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Biomedical subjects

A Weinberg

Publications and source records attributed to A Weinberg.

At least 37 records · Page 2Linked to original sources
PubMed2001

Effect of prenatal dexamethasone on rat renal development.

BACKGROUND: Prenatal insults can program the developing fetus to develop diseases that manifest in later life. Dexamethasone is often administered to the developing fetus to accelerate pulmonary development. The purpose of the present study was to determine whether prenatal dexamethasone adversely affects renal development and predisposes rats to develop renal disease and hypertension in later life. METHODS: Pregnant rats were given either vehicle or two daily intraperitoneal injections of dexamethasone (0.2 mg/kg body weight) on gestational days: 11 and 12, 13 and 14, 15 and 16, 17 and 18, 19 and 20, or 20 and 21. Tail cuff blood pressure, glomerular number, and inulin clearance were measured in control and prenatal dexamethasone-treated rats when the rats were 60 to 90 days of age. RESULTS: Prenatal dexamethasone did not affect the length of gestation, the number of animals per litter, or the total body weight or kidney weight measured at one day of age. Offspring of rats administered dexamethasone on days 15 and 16 gestation had a 30% reduction in glomerular number compared with control at 60 to 70 days of age (24,236 +/- 441 vs. 30,453 +/- 579, P < 0.01). Rats receiving prenatal dexamethasone on days 17 and 18 had an approximate 20% reduction in glomeruli compared with control (P < 0.01). Offspring of rats receiving dexamethasone on days 15 and 16 gestation had systolic blood pressures at 60 to 90 days of age that were higher than any other group (P < 0.05). The glomerular filtration rate was comparable in all of the groups. CONCLUSIONS: This study shows that two daily doses of prenatal dexamethasone (0.2 mg/kg body weight) in rats do not produce intrauterine growth retardation. Adult offspring of rats that received prenatal dexamethasone during specific times of gestation have a reduced number of nephrons and hypertension.

Animals↗
PubMed2001

Immunization of HIV-infected children with varicella vaccine.

OBJECTIVE: To determine the safety and immunogenicity of varicella vaccine in children with human immunodeficiency virus (HIV) infection. Children (n = 41) who were mildly affected by HIV (Centers for Disease Control and Prevention stage N1 or A1) and had no history or serum antibody indicative of prior varicella infection were immunized with two doses of live attenuated varicella vaccine. RESULTS: A minority of the vaccine recipients had mild local or systemic reactions. Vaccination had no effect on the clinical stage of HIV or the HIV RNA plasma load. CD4 cell percentage and CD4 cell count were marginally decreased at week 4 after the first vaccination; this effect was no longer present at week 8 after vaccination. Two months after the second dose of vaccine, 60% of vaccine recipients had anti-varicella antibody in their serum, and 83% had a positive lymphocyte proliferation assay response to varicella antigen. CONCLUSION: On the basis of its safety and immunogenicity, varicella vaccine should be considered in the childhood vaccines given to mildly affected HIV-infected children.

Antibodies, Viral↗
PubMed2001

Sequencing of cytomegalovirus UL97 gene for genotypic antiviral resistance testing.

The widespread use of ganciclovir (GCV) to treat cytomegalovirus (CMV) infections in immunosuppressed patients has led to the development of drug resistance. Phenotypic assays for CMV drug resistance are presently too time-consuming to be therapeutically useful. To support the development of genotypic assays for GCV resistance, the complete sequences of the UL97 phosphotransferase genes in 28 phenotypically GCV-sensitive CMV clinical isolates were determined. The gene was found to be highly conserved, with nucleotide sequence identity among strains ranging from 98.6 to 100% and amino acid sequence identity of >99%. Primers for a genotypic assay were designed to amplify codons 400 to 707, because all known UL97 mutations conferring drug resistance occur at three sites within this region. This part of the UL97 gene was amplified from over 50 clinical isolates, and two sequencing reactions for the coding strand were successfully used to identify GCV resistance mutations. This genotypic assay can be performed in 48 h using genomic DNA extracted from cell monolayers at very low levels of virus infectivity, thus rapidly providing therapeutically useful results.

