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G Kaplan

Publications and source records attributed to G Kaplan.

At least 37 records · Page 2Linked to original sources
PubMed2000

Thalidomide for the treatment of AIDS-associated wasting.

A double-blind, placebo-controlled trial of efficacy and safety of thalidomide in AIDS-associated wasting was carried out. Ninety-nine of 103 male patients had at least one on-study measurement (intent-to-treat [ITT] cohort). Patients were randomized to thalidomide at 100 mg/day (T100) or 200 mg/day (T200), or placebo for 8 weeks. By ITT analysis, the mean change in body weight of the placebo, T100, and T200 treatment groups was 0.3 kg (0.4%), 2.0 kg (3.0%), and 0.9 kg (1.4%), respectively (p = 0.021 for T100 versus placebo; p = 0.53 for T200 versus placebo). Of the 64 patients who completed the 8 weeks of study treatment, significant weight gain was observed in both the T100 group (2.2 kg, [33%]; p = 0.008 versus placebo) and the T200 group (1.5 kg [2.5%]; p = 0.019 versus placebo). Approximately half the weight gain was fat-free mass (bioimpedance analysis). Patients in the T100 or T200 groups had no significant change in CD4+ cell counts, neutrophil counts, or TNF-alpha levels, compared with placebo. HIV viral load measured as log10 copies/ml decreased by a median of 0.07 in the placebo group, and increased by a median of 0.29 (T100 group) and 0.23 (T200 group) (p = 0.024 andp = 0.018 versus placebo, respectively). Thalidomide therapy was associated with mild to moderate rashes and fevers, but not peripheral neuropathy. Although the anabolic benefits of high-dose thalidomide are limited by drug intolerance, 8 weeks of low-dose thalidomide results in significant weight gain in patients with AIDS-associated wasting.

Adult↗
PubMed2000

Carbacyclic peptide mimetics as VCAM-VLA-4 antagonists.

Substitution of carbon for sulfur in a potent 13-membered cyclic disulfide containing peptide was accomplished via an intramolecular Wittig reaction and resulted in a series of 'carba' analogues. Potency in the VCAM-VLA-4 assay was sensitive to ring size and lower than that of the parent disulfide.

Integrin alpha4beta1↗
PubMed2000

N-benzylpyroglutamyl-L-phenylalanine derivatives as VCAM/VLA-4 antagonists.

A series of N-(N-benzylpyroglutamyl)-4-substituted-L-phenylalanine derivatives was prepared as VLA-4/VCAM antagonists. Analogues substituted by electron deficient benzoylamino groups bearing bulky ortho substituents had low-nM potency in an ELISA assay and low-microM activity in a cell based assay.

Cell Line↗
PubMed2000

Strong human immunodeficiency virus (HIV)-specific CD4+ T cell responses in a cohort of chronically infected patients are associated with interruptions in anti-HIV chemotherapy.

Virus-specific CD4+ T-helper cell function is important in controlling human immunodeficiency virus (HIV) infection but is impaired in patients with progressive HIV disease. It has been reported that after highly active antiretroviral therapy (HAART), HIV-specific lymphoproliferative responses remain absent, whereas responses to non-HIV microbial antigens are restored. However, in analyzing immune responses in a cohort of chronically infected adults on HAART, we observed strong HIV-specific CD4+ T cell responses of Th-1 phenotype in 11 of 22 patients. The magnitude and frequency of HIV-specific lymphoproliferative responses was strongly associated with previous interruptions in HAART (P=.001). In contrast, the magnitude of CD8+ T cell responses to HIV Gag, Pol, Env, and Nef was similar in patients who had and those who had not interrupted HAART. We conclude that (1) a significant proportion of chronically HIV-infected patients on HAART can generate strong HIV-specific CD4+ and CD8+ T cell immunity and (2) transient interruptions in antiviral treatment may prime or boost HIV-specific CD4+ T-helper responses.

Adult↗
PubMed2000

Immune stimulation in scleroderma patients treated with thalidomide.

