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Biomedical subjects

L Weiss

Publications and source records attributed to L Weiss.

At least 73 records · Page 4Linked to original sources
PubMed1999

Short-term progressive resistance training increases strength and lean body mass in adults infected with human immunodeficiency virus.

BACKGROUND: To assess the efficacy of progressive resistance training (PRT) in increasing strength and lean body mass (LBM) in HIV-infected adults. METHODS: Twenty-five adults with HIV infection were trained using a highly intensive PRT regimen for 8 weeks, followed by an additional 8 weeks of observation under ad libitum physical activity conditions. RESULTS: Twenty-four of the 25 patients completed the first phase of the study. They had significant increases in strength on all four exercises tested (P < 0.0001), and an increase in LBM of 1.75 +/- 1.94 kg (mean +/- SD, P < 0.0002), with a concomitant decline in fat of 0.92 +/- 2.22 kg (P < 0.05), and no significant change in weight or bone mineral content. Twenty-one of the patients returned for follow-up 8 weeks after completing the PRT. Compared with their baseline values, their mean lean mass remained 1.40 +/- 1.8 kg higher (P < 0.003). Among those who continued to train to some extent, lean mass increased by a mean of 1.1 +/- 1.6 kg (n = 9, P < 0.05 versus end of PRT), whereas those who did no further training showed an increase in lean mass of 0.28 +/- 1.4 kg (n = 12, P = NS versus end of PRT). The difference between the two groups was not, however, significant (P = 0.25). Among six patients with AIDS wasting, the increase in LBM was larger than among non-wasted patients (2.8 versus 1.4 kg, P < 0.06), and there was an increase in both weight (+3.9 versus -0.2 kg, P < 0.002) and fat mass (+ 0.95 versus -1.5 kg, P < 0.002) at 8 weeks, which persisted at 16 weeks (weight: +4.0 versus -1.6 kg, P < 0.0002; fat: +1.6 versus -1.9 kg, P < 0.01). CONCLUSION: This preliminary study suggests that short-term, high intensity PRT can significantly increase LBM and strength in HIV infection, and may be used as an alternative or adjunct to pharmacological anabolic treatments in this disease.

Adult↗
PubMed1999

Familial aggregation of breast cancer with early onset lung cancer.

Site-specific familial aggregation and evidence supporting Mendelian codominant inheritance have been shown in lung cancer. In characterizing lung cancer families, a number of other cancers have been observed. The current study evaluates whether first-degree relatives of early onset lung cancer cases are at increased risk of breast cancer. Families were identified through population-based lung cancer cases and controls under 40 years of age. Cases were ascertained through the Metropolitan Detroit SEER registry; controls through random-digit dialing. Data were available for 384 female relatives of 118 cases and 465 female relatives of 161 controls. Breast cancer in relatives was evaluated after adjusting for age, race, sex, and smoking status of each family member and the sex and age of the probands. A positive family history of early onset lung cancer increased breast cancer risk among first-degree relatives 5. 1-fold (95% CI, 1.7-15.1). Relatives of cases with adenocarcinoma of the lung were at highest risk (RR = 6.3, 95% CI 2.0-20). Mean age of breast cancer diagnosis among relatives of cases was 52.2 years and not statistically different from relatives of controls. Three case families also reported early ovarian cancers (mean age of diagnosis of 35 years). These findings suggest that shared susceptibility genes may act to increase risk of early onset lung and breast cancer in families.

Adolescent↗
PubMed1999

Prevention and treatment of graft-versus-host disease by down-regulation of anti-host reactivity with veto cells of host origin.

