer.

At least 19 recordsLinked to original sources
PubMed1998

Clonally expanded Valpha12+ (AV12S1),CD8+ T cells from a patient with rheumatoid arthritis are autoreactive.

OBJECTIVE: Previously, we showed that 15-20% of patients with rheumatoid arthritis (RA) have oligoclonal expansions of peripheral blood CD8+ T cells expressing T cell receptors encoded by the V(alpha)12 (AV12S1) gene. To better understand the significance of these expansions, the present study was undertaken to determine their specificity. METHODS: We cloned and characterized V(alpha)12+,CD8+ T cells from the peripheral blood of 1 RA patient with a clonal expansion of these T cells. RESULTS: The T cell clones were autoreactive since they recognized autologous, but not allogeneic, antigen-presenting cells. Upon activation, these T cells secreted interleukin-4 and interleukin-10. The autoreactive T cell clones were class I major histocompatibility complex (MHC) restricted, by either HLA-B60 or HLA-Cw3. CONCLUSION: A large population of class I MHC-restricted CD8+ T cells in a patient with RA is clonally expanded and autoreactive. These cells define a novel immune aberration in RA and provide a tool for defining the autoantigens that activate expanded T cell populations in vivo.

Amino Acid Sequence↗
PubMed1997

MRC OX-2 defines a novel T cell costimulatory pathway.

T cell activation requires the engagement of the TCR as well as a second, costimulatory signal. In this study, we demonstrate that MRC OX-2 (OX-2) mediates a previously unrecognized T cell costimulatory signal leading to enhanced T cell proliferation. One extensively studied costimulatory pathway, the B7/CD28 pathway, delivers its signal when CD28 is engaged by either of two ligands, B7-1 or B7-2, expressed on APC. Recent data have suggested that an additional ligand may exist in this pathway. This possibility prompted us to search previously cloned genes with both structural and expression characteristics similar to B7-1 and B7-2. Our search yielded OX-2, a rat lymphocyte activation marker, as a promising candidate gene. We now report that Chinese hamster ovary cell transfectants expressing the OX-2 protein can costimulate murine CD4+ T cells to proliferate in an Ag-independent fashion using anti-CD3, as well as an Ag-dependent fashion using peptide. In contrast to B7-1-mediated costimulation, OX-2 does not result in detectable levels of IL-2, IL-4, or IFN-gamma. In addition, OX-2 transfectants do not bind the soluble receptor reagents of the B7/CD28 pathway (CD28-Ig and CTLA4Ig). Furthermore, OX-2 costimulation is not inhibited by CTLA4Ig, as is B7-1-mediated costimulation, but is readily inhibited with an anti-OX-2 mAb. Thus, OX-2 is a T cell costimulatory ligand that acts through a non-B7/CD28 pathway, which leads to functionally distinct consequences, as reflected by the resulting cytokine profile.

Amino Acid Sequence↗
PubMed1996

Interleukin-12 treatment restores normal resistance to bacterial challenge after burn injury.

BACKGROUND: Preliminary studies in this laboratory have shown that treatment with interleukin-12 (IL-12), a cytokine that induces expression of the T-helper-1 lymphocyte phenotype, in an animal model of burn injury increased survival after a septic challenge. The purpose of this study was to define the efficacy of IL-12 therapy and to explore its mechanism of action. METHODS: Adult male A/J mice were subjected to 25% full-thickness scald or sham burn. Starting on day 3 after burn, groups of mice received five daily injections of IL-12, interferon-gamma (IFN-gamma), or saline solution. Some animals received anti-IFN-gamma monoclonal antibody. At day 10 most animals underwent cecal ligation and puncture (CLP) and were observed for survival. Some animals were killed at day 10, and CD4-enriched splenocytes were stimulated with anti-CD3 antibody or concanavalin A and were studied for cytokine production and mRNA expression. RESULTS: IL-12 treatment, 25 ng daily for 5 days, increased survival of the burn group after CLP to that of the sham burn control group. Anti-IFN-gamma antibody, 500 micrograms, administered 1 day before IL-12 treatment, reduced the efficacy of IL-12. IFN-gamma treatment, 7000 units, moderately increased survival. IL-12 had no effect on survival of the sham burn group. At the time of CLP IL-12 therapy had induced a marked decrease in CD4+ lymphocyte IL-4 and a moderate increase in IFN-gamma production and mRNA expression without affecting IL-2. CONCLUSIONS: IL-12 is the most effective therapy so far tested in this burn plus CLP model. It acts at least in part through IFN-gamma. However, IFN-gamma therapy was not as effective as IL-12.

Animals↗
PubMed1995

The development of family medicine in Israel.