Amino Acid Sequence↗
PubMed2001

In vitro hydroxyurea decreases Th1 cell-mediated immunity.

Hydroxyurea (HU) is used in the treatment of hematologic disorders and is sometimes added to antiretroviral combination therapy to potentiate human immunodeficiency virus (HIV) suppression. However, HU has toxic effects on rapidly dividing cells, including the effectors of the immune response. To determine whether HU affects specific T-cell responses, we measured lymphocyte proliferation and cytokine production in response to microbial antigen and mitogen stimulation in the presence of added HU (10 to 1,000 microM). HU treatment of peripheral blood mononuclear cells obtained from HIV-infected patients and uninfected controls decreased lymphocyte proliferation and gamma interferon production compared with untreated cells. Interleukin-2 (IL-2) and IL-10 production was not affected by HU. The HU-mediated decrease of lymphocyte proliferation was similar in peripheral blood mononuclear cells from HIV-infected patients and from uninfected controls. The inhibitory effect of HU required continuous exposure to the drug and could be reverted by washing the drug out of the culture environment. These findings suggest that HU-containing therapeutic regimens might decrease Th1-cell-mediated immune responses in vivo.

Cell Division↗
PubMed2001

Frequency of acyclovir-resistant herpes simplex virus in clinical specimens and laboratory isolates.

The proportion of acyclovir (ACV)-resistant herpes simplex virus (HSV) isolates in clinical specimens and laboratory isolates was determined. HSV isolates in clinical specimens and laboratory isolates were cultured in the absence or presence of 5 microg of ACV per ml. The frequency of ACV-resistant HSV was calculated as (average virus titer in the wells with ACV)/(average virus titer in the wells without ACV). The mutation frequency of HSV type 1 isolates in clinical samples (directly from patient lesions) was 7.5 x 10(-4) +/- 2.5 x 10(-4) (mean +/- standard error), and that of HSV type 2 isolates was 15.0 x 10(-4) +/- 4.6 x 10(-4). The mutation frequencies of isolates derived in the laboratory from these clinical samples were very similar. Similarly, the 50% inhibitory concentrations for isolates in clinical samples and laboratory isolates were identical. The frequencies of ACV-resistant HSV types 1 and 2 were in a narrow range of 7.5 x 10(-4) to 15.0 x 10(-4) among isolates in clinical specimens and did not change for laboratory-derived pools of viral isolates.

Acyclovir↗
PubMed2001

The varicella-autoantibody syndrome.

This cross-sectional study was conducted to determine the incidence of autoantibodies to phospholipids and coagulation proteins in children with acute varicella zoster virus (VZV) infection. Study groups included children with VZV alone or complicated by purpura fulminans and/or thromboembolism. VZV naïve children and children who had VZV >1 y before sample collection formed a control group. Blood was assayed for the following: free protein S (PS), protein C, antithrombin, and prothrombin; antibody binding to these proteins; lupus anticoagulant; anticardiolipin antibody; antiphospholipid antibodies; and prothrombin fragment 1+2. Data regarding coinfections was collected. Forty-three VZV-infected children showed an increased frequency of lupus anticoagulant, anticardiolipin antibody, antiphospholipid antibodies, and autoantibodies to PS, protein C, prothrombin, and antithrombin in comparison to 52 children without acute VZV (p < 0.0001). Seventeen children with VZV and purpura fulminans and/or thromboembolism showed a statistically significant decrease in free PS, significantly increased PS IgG antibody, and significantly increased prothrombin fragment 1+2 (p < 0.0001) compared with the group without acute VZV and the group with uncomplicated VZV. Twenty-six children with uncomplicated VZV showed increased PS IgG antibody (p < 0.001) compared with the children without acute VZV. For all groups combined, elevated PS IgG antibody showed negative correlation with free PS (p < 0.0001) and positive correlation with prothrombin fragment 1+2 (p = 0.0002). Autoantibodies were transient. Transient antiphospholipid and coagulation protein autoantibodies were common with VZV infection, but were not predictive of thrombotic complications.

Adolescent↗
PubMed2000

Effect of cryopreservation on measurement of cytomegalovirus-specific cellular immune responses in HIV-infected patients.