Control of graft-versus-host disease (GVHD) post allogeneic spleen cell transplantation was partly achieved by administration of host-type lymphocytes. (C57BL/6 x BALB/c) F1 mice were conditioned by total body irradiation and transplanted with parental C57BL/6 spleen cells to induce severe GVHD. Infusion of mature host-type lymphocytes did not change the degree of chimerism but protected most of the recipients from lethal GVHD. Treatment of host-type blood cells with anti-CD8 antibodies resulted in loss of the GVHD protective effects mediated by host cells, whereas after treatment of the host with anti-CD4 antibodies protective host cells given 4 days after induction of GVHD resulted in successful rescue of all transplanted recipients from lethal GVHD. Administration of host blood cells could effectively protect against GVHD induced by donor spleen cells and low-dose rIL-2. GVHD protection resulted from down-regulation of alloreactive donor T cells and not by rejection of GVHD effector cells. Taken together, administration of host hematopoietic cells particularly host CD8+ T cells, may be considered for prevention or control of GVHD following allogeneic bone marrow transplantation, thus also explaining the increased resistance of mixed chimeras to GVHD.

Animals↗
PubMed1999

Restoration of normal interleukin-2 production by CD4+ T cells of human immunodeficiency virus-infected patients after 9 months of highly active antiretroviral therapy.

The present study investigated immune restoration in patients at intermediate stages of human immunodeficiency virus (HIV) disease after initiation of highly active antiretroviral therapy (HAART). A progressive increase in both memory and naive CD4+ T cells was observed from the first weeks of therapy, concomitant with a decrease in the expression of activation markers on CD8+ T cells. The early-activation marker CD69 remained, however, overexpressed on T cells after suboptimal stimulation in vitro, indicative of persistent immune activation. The percentage of interleukin (IL)-2-producing CD4+ T cells significantly increased from 9 months of HAART. In most patients, CD4+ T cells recovered an ability to produce IL-2 on stimulation, similar to that of HIV-seronegative controls. Reversal of T-cell anergy may be a key event in immune restoration for achieving long-term clinical benefit with HAART.

Adult↗
PubMed1999

The plasma levels of homocysteine are elevated in moderate renal insufficiency but do not predict the rate of progression.

BACKGROUND: Chronic renal failure is characterized by specific alterations of the lipoprotein metabolism. It is also characterized by elevated plasma levels of total homocysteine (tHcy). Hyperhomocysteinemia has been shown to be a risk factor for atherosclerosis in both the general population and in patients with end-stage renal disease. AIM: To analyze whether elevated tHcy levels also may contribute to a higher rate of progression of renal insufficiency in patients with moderately advanced renal failure. METHODS: To investigate whether tHcy concentrations are associated with an accelerated rate of progression of renal insufficiency, we have correlated baseline plasma concentrations of tHcy with the progressive decline of renal function in an observational study of human chronic renal disease. RESULTS: Sixty-three nondiabetic patients (49 men, 14 women) were studied as part of an observational study of patients with moderately advanced renal insufficiency. The average follow-up time of the patient population was 3.0 years, and the mean rate of decline in glomerular filtration rate ((51)Cr- EDTA clearance) was -3.2 +/- (SD) 3.9 ml/min x 1.73 m(2) body surface area. The mean plasma concentration of tHcy at the beginning of the study was 28.3 +/- 12.0 micromol/l. Plasma tHcy concentrations correlated significantly with the glomerular filtration rate (r = -0. 32, p < 0.01). However, there was no association between the initial plasma level of tHcy and the rate of progression as assessed by linear regression analysis (r = 0.02; NS). In contrast, increased levels of apolipoprotein B, low-density lipoprotein cholesterol, and proteinuria were all significantly associated with a more rapid decline in renal function. CONCLUSIONS: Patients with moderately advanced chronic renal insufficiency have elevated plasma levels of homocysteine. The tHcy plasma levels increase in parallel with the degree of reduction in renal function. However, the hyperhomocysteinemia is not prospectively associated with a higher rate of progression of the renal functional impairment. Hence, there is no indication that elevated homocysteine levels play a contributing role for an accelerated glomerulosclerotic process.

Adult↗
PubMed1999

The antiangiogenic agent linomide inhibits the growth rate of von Hippel-Lindau paraganglioma xenografts to mice.