Scleroderma (SSc) is a fibrosing connective tissue disease that is poorly responsive to any treatment, including immune suppression. SSc shares many characteristics with chronic graft-versus-host disease (GVHD). Because the immunomodulatory drug thalidomide has proven beneficial in chronic GVHD, we studied the immune response and clinical effects of thalidomide in SSc patients. We treated 11 SSc patients with thalidomide in an open label, dose escalating, 12 week study. Histologic comparison of skin biopsies showed changes in skin fibrosis and an increase in epidermal and dermal infiltrating CD8(+) T cells with thalidomide treatment. In thalidomide-treated SSc patients, plasma levels of IL-12 and TNF-alpha increased, while plasma IL-5 and IL-10 levels remained unchanged. These changes were associated with clinical effects, including dry skin, dermal edema, transient rashes, decreased gastroesophageal reflux symptoms, and healing of digital ulcers. When SSc PBMCs activated by anti-CD3 mAb were exposed to thalidomide, increases in both production of IL-2, IL-3, GM-CSF, and IFN-gamma and T cell expression of CD40L were observed. Thalidomide therefore appears to induce immune stimulation in SSc patients in association with clinical changes. However, it remains to be shown whether long-term enhancement of immune responses in SSc patients is clinically beneficial.

Adjuvants, Immunologic↗
PubMed2000

Aerosol infection of mice with recombinant BCG secreting murine IFN-gamma partially reconstitutes local protective immunity.

To better understand the contribution of interferon-gamma (IFN-gamma) to the immune response during the first 60 days of mycobacterial infection in the lungs, IFN-gamma gene disrupted (IFN-gamma-/-) mice were infected via aerosol with recombinant Mycobacterium bovis Bacillus Calmette-Guerin (BCG) secreting murine IFN-gamma (BCG-IFN-gamma) and compared to mice infected with recombinant BCG containing the vector only (BCG-vector). When IFN-gamma-/- mice were infected with BCG-vector, increasing bacillary loads and large undifferentiated granulomas that did not express inducible nitric oxide synthase (iNOS) were observed in the lungs. In contrast, infection with BCG-IFN-gamma resulted in reduced bacillary load and better differentiated granulomas containing epithelioid macrophages expressing iNOS as well as reduced levels of interleukin 10 (IL-10) mRNA. However, local production of IFN-gamma by the recombinant BCG did not protect IFN-gamma-/- mice from subsequent challenge with M. tuberculosis. Infection of IFN-gamma-/- peritoneal macrophages in vitro with BCG-IFN-gamma led to induction of iNOS expression and lower IL-10 mRNA levels. Nevertheless, the growth of the intracellular BCG was unaffected. Since IFN-gamma induced-iNOS protein and reduced IL-10 production were insufficient to control mycobacterial growth in vitro, the results suggest that additional mediator(s) present in vivo are required for control of mycobacterial growth.

Aerosols↗
PubMed2000

Multifocal osteogenic sarcoma in Paget's disease.

The most serious complication of Paget's disease is sarcomatous degeneration of pagetic bone. Multifocal sarcomatous degeneration occurs mainly in polyostotic Paget's disease. Multifocal Paget's sarcoma is uncommon and can arise in any site. We report two cases of synchronous multifocal sarcomatous degeneration. The two patients were elderly women (aged 77 and 86 years, respectively) who developed sarcomatous lesions concomitantly, in the first case report in left ilium, left tibia, and first lumbar vertebra and in the second case report in the skull, right ilium, and sacrum. Whether these cases are due to the simultaneous development of several primaries or to metastases from a single primary remains unclear.

Aged↗
PubMed2000

Coinfection of fibroblasts with Coxiella burnetti and Toxoplasma gondii: to each their own.

Intracellular pathogens have evolved distinct strategies to subvert host cell defenses. At diametrically opposed ends of the spectrum with regard to the host endosomal/lysosomal defenses are the obligate intracellular protozoan Toxoplasma gondii and the bacterium Coxiella burnetti. While the intracellular replication of T. gondii requires complete avoidance of the host endocytic cascade, C. burnetti actively subverts it. This results in these organisms establishing and growing in very different vacuolar compartments. In this study we examined the potential interaction between these distinct compartments following coinfection of mammalian fibroblasts. When present within the same cell, these organisms exhibit minimal interaction with each other. Colocalization of T. gondii and C. burnetti within the same vacuole occurs at a low frequency in doubly infected cells. In such instances only one of the organisms appears to be replication competent, emphasizing the different requirements for survival and/or intracellular growth. The potential basis for both the lack of interaction between these distinct pathogen-containing compartments, and the mechanisms to address their low frequency of colocalization are discussed in the context of our understanding of the biology of the organisms and membrane traffic in eukaryotic cells.

Animals↗
PubMed2000

Modulation of hyperoxia-induced TNF-alpha expression in the newborn rat lung by thalidomide and dexamethasone.