To determine the feasibility of cytomegalovirus (CMV)-specific cell-mediated immunity (CMI) studies using cryopreserved cells, we compared lymphocyte proliferation assays (LPA), responder cell frequency (RCF), interleukin-2 (IL-2) and interferon-gamma (IFN-gamma) production using fresh and cryopreserved peripheral blood mononuclear cells (PBMCs) from 53 HIV-infected patients and 15 uninfected controls. Qualitative CMV LPA results were concordant in >/=84% of the specimens from either HIV-infected patients or controls. Proliferation-based RCF, IL-2, and IFN-gamma comparisons showed that cryopreservation reduces the number of CMV-specific responders and decreases cytokine secretion, without changing the rank order of the results (p <.01). In contrast, the number of flow cytometry-enumerated IFN-gamma-producing CD4+ cells was not significantly changed by cryopreservation. In HIV-infected patients, the differences between fresh and frozen cell assays were not influenced by CD4 cell numbers or HIV viral load. These data indicate that cryopreserved cells are suitable for longitudinal studies of the CMV-specific immune response in HIV-infected patients and uninfected controls.

Antiretroviral Therapy, Highly Active↗
PubMed2000

Therapeutic efficacy of OX-40 receptor antibody depends on tumor immunogenicity and anatomic site of tumor growth.

The OX-40 receptor (OX-40R) is a cell surface glycoprotein of the tumor necrosis factor receptor family that is expressed primarily on activated CD4 T cells. Engagement of OX-40R by the OX-40 ligand (OX-40L) is known to costimulate the production of cytokines by activated T lymphocytes and to rescue effector T cells from activation-induced cell death. It was previously reported that in vivo ligation of OX-40R by administration of OX-40L:immunoglobulin fusion protein or OX-40R monoclonal antibody (mAb) resulted in a significant prolongation of survival of tumor-bearing mice in four histologically distinct solid tumors. In this study, we demonstrate that the therapeutic efficacy of OX-40R mAb was influenced by the tumor burden, the intrinsic immunogenicity of the tumor as well as by the histological site of tumor growth. Whereas subdermal and intracranial growth of weakly immunogenic MCA 203 and MCA 205 sarcomas and GL261 glioma were susceptible to the mAb treatment, established pulmonary MCA 205 metastases were refractory to the same regimen of treatment. Furthermore, the mAb administration had no impact on the growth of the poorly immunogenic B16/D5 mela noma. Tumor regression mediated by OX-40R mAb was dependent on the participation of both CD4 and CD8 T cells and as a result of tumor rejection, a long-term tumor-specific immunity was established. Analysis of tumor-infiltrating T cells revealed the presence of a far greater number of OX-40R+ T cells of both CD4 and CD8 phenotypes in the intracranial immunogenic GL261 glioma than that in the poorly immunogenic B16/D5 melanoma. These results suggest that ligation of OX-40R on activated T cells in situ in the tumor may provide a necessary costimulatory signal to augment immune responses leading to tumor regression and immunological memory.

Animals↗
PubMed2000

Stress and psychiatric disorder in healthcare professionals and hospital staff.