The aim of this study was to ascertain the potential usefulness of the antiangiogenic compound linomide for treatment of von Hippel-Lindau (VHL)-related tumors. Paraganglioma tissue fragments obtained at surgery from a VHL type 2a patient were transplanted s.c. to male BALB/c nu/nu (nude) mice: (a) 2-3-mm fragments for "prevention" experiments; and (b) 2-3-mm fragments allowed to grow to 1 cm for "intervention" studies. Both groups received either 0.5 mg/ml linomide in drinking water or acidified water and were followed until tumor diameter reached 3 cm or for 4 weeks. In both the prevention and intervention experiments, a significant diminution of tumor size and weight was observed in the drug-treated animals. In vivo nuclear magnetic resonance analysis of tumor blood flow in linomide-treated animals showed localization of blood vessels almost exclusively to the periphery of the poorly vascularized tumors with a significant reduction of both vascular functionality and vasodilation. Histological examination of tumors from linomide-treated animals revealed marked avascularity. Treated animals also displayed a 2.4-fold reduction of tumor vascular endothelial growth factor mRNA levels. Taken together, our data indicate that in VHL disease, therapy directed at inhibition of constitutively expressed VEGF induction of angiogenesis by VHL tumors may constitute an effective medical treatment.

Administration, Oral↗
PubMed1999

Allogeneic cell therapy in murine B-cell leukemia (BCL1): 1. Alloimmune-mediated graft-versus-leukemia (GVL) effects induced by unmodified and in vitro rIL-2-activated bone marrow and lymphocytes from different lymphoid compartments.

We have investigated the efficacy of graft-versus-leukemia (GVL) effects induced by cells obtained from different syngeneic and allogeneic lymphoid compartments, by comparing the response to cell therapy with syngeneic (BALB/c x C57BL/6)F1 (H-2d/b) (F1) or allogeneic C57BL/6 (H-2b) (B6) lymphocytes in F1 recipients inoculated with B-cell leukemia (BCL1) of BALB/c (H-2d) origin. Eradication of BCL1 was confirmed in vivo by adoptive transfer of 10(5) spleen cells obtained from treated mice into syngeneic BALB/c recipients. Immunotherapy induced by allogeneic but not syngeneic spleen and lymph node lymphocytes was therapeutically more effective than thymocytes and bone marrow cells (BMC). Alloreactive cells could be further activated in vivo with recombinant human interleukin-2 (rIL-2). The GVL effect of allogeneic lymphocytes was cell-dose-dependent; a heavy leukemia load was more efficiently eradicated after three doses than after a single dose of allogeneic spleen cells (100% versus 23% disease-free survival rate of secondary adoptive recipients respectively). The GVL effect induced by allogeneic spleen cells was preserved after ex vivo exposure of cells to 250 cGy, but not 500 cGy or more. Interestingly, GVL was preserved following administration of ex vivo irradiated (500 cGy) spleen cells when rIL-2 was administered in vivo (p < 0.05). Syngeneic effector cells did not induce GVL, regardless of in vitro and in vivo activation with rIL-2. Our data suggest that allogeneic but not syngeneic (in analogy to autologous) cell therapy may be an effective tool to control residual leukemia following high-dose chemo-radiotherapy. The feasibility of augmenting GVL by successive doses of activated allogeneic donor lymphocytes, partly inactivated in vitro by low-dose ionizing irradiation to prevent severe graft-versus-host disease (GVHD), may lead to safer therapeutic approaches that can be used to reduce the incidence of relapse while avoiding the risk of uncontrolled GVHD.

Animals↗
PubMed1999

Allogeneic cell therapy in murine B-cell leukemia (BCL1): 2. The role of non-activated and rIL-2-activated CD4+ and CD8+ T cells in immunotherapy for leukemia.