The effect of high oxygen concentrations on lungs of neonatal rats was studied. In addition, some oxygen-exposed animals were treated with either dexamethasone or thalidomide. No gross histologic changes were noted in the lungs following exposure to 95% oxygen nor were there changes in the total number or the phenotypic distribution of BAL cells obtained from these lungs compared to lungs from air exposed (control) neonatal rats. The majority of the BAL cells were CD45+ leukocytes (macrophages). However, when BAL cells were exposed to LPS in vitro, TNF-alpha production was higher in cells from rats exposed to 95% oxygen compared to cells from rats exposed to ambient air. In addition, lung TNF-alpha and IL-6 mRNA levels were increased after exposure to 95% oxygen. In the lungs of animals treated with either dexamethasone or thalidomide, TNF-alpha mRNA levels were reduced, while only dexamethasone treatment also reduced IL-6 mRNA levels.

Animals↗
PubMed2000

Body mass index in 17-year-old Israeli males of different ethnic backgrounds; national or ethnic-specific references?

OBJECTIVE: To evaluate whether a single national reference is appropriate for assessing prevalence of overweight in heterogeneous populations, or whether ethnic-specific references are needed. DESIGN: A population-based study of Israeli Jewish males who underwent routine physical and clinical examinations prior to army recruitment served as the basis for the development of two types of references for body mass index (BMI): a national reference (NR) and an ethnic-specific reference (ER). SUBJECTS: Consecutive cohorts of all 17-y-old Jewish male recruits (n=109, 570). MEASUREMENTS: Weight, height and blood pressure values were obtained. BMI was calculated, and the 85th percentile of BMI was used as a cut-off point for overweight, using both types of references. Prevalence of hypertension among recruits was used as a biomarker to support the reliability of the ER when discrepancy in classification between the two references was found. RESULTS: As compared to the NR, three ethnic groups had a BMI distribution shifted to the left (light sub-population) and five were shifted to the right (heavy sub-population). In the light sub-population, 7% of the inductees who were classified as having normal weight by the NR were considered overweight by the ER and had a hypertension rate similar to that of those defined as overweight by both references (3.1 per 1000). In the heavy sub-population the 4% of subjects who were overweight by NR and normal by ER had hypertension rates similar to those defined as normal weight by both references (2.7/1000), and significantly lower than that of those classified as overweight by both references (10.8/1000). CONCLUSION: In heterogeneous populations, ethnic references should be used to evaluate prevalence of overweight, rather than one national reference. International Journal of Obesity (2000)24, 88-92

Adolescent↗
PubMed2000

Thalidomide-induced antigen-specific immune stimulation in patients with human immunodeficiency virus type 1 and tuberculosis.

Thalidomide, which inhibits monocyte tumor necrosis factor (TNF)-alpha production and costimulates T cells, was tested for immune modulation in patients with human immunodeficiency virus (HIV) infection and tuberculosis (TB) in a placebo-controlled study. Thalidomide therapy resulted in increased levels of plasma interleukin (IL)-2 receptor, soluble CD8, interferon-gamma, and IL-12, indicating immune stimulation. TNF-alpha levels were not reduced. Thalidomide treatment increased CD4+ and CD8+ T cell counts and lymphocyte proliferation to purified protein derivative. Immune stimulation was not associated with an increase in plasma HIV levels. In vivo, a thalidomide dose-dependent costimulatory effect on T cell proliferation and HIV replication was observed after stimulation with antigens or anti-CD3, respectively. Thalidomide-induced increased viral replication in CD4+ T cells was abrogated by adding back autologous CD8+ T cells. Thus, in the presence of thalidomide, antigen-specific immune responses in vitro and in patients with HIV/TB were enhanced.

Acquired Immunodeficiency Syndrome↗
PubMed2000

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Journal Article↗
PubMed2000

Immunopathologic effects of tumor necrosis factor alpha in murine mycobacterial infection are dose dependent.

In experimental mycobacterial infection, tumor necrosis factor alpha (TNF-alpha) is required for control of bacillary growth and the protective granulomatous response, but may cause immunopathology. To directly examine the positive and detrimental effects of this cytokine, a murine model was used in which different amounts of TNF-alpha were delivered to the site of infection. Mice with a disruption in the TNF-alpha gene (TNF-KO) or wild-type mice were infected with low or high doses of recombinant Mycobacterium bovis BCG that secreted murine TNF-alpha (BCG-TNF). Infection of TNF-KO mice with BCG containing the vector (BCG-vector) at a low dose led to increased bacillary load in all organs and an extensive granulomatous response in the lungs and spleen. The mice succumbed to the infection by approximately 40 days. However, when TNF-KO mice were infected with low doses of BCG-TNF, bacillary growth was controlled, granulomas were small and well differentiated, the spleen was not enlarged, and the mice survived. Infection with high inocula of BCG-TNF resulted in bacterial clearance, but was accompanied by severe inflammation in the lungs and spleen and earlier death compared to the results from the mice infected with high inocula of BCG-vector. Wild-type mice controlled infection with either recombinant strain, but showed decreased survival following high-dose BCG-TNF infection. The effects of TNF-alpha required signaling through an intact receptor, since the differential effects were not observed when TNF-alpha receptor-deficient mice were infected. The results suggest that the relative amount of TNF-alpha at the site of infection determines whether the cytokine is protective or destructive.