Israeli family medicine provides an example of the accelerated development of a new discipline. This development occurred in a highly dynamic and rapidly growing society against a background of conflicting cultural traditions within the health care field. The developmental stages included: 1) the preponderance of specialists over generalists, 2) the introduction of family medicine teaching into the undergraduate medical curriculum, 3) the achievement of family medicine's independence from the status of a branch of internal medicine or community medicine, 4) the development of the residency training programs, and 5) the establishment of a national academic infrastructure. This paper analyzes the unsolved problem of gaining significant numbers of university academic appointments. Also, two major challenges for the future are examined: 1) the integration of preventive care into family practice, and 2) the exposure of primary care to competition from hospital-based specialists in an atmosphere of increasing commercialism. The Israeli experience forms a basis for comparison for family medicine in other countries.

Cross-Cultural Comparison↗
PubMed1994

Differentiation of the T helper phenotypes by analysis of the methylation state of the IFN-gamma gene.

Th1 and Th2 CD4+ T cell clones have been defined by their ability to produce different lymphokines. However, the processes by which CD4+ T cells differentially regulate lymphokine gene expression have not been well defined. In this report, we demonstrate that the methylation status of a CpG dinucleotide contained within a TATA proximal regulatory element of the IFN-gamma promoter correlates with the transcription of the gene. In murine Th1 clones and two human CD4+ Th0 clones, this site is either completely or partially hypomethylated, whereas in murine Th2 clones this site is > 98% methylated. Treatment of murine Th2 clones with 5-azacytidine, an agent that inhibits methylation of the DNA, converts these cells to IFN-gamma producers. Additional targets for methylation outside the transcriptional control regions of the IFN-gamma genetic locus were found to be hypomethylated in Th2 cells but not in Th1 cells. Electrophoretic mobility shift assays (EMSA) revealed at least five distinct protein-DNA complexes that are formed with an oligonucleotide containing the IFN-gamma promoter TATA proximal regulatory element, and in vitro methylation of this site results in a loss of these three complexes. Furthermore, a comparison of nuclear extracts prepared from Th1 and Th2 clones revealed that the EMSA patterns were qualitatively similar but differed quantitatively. In addition, transient transfection of a murine IFN-gamma promoter-chloramphenicol acetyl transferase (CAT) gene construct into both Th1 and Th2 clones produced CAT activity that was not inducible by anti-CD3, indicating that hypomethylation per se of the promoter alone is not sufficient for inducible gene expression.

Animals↗
PubMed1993

Characterization and identification of interleukin-1 receptors on bovine fibroblasts.

Interleukin-1 (IL-1), a pro-inflammatory cytokine, initiates its many biological effects by first binding to cell-surface receptors. Prior to this study, there were no published reports addressing the nature of the bovine IL-1 receptor. In this study, we characterized and identified cell-surface IL-1 receptors on bovine fibroblasts. Direct binding studies using [125I]-labeled bovine IL-1 beta demonstrated that bovine fibroblasts had approximately 130 high affinity and 2,500 low affinity binding sites (Kd = 4.9 x 10(-11) M and 3.7 x 10(-9) M, respectively). Competitive binding studies using unlabeled recombinant bovine IL-1 beta, IL-2, IFN-alpha, and bovine insulin demonstrated that only unlabeled bovine IL-1 beta competitively blocked fibroblast binding of [125I]-labeled bovine IL-1 beta. Affinity cross-linking of [125I]-labeled IL-1 beta to fibroblasts demonstrated that IL-1 receptors on bovine fibroblasts have an apparent M(r) of 71.5 kD. This report provides the first characterization and identification of IL-1 receptors on bovine fibroblasts.

Animals↗
PubMed1993

Prevalence of antibodies to Toxoplasma gondii in the Tel-Mond area.

Sera from 1,315 inhabitants of the Tel-Mond area were tested by the indirect immunofluorescent and Sabin Feldman tests for Toxoplasma antibodies. The overall prevalence of antibodies was 29.3%. Antibodies rose with age from 9.9% in the 1-4 year age-group up to 40.9% in the 45 age-group. There was no significant difference in prevalence of antibodies between the sexes. The prevalence of antibodies to Toxoplasma was lower in those born in Israel (21.2%) than in immigrants from Europe, America, Australia (49.4%), and Africa, Asia (40.8%) in the age groups of 20-45+. An extremely high prevalence of antibodies (41.5%) was found in Moshav Porat, a low socioeconomic settlement.

Adolescent↗
PubMed1991

The use of a self-report questionnaire to assess the frequency of sexual dysfunction in family practice clinics.

The epidemiology of sexual dysfunction has been investigated recently in various clinical and nonclinical conditions but, to date, little research has been conducted in the family practice setting. The authors have developed a brief self-report questionnaire addressing most of the common sexual problems, and assessed its usefulness as a screening device in two distinctly different family practice clinics. The proposed questionnaire has gained over 90% response rate in each practice, indicating an appropriate level of acceptability. The sex- and practice-specific prevalence ranged from 31% to 63%, and was found to be significantly higher among male patients than among female patients. Overall dissatisfaction with the present sexual life of either the respondent or his partner (as indicated by the former) was expressed by nearly 20% of the respondents, the majority of whom reported on both self and partner's dissatisfaction. Relatively few patients of those who reported on a sexual problem had ever sought any professional help, but approximately 50% of men and 25% of women indicated that the family physician was their preferred expert for this purpose. It is concluded that sexual dysfunction is highly prevalent in the family practice setting but is nevertheless under-reported. Anonymous screening in one's practice, as presented in this study, will provide the family physician with valuable information, and may contribute to further direct discussions of these delicate concerns.