Graft-versus-leukemia (GVL) effects play a key role in the elimination of residual leukemia cells in the course of allogeneic bone marrow transplantation (alloBMT). GVL effects can also be induced by donor lymphocyte infusion following alloBMT. We have investigated the role of CD4+ and CD8+ T cells in the development of GVL in mice with B-cell leukemia/lymphoma (BCL1) following allogeneic cell therapy. Sublethally irradiated (C57BL/6 x BALB/c)F1 mice were intravenously inoculated with 10(5) BCL1 cells and given untreated or recombinant human Interleukin-2 (rIL-2)-activated C57BL/6 spleen cells. Effective elimination of clonogenic BCL1 cells was confirmed by adoptive transfer of spleen cells obtained from treated mice into secondary BALB/c recipients. GVL effects were maintained after inactivation of CD4+ cells with monoclonal anti-CD4 antibodies in the inoculum, while inactivation of CD8+ cells with monoclonal anti-CD8 antibodies resulted in complete loss of GVL effects induced both by resting and rIL-2-activated allogeneic spleen lymphocytes. These results indicate that Thy-1 cells play the major role in the induction of GVL effects, mediated by C57BL/6 effector T cells in this model. Since the number of natural killer (NK) cells also increased during in vitro culture with rIL-2, their contribution, especially that of CD8+ NK cells, in GVL effects mediated by rIL-2-activated CD8+ cells cannot be ruled out.

Animals↗
PubMed1998

The JNK pathway regulates the In vivo deletion of immature CD4(+)CD8(+) thymocytes.

The extracellular signal-regulated kinase (ERK), the c-Jun NH2-terminal kinase (JNK), and p38 MAP kinase pathways are triggered upon ligation of the antigen-specific T cell receptor (TCR). During the development of T cells in the thymus, the ERK pathway is required for differentiation of CD4(-)CD8(-) into CD4(+)CD8(+) double positive (DP) thymocytes, positive selection of DP cells, and their maturation into CD4(+) cells. However, the ERK pathway is not required for negative selection. Here, we show that JNK is activated in DP thymocytes in vivo in response to signals that initiate negative selection. The activation of JNK in these cells appears to be mediated by the MAP kinase kinase MKK7 since high levels of MKK7 and low levels of Sek-1/MKK4 gene expression were detected in thymocytes. Using dominant negative JNK transgenic mice, we show that inhibition of the JNK pathway reduces the in vivo deletion of DP thymocytes. In addition, the increased resistance of DP thymocytes to cell death in these mice produces an accelerated reconstitution of normal thymic populations upon in vivo DP elimination. Together, these data indicate that the JNK pathway contributes to the deletion of DP thymocytes by apoptosis in response to TCR-derived and other thymic environment- mediated signals.

Animals↗
PubMed1998

Duplication 6q21q23 in two unrelated patients.

We report on two patients with rare 6q duplications. The karyotype of patient 1 is 46,XY,dup(6)(q21q23.3). The karyotype of patient 2 is 46,XX,dup(6)(q21.15q23.3). These two patients have some nonspecific physical findings in common including a depressed nasal bridge, epicanthal folds, mild heart defects, and developmental delay, but each had other congenital anomalies.

Abnormalities, Multiple↗
PubMed1998

Discrepant responses to triple combination antiretroviral therapy in advanced HIV disease.

OBJECTIVES: To determine the clinical, virological and immunological outcome in a cohort of unselected patients receiving triple combination therapy for more than 1 year. METHODS: Prospective follow-up of a cohort of 162 unselected, protease inhibitor-naive, antiretroviral-experienced patients with advanced HIV disease, treated with indinavir combined with two nucleoside analogues. RESULTS: The mean CD4 cell count and plasma HIV RNA level in the study group at baseline were 69+/-5 x 10(6)/l and 4.75+/-0.07 log10 copies/ml, respectively. Five per cent of patients died prematurely or were lost to follow-up. Fifty-seven per cent of patients responded to therapy, as assessed by a sustained increase in CD4 cell counts above 50 x 10(6)/l and a decrease in plasma HIV RNA greater than 1 log10 copies/ml, throughout 12.1 months of follow-up. Seventeen per cent of patients were immunological and virological non-responders. Twenty-one per cent of patients exhibited discrepant virological and immunological responses to treatment, of whom one-half failed to exhibit significant increases in CD4 cells despite a virological response to therapy and one-half exhibited increased CD4 cell counts in the absence of significant decrease in plasma viral load. The incidence of AIDS-defining events in the latter group of patients was similar to that of responder patients, whereas their incidence was higher in patients who failed to exhibit a virological and immunological response and those who failed to increase CD4 cells despite a significant decrease in viral load. CONCLUSION: Our observations of discrepant immunological and virological responses to treatment raise the issue of the significance of persistent elevated levels of plasma HIV RNA and of the relevance of measurements of plasma viral load for assessing the efficacy of antiretroviral therapy in patients whose CD4 cell counts increase despite the absence of significant decrease in plasma HIV viral load.

