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Biomedical subjects

G Kaplan

Publications and source records attributed to G Kaplan.

At least 145 records · Page 8Linked to original sources
PubMed1994

GM-CSF activates regenerative epidermal growth and stimulates keratinocyte proliferation in human skin in vivo.

Granulocyte/macrophage-colony-stimulating factor (GM-CSF), an immunomodulator of hematopoietic cells, has also been shown to stimulate human keratinocyte proliferation in vitro and speed healing of wounds in the skin of lepromatous leprosy patients. In this study we have examined the in vivo effects of recombinant human GM-CSF on epidermal keratinocyte proliferation and on expression of proteins marking regenerative epidermal growth. Skin biopsies from GM-CSF injected cutaneous sites were obtained between 1 and 6 d following administration of 7.5 or 15 micrograms of the growth factor. Activation of keratinocyte proliferation, quantified as the expression of the Ki67+ nuclear antigen, was noted 1 d following GM-CSF administration. A regenerative epidermal phenotype, demonstrated by immunohistochemical staining of cellular proteins involucrin, filaggrin, and keratin 16, was similarly noted as early as 1 d following GM-CSF injection. This phenotype persisted as late as 6 d post-injection. These results suggest that GM-CSF injection into human skin induces keratinocyte proliferation as well as regenerative differentiation of the epidermis. To date no other cytokine has been shown to be mitogenic for human keratinocytes both in vivo and in vitro or to alter keratinocyte differentiation along the "alternate" or regenerative pathway.

Cell Differentiation↗
PubMed1994

Susceptibility of nonprimate cell lines to hepatitis A virus infection.

Hepatitis A virus (HAV) has been adapted to grow in primate cell cultures. We investigated replication of HAV in nonprimate cells by inoculating 20 cell lines from different species with the tissue culture-adapted HM175 strain. Slot blot hybridization and immunofluorescence analysis revealed that HAV replicated in GPE, SP 1K, and IB-RS-2 D10 cells of guinea pig, dolphin, and pig origin, respectively. Studies in IB-RS-2 D10 cells were discontinued because cultures were contaminated with classical swine fever virus. A growth curve showed that HAV grew poorly in GPE cells and intermediately in SP 1K cells compared with growth in FRhK-4 cells. Therefore, the cell surface receptor(s) and other host factor(s) required for HAV replication are present in nonprimate as well as primate cells.

Animals↗
PubMed1994

Noncompliance with family court mandated evaluations in a juvenile justice clinic.

This study identified factors correlating with noncompliance with family court ordered evaluations. Ninety charts from a juvenile justice clinic were reviewed. Subject noncompliance was defined as failure to attend three consecutive appointments. Patient, family, and environmental factors were analyzed. Forty-two percent of the subjects were noncompliant. Five variables discriminated compliant from noncompliant subjects: parental cooperation, prior criminal charge, school behavior problems, treatment at another facility, and disruptive behavior disorder. Utilizing these predictors, only 13 percent of subjects were misclassified as noncompliant in a discriminant analysis. It is concluded that a Court order by itself does not guarantee compliance with a mental health evaluation. However, the findings suggest that the risk for noncompliance may be assessed at the outset of the evaluation utilizing the above identified factors.

Adolescent↗
PubMed1993

Differences in prevalence and extent of coronary artery calcium detected by ultrafast computed tomography in asymptomatic men and women.

Coronary artery calcium is a marker of atherosclerosis in asymptomatic subjects. Ultrafast computed tomography (CT) can detect and quantify coronary calcium, simply and noninvasively, with greater sensitivity than can other techniques. The prevalence and extent of coronary calcium in a large population of asymptomatic men and women were measured and compared. Coronary calcium studies were performed in an asymptomatic population of 1,396 male and 502 female subjects (age range 14 to 88 years). The prevalence of calcium, and the distribution of total calcium scores (which reflect the amount of calcium present) were determined and compared for men and women at 5- and 10-year intervals. The prevalence of calcium in women was half that of men, until the age of 60 years when the difference diminished. The mean total calcium score distributions of men between the ages of 40 and 69 years were virtually identical to those of women between the ages of 50 and 79. The quantitative data obtained by Ultrafast CT showed very close agreement with autopsy studies of coronary calcium. Ultrafast CT is a sensitive technique to measure coronary calcium in both men and women. The differences in prevalence and extent of coronary calcium appear to be parallel to those observed in the clinical incidence of coronary artery disease in men and women. Ultrafast CT may have a greater impact on the treatment of women than of men, because it can be used to provide objective evidence of coronary atherosclerosis.

Adolescent↗
PubMed1993

Thalidomide inhibits the replication of human immunodeficiency virus type 1.