Animals↗
PubMed2000

Staphylococcus aureus RN6390 replicates and induces apoptosis in a pulmonary epithelial cell line.

Staphylococcus aureus frequently colonizes the airways of patients with compromised airway defenses (e.g., cystic fibrosis [CF] patients) for extended periods. Persistent and relapsing infections may be related to live S. aureus bacteria actively residing inside epithelial cells. In this study, we infected a respiratory epithelial cell line, which was derived from a CF patient, with S. aureus RN6390. Internalization of S. aureus was found to be time and dose dependent and could be blocked by cytochalasin D. Transmission electron microscopy revealed that internalized bacteria resided within endocytic vacuoles without any evidence of lysosomal fusion in a 24-h period. The results of internalization experiments and time-lapse fluorescence microscopy of epithelial cells infected with green fluorescent S. aureus indicate that, after an initial lag period of 7 to 9 h, intracellular bacteria began to replicate, with three to five divisions in a 24-h period, leading to apoptosis of infected cells. Induction of apoptosis required bacterial internalization and is associated with intracellular replication. The slow and gradual replication of S. aureus inside epithelial cells hints at the role of host factors or signals in bacterial growth and further suggests possible cross talk between host cells and S. aureus.

Apoptosis↗
PubMed2000

Adjunctive thalidomide therapy of childhood tuberculous meningitis: possible anti-inflammatory role.

The objective of this study was to determine the safety and tolerability of the immunomodulatory agent thalidomide as adjunct therapy in children with tuberculous meningitis. Children with stage 2 tuberculous meningitis received oral thalidomide for 28 days in a dose-escalating study, in addition to standard four-drug antituberculosis therapy, corticosteroids, and specific treatment of complications such as raised intracranial pressure. Clinical and laboratory evaluations were carried out. Fifteen patients (median age, 34 months) were enrolled. Thalidomide was administered via nasogastric tube in a dosage of 6 mg/kg/day, 12 mg/kg/day, or 24 mg/kg/day. The only adverse events possibly related to the study drug were transient skin rashes in two patients. Levels of tumor necrosis factor-alpha in the cerebrospinal fluid decreased markedly during thalidomide therapy. Clinical outcome and neurologic imaging showed greater improvement than that experienced with historical controls. Thalidomide appeared safe and well tolerated in children with stage 2 tuberculous meningitis and could have important anti-inflammatory effects. These promising results have led us to embark on a randomized, double-blind, placebo-controlled trial of the efficacy of thalidomide in tuberculous meningitis.

Adjuvants, Immunologic↗
PubMed2000

Dynamic MR imaging of the pelvic floor in asymptomatic subjects.

OBJECTIVE: Dynamic MR imaging may be used as an alternative to dynamic cystoproctography for the evaluation of pelvic floor prolapse and configuration. MR criteria for normality are derived from proctographic studies because no large MR study of asymptomatic individuals has been performed. Our study aimed to define the normal range of dynamic pelvic MR appearances in a large group of asymptomatic individuals. SUBJECTS AND METHODS: Fifty healthy adult volunteers (25 men and 25 women; age range, 20-66 years; mean age, 34 years) were prospectively recruited and examined using dynamic MR imaging. All subjects were interviewed and established as healthy using a validated questionnaire. Axial, coronal, and sagittal MR imaging was performed at rest and during maximum pelvic strain using a static 1.0-T unit and a fast-field-echo sequence, providing 10 slices in 31 sec. Standardized measurements of pelvic configuration were taken, and rest and strain imaging were compared to determine the range of normal appearances. RESULTS: Three women developed a cystocele during maximum pelvic strain, two of whom also showed grade 1 uterocervical prolapse, which was also seen in another woman. Three men showed posterior pelvic floor descent in excess of 3 cm during straining. No rectocele, enterocele, rectal prolapse, or perineal hernia was seen in any subject. CONCLUSION: The normal range of pelvic organ descent in asymptomatic subjects seen on dynamic MR imaging included cystocele, uterocervical prolapse, and excessive anorectal junction descent. Although we encountered pelvic prolapse in seven volunteers, it was infrequent and low grade, suggesting that criteria for abnormality derived from proctography are generally applicable to MR imaging.

Adult↗