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Biomedical subjects

L Weiss

Publications and source records attributed to L Weiss.

At least 145 records · Page 8Linked to original sources
PubMed1995

Down-regulation of c-neu receptors by nerve growth factor in PC12 cells.

A small number of p185c-neu receptors have been found on PC12 cells. These receptors show some basal phosphorylation in quiescent cells. When the cells are treated with nerve growth factor (NGF) for a short time, some increase in phosphorylation is seen, mainly on serine and threonine residues, and this is accompanied by a slight shift in the apparent molecular weight. Epidermal growth factor (EGF) also increases the phosphorylation of p185c-neu, in this case on tyrosine residues. Neither heregulin-beta 1 nor gp30 stimulates the tyrosine phosphorylation of p185c-neu, and neither has a proliferative effect on the cells. Treatment of the cells with NGF for 5 days produces a 70-80% reduction in the number of p185c-neu receptors. This down-regulation does not occur when PC12nnr5 cells, which lack the high-affinity NGF receptor, p140trk, are treated with NGF. The level of p185c-neu mRNA is not altered by NGF treatment, suggesting that the down-regulation is due to either a translational or a posttranslational alteration.

Amino Acid Sequence↗
PubMed1995

Involvement of interleukin-2 in immunologic reconstitution following bone marrow transplantation in mice.

Allogeneic or autologous bone marrow transplantation (BMT) is a curative form of treatment for patients with a variety of hematologic disorders. Impaired immune reconstitution following BMT may seriously impede successful outcome. In this study, the immune function of spleen and thymus was investigated in mice exposed to myeloablative total-body irradiation followed by syngeneic BMT. The T cell mitogen-induced proliferation of both splenic and thymic cells was delayed. Spleen cells started to respond only after 21 days, whereas thymic cells remained unresponsive. Kinetic analysis of surface markers revealed the early appearance of spleen cells with the CD3+CD4-CD8- phenotype, and the thymus, despite a low total number of cells, displayed fast recovery of CD3+CD4+CD8+. At the level of mRNA, a mild decrease in interleukin-2 (IL-2) induction following phytohemagglutinin activation of spleen cells correlated with a decrease in IL-2 secretion for only the first 2 weeks following transplantation. The early restoration of IL-2 implies other avenues for investigation of the immune dysfunction and its correction following syngeneic BMT.

Animals↗
PubMed1995

Antiretroviral therapy suppresses the constitutive production of interleukin-1 associated with human immunodeficiency virus infection.

Interleukin (IL)-1 is constitutively produced by monocytes of human immunodeficiency virus (HIV)-seropositive persons. The changes in the production of IL-1 by monocytes of 24 HIV-infected patients were investigated during the course of 8 months of antiretroviral therapy. At month 8, the amounts of biologically active IL-1 and IL-1 alpha and -beta proteins produced by freshly obtained monocytes and by monocytes cultured for 24 h in the absence of lipopolysaccharide (LPS) decreased significantly compared with pretreatment values or decreased below the limits of detection in the assays. Antiretroviral therapy also resulted in enhanced secretion of IL-1 receptor antagonist (IL-1Ra) by LPS-stimulated patients' monocytes. The reduction in the constitutive production of IL-1 and the increased ability of stimulated cells to produce IL-1Ra associated with antiretroviral therapy may also be of importance in reducing a major pathway of amplification of viral replication in infected monocytes and lymphocytes.

Adult↗
PubMed1995

Genetic and biochemical normalization in female carriers of Duchenne muscular dystrophy: evidence for failure of dystrophin production in dystrophin-competent myonuclei.

We studied 19 symptomatic female carriers of the Duchenne muscular dystrophy (DMD) gene. Most of these dystrophinopathy patients had had an erroneous or ambiguous diagnosis prior to dystrophin immunofluorescence testing. We assessed clinical severity by a standardized protocol, measured X-chromosome inactivation patterns in blood and muscle DNA, and quantitated the dystrophin protein content of muscle. We found that patients could be separated into two groups: those showing equal numbers of normal and mutant dystrophin genes in peripheral blood DNA ("random" X-inactivation), and those showing preferential use of the mutant dystrophin gene ("skewed" X-inactivation). In the random X-inactivation carriers, the clinical phenotype ranged from asymptomatic to mild disability, the dystrophin content of muscle was > 60% of normal, and there were only minor histopathologic changes. In the skewed X-inactivation patients, clinical manifestations ranged from mild to severe, but the patients with mild disease were young (5 to 10 years old). The low levels of dystrophin (< 30% on average) and the severe symptoms of the older patients suggested a poor prognosis for those with skewed X-inactivation, and they all showed morphologic changes of dystrophy. The random inactivation patients showed evidence of biochemical "normalization," with higher dystrophin content in muscle than predicted by the number of normal dystrophin genes. Seventy-nine percent of skewed X-inactivation patients (11/14) showed genetic "normalization," with proportionally more dystrophin-positive nuclei in muscle than in blood. In 65% of the skewed X-inactivation patients, dystrophin was not produced by dystrophin-positive nuclei; an average of 20% of myofiber nuclei were genetically dystrophin-positive but did not produce stable dystrophin. Biochemical normalization seems to be the main mechanism for rescue of fibers from dystrophin deficiency in the random X-inactivation patients. In the skewed X-inactivation patients, genetic normalization is active, but production failure of dystrophin by dystrophin-normal nuclei may counteract any effect of biochemical normalization. In the skewed X-inactivation patients, the remodeling of the muscle through cycles of degeneration and regeneration led to threefold increase in the number of dystrophin-competent nuclei in muscle myofibers (3.3 +/- 4.6), while dystrophin content was on the average 1.5-fold less then expected (-1.54 +/- 3.38). Our results permit more accurate prognistic assessment of isolated female dystrophinopathy patients and provide important data with which to estimate the potential effect of gene delivery (gene therapy) in DMD.