BACKGROUND: Previous studies of stress in healthcare staff have indicated a probable high prevalence of distress. Whether this distress can be attributed to the stressful nature of the work situation is not clear. No previous study has used a detailed interview method to ascertain the link between stress in and outside of work and anxiety and depressive disorders. METHODS: Doctors, nurses, and administrative and ancillary staff were screened using the general health questionnaire (GHQ). High scorers (GHQ>4) and matched individuals with low GHQ scores were interviewed by means of the clinical interview schedule to ascertain definite anxiety and depressive disorders (cases). Cases and controls, matched for age, sex, and occupational group were interviewed with the life events and difficulties schedule classification and an objective measure of work stress to find out the amount of stress at work and outside of work. Sociodemographic and stress variables were entered into a logistic-regression analysis to find out the variables associated with anxiety and depressive disorders. FINDINGS: 64 cases and 64 controls were matched. Cases and controls did not differ on demographic variables but cases were less likely to have a confidant (odds ratio 0.09 [95% CI 0.01-0.79]) and more likely to have had a previous episode of psychiatric disorder (3.07 [1.10-8.57]). Cases and controls worked similar hours and had similar responsibility but cases had a greater number of objective stressful situations both in and out of work (severe event or substantial difficulty in and out of work-45 cases vs 18 controls 6.05 [2.81-13.00], p<0.001; severe chronic difficulty outside of work-27 vs 8, 5.12 [2.09-12.46], p<0.001). Cases had significantly more objective work problems than controls (median 6 vs 4, z=3.81, p<0.001). The logistic-regression analyses indicated that even after the effects of personal vulnerability to psychiatric disorder and ongoing social stress outside of work had been taken into account, stressful situations at work contributed to anxiety and depressive disorders. INTERPRETATION: Both stress at work and outside of work contribute to the anxiety and depressive disorders experienced by healthcare staff. Our findings suggest that the best way to decrease the prevalence of these disorders is individual treatment, which may focus on personal difficulties outside of work, combined with organisational attempts to reduce work stress. The latter may involve more assistance for staff who have a conflict between their managerial role and clinical role.

Adult↗
PubMed2000

Danger and OX40 receptor signaling synergize to enhance memory T cell survival by inhibiting peripheral deletion.

This report defines a cell surface receptor (OX40) expressed on effector CD4 T cells, which when engaged in conjunction with a danger signal, rescues Ag-stimulated effector cells from activation-induced cell death in vivo. Specifically, three signals were necessary to promote optimal generation of long-lived CD4 T cell memory in vivo: Ag, a danger signal (LPS), and OX40 engagement. Mice treated with Ag or superantigen (SAg) alone produced very few SAg-specific T cells. OX40 ligation or LPS stimulation, enhanced SAg-driven clonal expansion and the survival of responding T cells. However, when SAg was administered with a danger signal at the time of OX40 ligation, a synergistic effect was observed which led to a 60-fold increase in the number of long-lived, Ag-specific CD4 memory T cells. These data lay the foundation for the provision of increased numbers of memory T cells which should enhance the efficacy of vaccine strategies for infectious diseases, or cancer, while also providing a potential target (OX40) to limit the number of auto-Ag-specific memory T cells in autoimmune disease.

Adjuvants, Immunologic↗
PubMed2000

Acellular components of Chlamydia pneumoniae stimulate cytokine production in human blood mononuclear cells.

Accumulating evidence suggest that infection with Chlamydia pneumoniae is associated with atherosclerosis, but the mechanisms involved remain unclear. Inflammation is important in the initial phase of atherogenesis, and cytokines are important in the initiation and progression of inflammation. The aim of this study was to assess the capacity of acellular components of C. pneumoniae to stimulate the production of pro-inflammatory cytokines and chemokines. Peripheral blood mononuclear cells were stimulated in vitro with sonicated C. pneumoniae. Significant amounts of TNF-alpha, IL-1, IL-6, IL-8, monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-1alpha (MIP-1alpha) were produced. Inhibition of endotoxin using polymyxin B revealed that chlamydial endotoxin plays a minor role in the cytokine induction. Neutralization of TNF by TNF-binding protein and blockade of IL-1 receptors by IL-1 receptor antagonist revealed that TNF, IL-1 and IL-6 production was independent from each other, whereas IL-8 synthesis was strongly dependent on endogenous TNF and IL-1. In contrast, synthesis of MCP-1 and MIP-1alpha was dependent on endogenous TNF, but not IL-1. In conclusion, acellular components of C. pneumoniae are a potent stimulus for cytokine production, and this mechanism may have an important role in the inflammatory aspects of atherogenesis.

Cells, Cultured↗
PubMed2000

Immunohistochemical analysis of primary breast tumors and tumor-draining lymph nodes by means of the T-cell costimulatory molecule OX-40.

