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Biomedical subjects

L Weiss

Publications and source records attributed to L Weiss.

At least 109 records · Page 6Linked to original sources
PubMed1997

Combined heterozygous deficiency of the classical complement pathway proteins C2 and C4.

Genetic deficiencies of components of the classical pathway of complement activation are associated with an increased risk for the development of autoimmune and immune complex-mediated diseases. In the present study we report on the molecular and clinical features associated with combined heterozygous C4 and C2 deficiency in 15 individuals investigated within six families. Approximately 30% of the individuals manifested SLE or another autoimmune condition. Heterozygous C2 deficiency was related to a 28-bp deletion in the C2 gene (C2 deficiency type I), in most cases within the HLA-A25 B18 C2Q0 BfS C4A4B2 DR2 haplotype. Among 13 partial C4-deficient haplotypes transmitted, 8 carried C4A*Q0 alleles and 5 C4B*Q0 alleles. In seven cases the C4A*Q0 alleles were associated with a deletion of the C4A/CYP21P genes within the HLA-B8 C2C BfS C4AQ0B1 DR3 haplotype. In three cases, the C4B*Q0 allele was associated with a deletion of the C4B/CYP21P genes within the HLA-B18 C2C BfF1 C4A3BQ0 DR3 haplotype. In the other cases, C4A*Q0 or C4B*Q0 was dependent on as yet uncharacterized defects in the C4 gene or in C4 gene expression. In view of the relatively high frequency of heterozygous C4 deficiency in the normal Caucasian population, the expected frequency of the combined deficiency should approximate 0.001.

Adult↗
PubMed1997

Interleukin-7-enhanced cytotoxic T lymphocyte activity after viral infection in marrow transplanted mice.

Lethally irradiated BALB/c mice were reconstituted by syngeneic bone marrow transplantation (BMT), and injected with recombinant interleukin 7 (rIL-7), recombinant interleukin 2 (rIL-2), or saline 10 days post-transplantation. Intranasal infection with A/PR8/34 influenza virus 2 weeks after BMT was associated with the highest survival rate in the rIL-7 treated group. The protective mechanism elicited by rIL-7, as manifested by very low virus titers in the lung, involves T and B cell functions. High hemagglutinin inhibition antibody levels were observed on days 7 and 12 post-challenge in the rIL-7 mice. Moreover, the anti-influenza cytotoxic T lymphocyte activity was induced primarily by rIL-7, leaving the effect of rIL-2 on the same level as that of the control. Thus, rIL-7 promotes both T cell-mediated function and B cell production during the immunodeficient state after BMT. This cytokine may prove a potential immunotherapeutic modality in BMT recipients.

Animals↗
PubMed1997

Coding mutations in p57KIP2 are present in some cases of Beckwith-Wiedemann syndrome but are rare or absent in Wilms tumors.

The Beckwith-Wiedemann syndrome (BWS) is marked by fetal organ overgrowth and conveys a predisposition to certain childhood tumors, including Wilms tumor (WT). The genetics of BWS have implicated a gene that maps to chromosome 11p15 and is paternally imprinted, and the gene encoding the cyclin-cdk inhibitor p57KIP2 has been a strong candidate. By complete sequencing of the coding exons and intron/exon junctions, we found a maternally transmitted coding mutation in the cdk-inhibitor domain of the KIP2 gene in one of five cases of BWS. The BWS mutation was an in-frame three-amino-acid deletion that significantly reduced but did not fully abrogate growth-suppressive activity in a transfection assay. In contrast, no somatic coding mutations in KIP2 were found in a set of 12 primary WTs enriched for cases that expressed KIP2 mRNA, including cases with and without 11p15.5 loss of heterozygosity. Two other 11p15.5 loci, the linked and oppositely imprinted H19 and IGF2 genes, have been previously implicated in WT pathogenesis, and several of the tumors with persistent KIP2 mRNA expression and absence of KIP2 coding mutations showed full inactivation of H19. These data suggest that KIP2 is a BWS gene but that it is not uniquely equivalent to the 11p15.5 "WT2" tumor-suppressor locus.

Beckwith-Wiedemann Syndrome↗
PubMed1997

Maternal uniparental disomy of chromosome 1 with reduction to homozygosity of the LAMB3 locus in a patient with Herlitz junctional epidermolysis bullosa.

Junctional epidermolysis bullosa (JEB) is an autosomal recessive disorder characterized by blister formation at the level of the lamina lucida within the cutaneous basement-membrane zone. Classic lethal JEB (Herlitz type [H-JEB]; OMIM 226700) is frequently associated with premature-termination-codon mutations in both alleles of one of the three genes (LAMA3, LAMC2, or LAMB3) encoding the subunit polypeptides (alpha3, beta3, and gamma2) of laminin 5. In this study, we describe a unique patient with H-JEB, who was homozygous for a nonsense mutation, Q243X, in the LAMB3 gene on chromosome 1 and who had normal karyotype 46,XY. The mother was found to be a carrier of the Q243X mutation, whereas the father had two normal LAMB3 alleles. Nonpaternity was excluded by use of 11 microsatellite markers from six different chromosomes. The use of 17 partly or fully informative microsatellite markers spanning the entire chromosome 1 revealed that the patient had both maternal uniparental meroisodisomy of a 35-cM region on 1q containing the maternal LAMB3 mutation and maternal uniparental heterodisomy of other regions of chromosome 1. Thus, the results suggested that reduction to homozygosity of the 1q region containing the maternal LAMB3 mutation caused the H-JEB phenotype. The patient was normally developed at term and did not show overt dysmorphisms or malformations. This is the first description of uniparental disomy of human chromosome 1.