Adult↗
PubMed1995

Evidence for a distinct region causing a cat-like cry in patients with 5p deletions.

The cri-du-chat syndrome is a contiguous gene syndrome that results from a deletion of the short arm of chromosome 5 (5p). Patients present with a cat-like cry at birth, which is usually considered diagnostic of this syndrome. Additional features of the syndrome include failure to thrive, microcephaly, hypertelorism, epicanthal folds, hypotonia, and severe mental retardation. We report on four families in which patients with 5p deletions have only the characteristic cat-like cry, with normal to mildly delayed development. The precise locations of the deletions in each family were determined by FISH using lambda phage and cosmid clones. All of the deletion breakpoints map distal to a chromosomal region that is implicated with the facial features and severe mental and developmental delay in the cri-du-chat syndrome. DNA clones mapping in the chromosomal region associated with the cat-like cry feature will be useful diagnostic tools. They will allow for the distinction between 5p deletions that will result in the severe delay observed in most cri-du-chat syndrome patients and those deletions that result in the isolated cat-like cry feature, which is associated with a better prognosis.

Adult↗
PubMed1995

The role of antibodies to IL-2 receptor and Asialo GM1 on graft-versus-leukemia effects induced by bone marrow allografts in murine B cell leukemia.

The role of various cell subpopulations involved in the graft-versus-leukemia (GVL) effect induced by allogeneic bone marrow transplantation (BMT) was investigated in (BALB/c x C57BL/6)F1 (F1) recipients, inoculated with murine B cell leukemia (BCL1), by using monoclonal murine anti-IL-2 receptor antibodies or rabbit anti-Asialo GM1 antibodies directed predominantly against murine NK cells. F1 mice with BCL1 were irradiated and reconstituted with parental (C57BL/6) bone marrow cells (BMC) or a mixture of BMC and spleen cells and treated in vivo for 10 days with anti-IL-2 receptor antibody or anti-Asialo-GM1 antibody. Both treatments lessened the GVL effects induced by the allograft and resulted in development of leukemia relapse, as documented in vivo by adoptive transfer of 10(5) spleen cells obtained from treated mice into secondary syngeneic adoptive recipients. Our data indicate that IL-2 receptor-positive T cells and possibly IL-2-activated allogeneic NK cells play a key role in inducing GVL following allogeneic BMT.

Animals↗
PubMed1994

[Idiopathic CD4 lymphocytopenia].

In healthy adults the CD4+ lymphocyte count in circulating blood is remarkably stable over a prolonged period. In patients infected with the human immunodeficiency virus (HIV) CD4 counts drop off sharply and can be used as a predictive marker of midterm outcome. However certain case reports of patients with out HIV infection, some reported as early as 1983, have led to a much publicized search for another immunosuppressive retrovirus. In reality no evidence of any such virus has been found and the Centers for Disease Control and the World Health Organisation have now defined the syndrome of idiopathic CD4 lymphocytopenia which includes a CD4 count below 300/mm3 or less than 20% of total lymphocytes in at least two successive counts without anti-HIV antibodies and without a known cause of immune deficiency or immunosuppressor treatment. The syndrome is extremely rare and although only recently identified, is probably not new. No endemic zone is known and there is no evidence of inter-human transmission. The clinical presentation is different from HIV infection. Although patients are susceptible to opportunistic infections, CD4 counts have relative stability and no hypergammaglobulinaemia occurs. Idiopathic CD4 lymphopenia is probably a primary immunodeficiency syndrome.

AIDS-Related Opportunistic Infections↗
PubMed1994

Effective graft-versus-leukemia effects independent of graft-versus-host disease after T cell-depleted allogeneic bone marrow transplantation in a murine model of B cell leukemia/lymphoma. Role of cell therapy and recombinant IL-2.