OBJECTIVES: The OX-40 receptor (OX-40R/CD134) is expressed primarily on activated CD4(+) ("helper") T cells. We have previously reported the presence of OX-40(+) T cells in head and neck cancer and melanoma, where they appear to be restricted to tumor compartments (primary tumor infiltrating lymphocytes [TILs] and draining lymph node cells) and therefore may represent the tumor antigen-specific CD4(+) T cells. METHODS: In order to determine the degree of OX-40R expression, and any relationship with the presence of tumor cells (lobular and/or infiltrating ductal carcinoma), 45 archived paraffin-embedded breast primary tumors and their associated draining (axillary) lymph nodes were retrospectively analyzed using standard immunohistochemical techniques. RESULTS: Seven of 45 primary tumors (16%) and 7 of 29 with lympocytic infiltrates (24%) were noted to have elevated levels of OX-40R(+) lymphocytes within the tumor specimens, including 2 of 4 specimens thought to have only "pure" ductal carcinoma in situ (DCIS). No OX-40R(+) lymphocytes were noted in normal breast tissue. Twenty-one (43%) patients had axillary metastases at the time of resection. High levels of OX-40R expression was seen in 9 (45%) of these 21 axillary node specimens, whereas no such staining was seen in the node-negative specimens (P <0.001). Furthermore, in a patient thought to be without axillary disease, several subcapsular single-cell metastases were retrospectively discovered near a lone cluster of OX-40R(+) lymphocytes. In general, visual inspection showed OX-40R(+) T cells to be in close proximity to tumor and often in direct contact with metastatic cells. CONCLUSIONS: The OX-40R is upregulated on lymphocytes within tumor draining lymph nodes, and these lymphocytes are specifically localized around tumor deposits. These data imply that OX-40R immunostaining may be useful for both determination of occult involvement of lymph nodes by tumor and for identification of potential candidates for future OX-40 based immunotherapy.

Breast Neoplasms↗
PubMed2000

Six-year experience of caring for forty-four patients with a left ventricular assist device at home: safe, economical, necessary.

OBJECTIVE: With increasing numbers of implantations, left ventricular assist device programs can put a financial strain on a hospital unless an efficient and safe outpatient program is developed. However, the left ventricular assist device is not widely recognized in the medical community as being reliable enough to support a patient at home. We reviewed our experience with these patients at home to assess the safety and the benefits of such a program. METHODS: Our institutional 6-year experience with 90 consecutive recipients of a wearable left ventricular assist device was analyzed. RESULTS: Forty-four (49%) of the 90 patients who received TCI vented-electric left ventricular assist devices (Thermo Cardiosystems, Inc, Woburn, Mass) were discharged, spending a total of 4546 days (12.5 years) at home with an average of 103 +/- 16 days of outpatient support (range 9-436 days). Of these 44 patients, all were successfully bridged to transplantation (42 patients, 96%) or planned explantation (2 patients, 4%). None of the outpatients died. The cumulative events per outpatient month were 0.020 for bleeding, 0.053 for device infection, 0.0068 for thromboembolus, and 0.020 for major malfunctions. Our estimated average cost to bridge a patient to transplantation or explantation once discharged is $13,200 and as an inpatient over the same length of time, including only room and board, is $165,200. Thirty percent of outpatients were able to return to work or school, 33% to sexual activity, and 44% to driving. All outpatients performed activities of daily living. CONCLUSION: Current left ventricular assist device technology provides effective and economical outpatient support and is associated with limited morbidity and a satisfactory quality of life.

Ambulatory Care↗
PubMed2000

Warfarin skin necrosis: local and systemic factors.

Warfarin induced skin necrosis occurs in 0.01-0.1% of warfarin treated patients. The usual presentation is that of painful lesions developing in obese women after the initiation of warfarin treatment. The lesions usually evolve into full thickness skin necrosis within a few days. Although the exact mechanism is not totally clear, low levels of Protein C or S, either functional or inherited, are associated with many of the cases. We report the case of a 17-year-old patient treated with warfarin because of iliofemoral deep vein thrombosis post abortion. The patient developed several huge haemorrhagic blisters on the affected leg. The condition rapidly developed into full thickness skin and fat necrosis. The necrotic lesions were excised and eventually covered with skin graft. The combination of the patient tendency towards hyper-coagulation and the local factors is discussed.

Adolescent↗
PubMed2000

Two decades of abdominal aortic aneurysm repair: have we made any progress?