Thalidomide, a selective inhibitor of tumor necrosis factor alpha (TNF-alpha) synthesis, suppresses the activation of latent human immunodeficiency virus type 1 (HIV-1) in a monocytoid (U1) line. The inhibition is dose dependent and occurs after exposure of the cells to recombinant TNF-alpha, phorbol myristate acetate, lipopolysaccharide, and other cytokine combinations. Associated with HIV-1 inhibition is a reduction in agonist-induced TNF-alpha protein and mRNA production. Thalidomide inhibition of virus replication in the phorbol myristate acetate- and recombinant TNF-alpha-stimulated T-cell line ACH-2 is not observed. The presence of thalidomide also inhibits the activation of virus in the peripheral blood mononuclear cells of 16 out of 17 patients with advanced HIV-1 infection and AIDS. These results suggest the use of thalidomide in a clinical setting to inhibit both virus replication and the TNF-alpha-induced systemic toxicity of HIV-1 and opportunistic infections.

Acquired Immunodeficiency Syndrome↗
PubMed1993

Thalidomide exerts its inhibitory action on tumor necrosis factor alpha by enhancing mRNA degradation.

We have examined the mechanism of thalidomide inhibition of lipopolysaccharide (LPS)-induced tumor necrosis factor alpha (TNF-alpha) production and found that the drug enhances the degradation of TNF-alpha mRNA. Thus, the half-life of the molecule was reduced from approximately 30 to approximately 17 min in the presence of 50 micrograms/ml of thalidomide. Inhibition of TNF-alpha production was selective, as other LPS-induced monocyte cytokines were unaffected. Pentoxifylline and dexamethasone, two other inhibitors of TNF-alpha production, are known to exert their effects by means of different mechanisms, suggesting that the three agents inhibit TNF-alpha synthesis at distinct points of the cytokine biosynthetic pathway. These observations provide an explanation for the synergistic effects of these drugs. The selective inhibition of TNF-alpha production makes thalidomide an ideal candidate for the treatment of inflammatory conditions where TNF-alpha-induced toxicities are observed and where immunity must remain intact.

Animals↗
PubMed1993

Recognition and destruction of Bacillus Calmette-Guerin-infected human monocytes.

We have established a long-term culture system to study macrophages chronically infected with mycobacteria. Monocytes are infected with Bacillus Calmette-Guerin (BCG) and support exponential intracellular replication without profound perturbation of normal host cell function. We have used this system to investigate lymphokine-activated killer (LAK)-mediated cytolysis. We have found that interleukin 2 stimulation of peripheral blood lymphocytes generates a cytotoxic activity against human monocytes. A CD56- subpopulation of LAK cells specifically recognizes and lyses BCG-infected cells. Lysis of the host cell has no effect on parasite viability and results in the liberation of bacteria capable of infecting more cells.

Animals↗
PubMed1993

Prolonged immunostimulatory effect of low-dose polyethylene glycol interleukin 2 in patients with human immunodeficiency virus type 1 infection.

13 patients with human immunodeficiency virus type 1 infection class II-IV, but without opportunistic infection or neoplasm, received 6 micrograms (3.6 x 10(4) IU) of polyethylene glycol recombinant human interleukin 2 (PEG IL-2) intradermally twice a week for 4 mo were then followed for an additional 6 mo. Clinical, immunological, and viral parameters were monitored in the patients, all of whom were taking zidovudine. The cutaneous administration of PEG IL-2 resulted in an indurated zone resembling a delayed-type hypersensitivity response of 26 +/- 1 mm diameter (676 mm2) at 72-96 h after injection throughout the 4 mo of administration. This dose, which was appreciably lower than in most previous trials, was not associated with local or systemic toxicity. No increase in the viral burden of circulating leukocytes or plasma occurred. A number of immunological functions were stimulated by this course of therapy. All patients demonstrated high levels of lymphokine-activated killer cell activity by cells freshly removed from the circulation and in the absence of in vitro exposure to IL-2. Natural killer cell activity was also enhanced. Limiting dilution analysis revealed an increase in the frequency of IL-2-responsive cells from abnormally low to levels above normal during the course of injections. In a subgroup of four patients with > or = 400 CD4+ T cells/microliter at entry, there was a trend to sustained increases in CD4+ T cell numbers. However, this increase did not reach statistical significance. This subset of patients also exhibited higher proliferative responses to phytohemagglutinin as mitogen. Several of these effects persisted for 3-6 mo after cessation of therapy. In conclusion, low-dose IL-2 regimens lead to sustained immune enhancement in the absence of toxicity. We suggest pursuit of this approach for further clinical trials both as prophylaxis and therapy.

Adult↗
PubMed1993

Characterization of poliovirus conformational alteration mediated by soluble cell receptors.

Soluble extracts of Spodoptera frugiperda cells expressing the poliovirus receptor (PVR) induce the native poliovirus (PV) to "A" particle conformational change (J. Virol. 64, 4697-4702). We describe the variables that regulate this passage and study the suitability of solubilized PVR both for use as an in vitro system to characterize the receptor-mediated conformational alteration and for the production of large amounts of altered virus for structural analysis. PVR seems to function in a stoichiometric fashion and the A particles produced appear as intact, stain excluding, spherical structures by electron microscopy, regardless of the extensive proteolysis of the capsid protein VP1, which takes place during the conversion. The products obtained, time course, and temperature and ionic strength dependence of the alteration of PV by the solubilized PVR are indistinguishable from those of the alteration that leads to productive infection in cultured cells. Therefore, solubilized PVR may provide a convenient in vitro system for further characterization of the cell entry process.