Adult↗
PubMed1998

Adult and two children with fetal methotrexate syndrome.

The folic acid antagonists, methotrexate and aminopterin, are known to be teratogenic in humans. The critical period for their teratogenecity is suspected to be between 6 to 8 weeks post-conception. Fetal exposure from 10 to 32 weeks weeks post-conception to methotrexate alone or in combination with other anti-cancer drugs has not resulted in obvious teratogenic effects. Methotrexate is often used to treat cancers but is occasionally used as an abortifacient. The long-term outcome of the fetal aminopterin syndrome has been published in only four adults. We report on a 28-year-old man with fetal methotrexate syndrome and two children with mild manifestations of the syndrome. One child was inadvertently exposed to methotrexate from 7 1/2 through 30 weeks post-conception because his mother was receiving it for treatment of breast cancer. The other was exposed from 11 weeks and 5 days through 25 weeks in an attempt to induce abortion. The 28-year-old man has craniofacial and digital anomalies, growth retardation but normal intelligence as noted in the previously reported cases. These cases remind us of the teratogenicity of methotrexate and should serve as a warning that if methotrexate is used as an abortifaciant and an abortion does not ensue, there is a teratogenic risk.

Abnormalities, Drug-Induced↗
PubMed1998

The sequential occurrence of pol 215 and pol 41 zidovudine resistance mutations is associated in an additive fashion with low CD4 cell counts and high plasma and cellular HIV viral load.

We report on a cross-sectional study of virological and immunological surrogate markers of HIV infection in 115 patients for whom a determination of the pol 215 and pol 41 zidovudine (ZDV) resistance mutations had been described between January 1995 and February 1996. The patients received ZDV alone or a combination of ZDV and zalcitabine or didanosine. A total of 55, 15 and 45 patients exhibited a wild (W), a mixed (MIX) or a mutant (M) genotype at codon pol 215, respectively; 85, 10 and 20 patients exhibited a W, a MIX or a M genotype at codon pol 41, respectively. Patients exhibiting the pol 215 M genotype had lower CD4 cells, higher plasma viral load and higher proviral burden than patients exhibiting the pol 215 W genotype. Patients who had variants exhibiting both pol 215 M and pol 41 M or MIX genotypes had significantly worsened surrogate marker values than patients having variants only carrying the pol 215 M genotype. These observations demonstrate that the two mutations additively associate with pejorative surrogate markers.

Adult↗
PubMed1998

Persistent expansion, in a human immunodeficiency virus-infected person, of V beta-restricted CD4+CD8+ T lymphocytes that express cytotoxicity-associated molecules and are committed to produce interferon-gamma and tumor necrosis factor-alpha.

The present study describes the persistent expansion of a subpopulation of circulating double-positive CD4+CD8+ T cells in a human immunodeficiency virus (HIV)-infected person over 8 years. The percentage of double-positive cells was remarkably stable with time and was not related to HIV plasma virus load. CD4+CD8+ cells exhibited phenotypic characteristics of activated memory T lymphocytes. Analysis of V beta usage by the T cell receptors of these cells indicated restricted expression to the V beta 14 and V beta 17 families. Most CD4+CD8+ cells constitutively expressed cytotoxicity-associated molecules (C1.7 and perforin) and were selectively committed to produce interferon-gamma and tumor necrosis factor-alpha, cytokines involved in cytotoxic function. The kinetics of changes in the relative proportion of single-positive CD4+ and double-positive CD4+CD8+ T cell subsets and a similar bias in V beta usage by these subsets suggest that CD4+CD8+ lymphocytes originate from peripheral expansion of mature CD4+ T cells.

CD4 Antigens↗