PURPOSE: Over the past 20 years, there have been numerous advances in our ability to detect and to treat abdominal aortic aneurysms (AAAs). We hypothesized that these advances would lead to (1) an increase in the rate of elective repair and a decrease in the incidence of ruptured AAA (rAAA) and (2) a decrease in operative deaths for both elective AAA (eAAA) and rAAA. METHODS: To test these hypotheses, we investigated the incidence and outcomes of eAAA and rAAA surgery between 1979 and 1997, using the National Hospital Discharge Survey. This data set is a randomized, stratified sample representing discharges from the nation's acute care, nonfederally funded hospitals. Codes from the International Classification of Diseases, Ninth Revision were used to identify our study population. RESULTS: Over the past 19 years, there has been no change in the incidence rate of eAAA repair (range, 44.1-77.9 per 100,000). Moreover, the incidence of rAAAs presenting to the nation's hospitals has not changed (range, 6.6-16.3 per 100,000). There has been no consistent improvement over time in operative deaths associated with either eAAA or rAAA repair (average rates over the study period: eAAA, 5.6%; rAAA, 45.7%). Significant predictors of death from eAAA in patients included an age older than 80 years, African American race, congestive heart failure (CHF), and diabetes (P<.0001 for all). Significant predictors of death from rAAA in patients included age older than 70 years, African American race, female sex, renal failure, and a hospital bed size more than 500 (P<.05 for all). CONCLUSION: On a national level, over the past 19 years, our ability to identify and to treat patients with AAA has not improved. Advances in technology and critical care have not affected outcome. Regionalization of care, screening of high-risk populations, and endovascular repair are strategies that might allow further improvement in the outcome of patients with aneurysmal disease.

Black or African American↗
PubMed2000

Alloreactive cytotoxic CD4+ responses elicited by cytomegalovirus-infected endothelial cells: role of MHC class I antigens.

Cytomegalovirus (CMV) has been associated with chronic graft rejection in solid organ transplant patients. To elucidate the mechanism by which CMV leads to graft rejection, we hypothesized that CMV infection of endothelial cells could stimulate alloreactive cytotoxic T lymphocytes (CTL). This hypothesis was explored using the following experimental model: peripheral blood mononuclear cells (MNC) obtained from normal hosts were grown on monolayers of umbilical vein endothelial cells (UVEC) infected with CMV (CMV-UVEC) or not (control) and tested for CTL activity against uninfected UVEC. We showed that CMV-UVEC-stimulated MNC have significant CTL activity against uninfected UVEC. The CTL activity elicited by CMV-UVEC stimulation was significantly higher compared with that stimulated by uninfected UVEC or by ganciclovir-treated CMV-UVEC, indicating the critical role of productive CMV infection. The CTL activity was specific for the UVEC used as stimulators and did not affect MHC-unrelated UVEC. However, lymphoblastoid lines (LBL) major histocompatibility complex (MHC)-identical with the stimulator UVEC were also killed by the CMV-UVEC-stimulated MNC. CTL killed identical UVEC and LBL in a competitive fashion. Blocking experiments with monoclonal antibodies (mAbs) identified CD4 cells as the main effector of CTL activity and MHC class I as the antigenic target of CTL. Although natural killer (NK) cells did not significantly contribute to the CTL activity of CMV-UVEC-stimulated MNC, their presence in the MNC cultures during the stimulation process was critical for the development of CTL. This model offers a framework for understanding the role of CMV infection in graft rejection and for devising preventative strategies.

B-Lymphocytes↗
PubMed2000

A standardized plaque reduction assay for determination of drug susceptibilities of cytomegalovirus clinical isolates.

Twelve laboratories collaborated in formulating and testing a standardized plaque reduction assay for cytomegalovirus (CMV) cell-associated clinical isolates. Four characterized and plaque-purified CMV strains, as well as six coded clinical isolates obtained after antiviral therapy, were distributed and tested. Good agreement was obtained for four of the clinical isolates, but a broad distribution of results was obtained for two isolates. Analysis of these results indicates the problems associated with clinical isolates, including the large genetic variability and the highly cell-associated phenotype. This collaborative effort, by addressing these problems, represents a significant step toward the development of a standardized assay.

Antiviral Agents↗