Adolescent↗
PubMed1990

Asthenic symptoms in a rural family practice. Epidemiologic characteristics and a proposed classification.

Asthenic symptoms (eg, fatigue, lassitude, weakness) are of major concern in family practice setting, yet relatively little research has addressed this issue. A retrospective chart review over a 10-year period was conducted to better characterize these symptoms in a rural family practice providing health care to 508 adult patients. Asthenic complaints were recorded at least once in the medical charts of 164 patients (32%) with a preponderance of female patients. Peak prevalence occurred in the third decade of age and during the summer months. Associated symptoms, mainly pain and dizziness, were reported in 75% of the cases. A cause or diagnosis was not identified by the practicing physician in nearly 50% of the encounters; nevertheless, most episodes resolved spontaneously. Patients could be subclassified into three categories according to the recurrence pattern of their asthenic symptoms during the study period. The largest category (64%) included patients who had a single or two episodes and was thus termed "episodic asthenia." Forty-five patients (27%) with recurrent episodes (mean 4.4, range 3 to 10) were classified as having "recurrent episodic asthenia." A third small group (14 patients, 9%) with persistent complaints over the years but no evidence of the chronic fatigue syndrome were classified as having "chronic persistent asthenia." The proposed classification may help future research of asthenic symptoms in the family practice setting.

Adult↗
PubMed1989

[The problem of the prevention of selenium deficiency in Belgium].

In Belgium the dietary intake of selenium is moderately insufficient. It is in the neighbourhood of the minimum of the recommended allowance. The administration of selenium supplements to healthy Belgian adults favorably modifies biological indices: plasma Se, glutathione peroxidase activity of plasma and thrombocytes. A supplement of 100 micrograms/d is adequate, in salt or in cereals grown with enriched fertilizer.

Adolescent↗
PubMed1987

Glucose homeostasis in magnesium-deficient rats.

Glucose homeostasis was studied in rats fed diets containing 750,200, or 100 mg/kg Mg for 6 to 8 weeks, from the age of 4 weeks. Weight gain of the rats receiving 200 and 100 mg/kg diets was decreased. This resulted from both a lower food intake and reduced effectiveness of the ingested food. Fed or fasting plasma glucose levels were similar in the three groups. During an intravenous glucose tolerance test, the rate of glucose disappearance was higher in Mg 100 rats than in controls. By contrast, during an oral glucose tolerance test, the rise in plasma glucose was greater and more sustained in Mg 100 rats. During both tests, the insulin response was markedly lower in Mg-deficient rats than in controls. This could be partially due to the reduced insulin content of the pancreas of these animals. The impairment of tolerance to oral glucose was corrected by 5 weeks on a high-Mg diet. After intravenous injection of insulin, the fall in plasma glucose levels was also slightly more pronounced in Mg 100 rats. During no test did we observe a significant difference between glucose or insulin responses in Mg 200 or Mg 750 rats. These results, thus, show that chronic Mg deficiency alters several parameters of glucose homeostasis in the rat.

Animals↗
PubMed1984

[Ocular lesions induced by saccharin and its pollutants in the rat fetus].

The authors analyze and compare the teratogenic effects produced on the embryo eyes of rats by Maumee saccharin, by non purified Remsem saccharin and several pollutants. The study has been made on 2708 embryos of rats whose mothers have received per os several pollutants at several rates; 16 diets have been studied. The histological lesions are described: the cataract, the retinal coloboma, the major microphthalmos, the anophthalmos, the presence of aberrant nervous fibers, the anarchic globes. The authors describe the retinal eversion phenomenon in the retinal coloboma as well as its repercussion on the ocular malformations (retinal dysplasia and colobomatous cyst of the orbit). The presence of aberrant nervous fibers inside the retinal coloboma could explain the cases of double papilla, which were observed in clinic. The major microphthalmia are frequent. The serious anophthalmia are explained by an early perturbation of the embryogenesis. The anarchic globes could be interpreted as a form of congenital cystic eye. Under the different pollutants of the saccharin, four of them are more toxic: it is the ortho-sulfobenzoic acid, the para-sulfobenzoic acid, the para-sulfamolybenzoic acid, the para-toluenesulfonamide which communicate the Remsen saccharin its teratogenic effect. On the other hand, the ortho-toluene sulfonamide is without any teratogenic effect. The authors conclude on the necessity of a large purity of the commercial saccharin.

Animals↗