After allogeneic bone marrow transplantation (BMT) for leukemia, beneficial graft-vs-leukemia (GVL) effects are usually accompanied by potentially serious graft-vs-host disease (GVHD). Because T cell depletion is the only effective way to prevent GVHD it seems important to understand whether effective GVL can develop after BMT with T cell depletion in GVHD-free recipients. Well-established C57BL/6-->BALB/c chimeras that were free of GVHD, reconstituted with T cell-depleted allogeneic bone marrow cells, and inoculated 3 mo after BMT with a high inoculation of murine B cell leukemia (BCL1) showed no evidence of disease, whereas all control mice developed leukemia and died within 58 days. Results from adoptive transfer experiments in secondary naive BALB/c recipients indicated that all BCL1 cells were eliminated in the chimeras within 14 days. Hence, complete resistance to BCL1 developed in the chimeras despite complete tolerance to host alloantigens. The GVL effects observed in tolerant chimeras were further amplified by administration of immunocompetent allogeneic C57BL/6 spleen cells, low dose rIL-2, or both for 5 days. Our data suggest that GVL effects can develop even after T cell depletion in the absence of clinically overt GVHD and that GVL can be further amplified by rIL-2, either with or without use of additional immunocompetent donor T cells. Our data may provide the basis for new approaches to induce effective GVL after allogeneic BMT with cell therapy and rIL-2 at the stage of minimal residual disease, while avoiding early GVHD induced by the BMT procedure.

Animals↗
PubMed1994

Prevention of diabetes mellitus in non-obese diabetic mice by Linomide, a novel immunomodulating drug.

Oral administration of the synthetic immunomodulating drug quinoline-3-carboxamide (Linomide) in the drinking water to 5-week-old female non-obese diabetic (NOD) mice resulted in complete protection from insulitis and maintenance of normal glucose tolerance for over 40 weeks (impaired glucose tolerance: treated n = 2 of 18; control n = 17 of 18, p < 0.0001). Delayed administration of the drug at 16 weeks resulted in slowing of the progression to diabetes when assessed at 42 weeks (treated with diabetes n = 7 of 25; control with diabetes 25 of 43, p < 0.0234). No gross changes of immune system cell phenotype or function were observed in the Linomide-treated group. Adoptive transfer of spleen and lymph node cells from treated female NOD mice into sub-lethally irradiated male recipients failed to transfer diabetes, whereas a similar transfer of cells obtained from untreated age-matched controls resulted in diabetes in all secondary recipients (diabetes in control group n = 12 of 13; in Linomide group n = 0 of 11, p < 0.0001). Linomide pretreatment of the secondary recipients also inhibited the transfer of diabetes (diabetes in pretreated group n = 2 of 9, control group n = 12 of 13, p < 0.015), as did adoptive co-transfer of cell mixtures obtained from treated female NOD mice, free of diabetes, and from diabetic NOD female mice (diabetes in Linomide group n = 4 of 9; in control group 7 of 7, p < 0.0337).(ABSTRACT TRUNCATED AT 250 WORDS)

Adjuvants, Immunologic↗
PubMed1994

An updated review of the clinical development of coumarin (1,2-benzopyrone) and 7-hydroxycoumarin.

Several authors have demonstrated that coumarin (1,2-benzopyrone) in combination with cimetidine can produce objective antitumor responses in some patients with advanced renal cell carcinoma. The purpose of this report is to review the clinical development of coumarin, with or without cimetidine, with special reference to renal cell carcinoma (RCC). Previously unpublished data concerning the survival of a population of patients with RCC, who were treated on a phase I trial of coumarin and cimetidine, are presented. The rationale and study design of an active randomized, double-blinded, placebo-controlled trial of coumarin for RCC are discussed. A progress report is given for an ongoing phase I trial of oral 7-hydroxycoumarin, the major human metabolite of coumarin.

Adult↗
PubMed1994

Complete inherited deficiency of the fourth complement component in a child with systemic lupus erythematosus and his disease-free brother in a north African family.

Although null alleles of complement C4 genes (C4A*Q0 and C4B*Q0) are frequent in the normal population, the occurrence of two null alleles on the same chromosome is very rare and therefore complete C4 deficiency is exceptional. We describe a 16-year-old North African boy who presented with systemic lupus erythematosus with renal involvement and persistent undetectable classical pathway activity and C4 protein and hemolytic activity in plasma, with normal C3 levels. Similar complement abnormalities were observed in his healthy 12-year-old brother. Complete C4 deficiency was documented in the two brothers by investigation of the family and the lack of C4A and C4B bands upon phenotyping of C4. Southern blot analysis of the C4/CYP21 gene organization in the family indicated that the deficiency resulted from a deletion of the C4B/CYP21A genes associated with nonexpression of a C4A gene. The double-null haplotype was found to be associated with homozygous A2 B17 C2C BFF C4 AQ0 BQ0 DR7 HLA haplotype. Thus, similar C4 deficiencies with HLA identity may lead to different clinical presentations.

Adolescent↗