Animals↗
PubMed1993

Efficacy of low doses of the polyethylene glycol derivative of interleukin-2 in modulating the immune response of patients with human immunodeficiency virus type 1 infection.

Interleukin-2 (IL-2) is a key cytokine in cellular immunity. Human immunodeficiency virus type 1 (HIV-1)-infected individuals lack IL-2 because of low CD4+ T lymphocyte numbers. In an attempt to enhance cellular immunity, low-dose recombinant human (rh) IL-2 at 10 micrograms or 180,000 units or its polyethylene glycol (PEG) derivative at 9 micrograms or 36,000 units was given by intracutaneous injection to 8 HIV-1-infected men for 30 days. Participants had no evidence of opportunistic infection and received concurrent zidovudine. IL-2 treatment was nontoxic and elicited a local cellular response resembling classic delayed-type hypersensitivity (DTH) with local interferon-gamma production, even in anergic patients. Systemic responses included enhanced DTH responses to recall antigens, improved in vitro proliferative responses to mitogen, and enhanced NK cell activity. Peripheral leukocyte phenotype and virus titers were unchanged. Long-term studies of low-dose IL-2 are warranted to determine whether immunoenhancing effects can be sustained and if they are associated with improved clinical course.

Adult↗
PubMed1993

Recent advances in cytokine therapy in leprosy.

Lepromatous leprosy is characterized by a selective anergy to Mycobacterium leprae and its antigens. The inadequate immune response and the resulting reduced interferon-gamma (IFN-gamma) production lead to a lack of macrophage activation and unrestricted bacterial growth. Purified protein derivative of tuberculin induced a normal local immune response in many lepromatous leprosy patients. Interleukin-2 induced an accelerated equivalent of an antigen response in the skin. In both, monocytes and T cells were recruited, and changes in keratinocytes, including expression of major histocompatibility complex class II antigens, were induced. Skin macrophages appeared to be activated and bacteria were eliminated. Similar effects were generated by IFN-gamma, a more distal molecule in the immune response. Cytokine treatment induced large amounts of tumor necrosis factor-alpha, which is toxic in this context but can be selectively down-regulated by thalidomide without interfering with other monocyte cytokines necessary for normal immune function.

Cytokines↗
PubMed1993

The influence of thalidomide on the clinical and immunologic manifestation of erythema nodosum leprosum.

Immunologic and clinical manifestations of erythema nodosum leprosum (ENL) and their response to thalidomide therapy were evaluated. Circulating tumor necrosis factor-alpha (TNF alpha) levels were assayed in serum obtained from lepromatous leprosy patients at diagnosis, during multidrug therapy, at the onset of ENL episodes, and during treatment with thalidomide. Patients with systemic ENL demonstrated the highest serum TNF alpha levels, which decreased significantly during thalidomide treatment. Serum TNF alpha in nonreactional patients was associated with mild flu-like symptoms and local inflammatory lesions. Serum interferon-gamma (IFN-gamma) was also elevated in patients with high TNF alpha levels. Thalidomide therapy reduced not only serum TNF alpha levels and the clinical symptoms but also the dermal infiltration of polymorphonuclear leukocytes and T cells. The expression of intercellular adhesion molecule 1 and major histocompatibility complex class II antigens on the epidermal keratinocytes was also down-regulated. These results indicate that the thalidomide-induced alleviation of clinical symptoms of ENL was associated with a reduction of TNF alpha levels.

Adult↗
PubMed1993

Cytokine gene activation and modified responsiveness to interleukin-2 in the blood of tuberculosis patients.

Selected parameters of cellular immunity relating to cytokine gene activation and responsiveness to interleukin-2 (IL-2) were analyzed in 27 patients with active pulmonary tuberculosis and no human immunodeficiency virus type 1 infection. Cytokine mRNAs were not expressed by peripheral blood mononuclear cells (PBMC) of normal controls. In PBMC of tuberculosis patients, messages for IL-1, IL-8, and tumor necrosis factor-alpha were uniformly expressed, whereas PBMC of only 5 of 18 patients expressed IL-6. PBMC of 7 patients (all of those with systemic symptoms) expressed interferon-gamma mRNA and none expressed IL-2 mRNA. Most patients' cells demonstrated IL-4 mRNA. Limiting dilution analysis of IL-2-responsive cells in PBMC revealed that tuberculosis patients had 10-fold fewer IL-2-responsive cells than did controls.

Cytokines↗
PubMed1993

Cutaneous vasculitis and IgA glomerulonephritis in ankylosing spondylitis.

Two patients with ankylosing spondylitis were found to have IgA nephropathy and leucocytoclastic cutaneous vasculitis. Immunofluorescence showed perivascular deposition of IgA in the skin of one patient and in the mesangium of both patients. Such an association has been reported only once before. This supports the concept of abnormal IgA immune stimulation in the pathogenesis of ankylosing spondylitis.

Glomerulonephritis, IGA↗