Alleles↗
PubMed1997

Plasma levels of monocyte chemoattractant protein-1 but not those of macrophage inhibitory protein-1alpha and RANTES correlate with virus load in human immunodeficiency virus infection.

Plasma levels of proinflammatory cytokines, cytokine inhibitors, and the beta chemokines RANTES, macrophage inhibitory protein (MIP)-1alpha, and monocyte chemoattractant protein (MCP)-1 were studied in relationship with virus load in 40 patients exhibiting plasma levels of HIV RNA ranging between undetectable and levels >10(6) copies/mL. Mean plasma levels of MCP-1 were increased in patients with high virus load compared with HIV-seropositive subjects with undetectable plasma viral RNA and healthy controls. MCP-1 levels were directly correlated with plasma levels of HIV RNA. No correlation was observed between virus load and plasma concentrations of MIP-1alpha and RANTES. The results suggest that low rates of viral replication in vivo are not dependent on increased production of the suppressive chemokines RANTES and MIP-1alpha. Since MCP-1 upregulates viral replication in vitro, the results may suggest a role for MCP-1 in triggering viral replication in HIV disease.

Chemokine CCL2↗
PubMed1997

Lipoprotein abnormalities are associated with increased rate of progression of human chronic renal insufficiency.

BACKGROUND: Chronic renal insufficiency is accompanied by specific alterations of the lipoprotein metabolism. It has been suggested that the renal dyslipoproteinaemia of renal insufficiency contributes to the progression of glomerular and tubular lesions, with subsequent deterioration of renal function. The objective of this prospective study was to investigate whether the specific lipoprotein abnormalities of renal insufficiency are associated with the rate of decline of renal function in patients with moderately advanced chronic renal failure. METHODS: A patient population of 73 adult non-diabetic patients with primary chronic renal disease were followed with repeated measurements of the glomerular filtration rate (GFR) for an average of 3.2 (SD 0.7) years. Forty-three of these patients had chronic glomerulonephritis as the underlying renal disease. Patient characteristics including plasma levels of lipids and apolipoproteins were determined at entry and were prospectively related, using linear regression, to the rate of progression. RESULTS: The mean GFR at entry was 41.3 (SD 15.3) ml/min x 1.73 m2 BSA. The average rate of progression was a decline in GFR of -2.8 (SD 3.7) ml/min x 1.73 m2 BSA per year. In the whole patient study group total cholesterol, low-density lipoprotein (LDL) cholesterol, and apolipoprotein B (apoB) were all significantly associated with a more rapid decline in renal function, whereas triglycerides, high-density lipoprotein (HDL) cholesterol, and apolipoprotein A (apoA) were not. In the more homogeneous subgroup of patients with chronic glomerulonephritis the association between dyslipidaemia and the rate of progression was even more pronounced. In this subgroup of patients also serum triglycerides and apoE were significantly associated with a higher rate of progression. Both the initial blood pressure and proteinuria were also significantly associated with a more rapid decline in renal function in the whole study group as well as in patients with chronic glomerulonephritis. The associations between these variables with the rate of progression were all independent of the entry GFR values. CONCLUSIONS: These results indicate that the lipoprotein abnormalities of renal insufficiency contribute to the progression of renal failure in human chronic renal disease.

Adult↗
PubMed1997

Effect of gemfibrozil on lipoprotein abnormalities in chronic renal insufficiency: a controlled study in human chronic renal disease.

BACKGROUND: Renal dyslipoproteinemia is characterized by the accumulation of intact and partially metabolized triglyceride-rich lipoproteins. Reduced lipolytic enzyme activities may be one of the major pathophysiological mechanisms contributing to a retarded catabolism of these lipoproteins in patients with renal insufficiency. OBJECTIVE: To evaluate the effect of gemfibrozil treatment on renal dyslipoproteinemia. STUDY DESIGN: A randomized, controlled open study with 2 parallel groups. OUTCOME VARIABLES: Plasma concentrations of lipids, apolipoproteins and lipoprotein particles. PATIENTS AND METHODS: Fifty-seven non-nephrotic, non-diabetic patients with moderately advanced renal insufficiency were randomized to either treatment with gemfibrozil at dosages from 300 to 900 mg/day (n = 28) or dietary counseling (n = 29). The intervention period was 12 months. Plasma concentrations of lipids, apolipoproteins and apoA- and apoB-containing lipoprotein particles were determined at the entry and after 6 and 12 months of treatment. RESULTS: No serious adverse effects occurred during the study. Six patients experienced mild gastrointestinal symptoms and prematurely withdrew from the drug treatment. In the group treated with gemfibrozil the plasma concentrations of triglycerides, total cholesterol, very low density lipoprotein (VLDL) and low density (LDL) cholesterol decreased significantly by 47, 13, 43 and 14%, respectively, in comparison to baseline. High density lipoprotein (HDL) cholesterol increased significantly by 18%. ApoB, apoC-III, apoC-III in heparin-manganese precipitate (reflecting apoC-III in VLDL and LDL) and apoE decreased significantly by 21, 18, 26 and 49%, respectively. Furthermore, gemfibrozil treatment resulted in the reduction of plasma concentrations of complex (LP-Bc) and simple (LP-B) apoB-containing lipoprotein particles by 22 and 7%, respectively. However, these changes were not statistically significant. There was a slight, insignificant increase in the levels of LP-A-I:A-II particles and no change in the levels of LP-A-I particles. In contrast to the effect of the pharmacological intervention, the dietary counseling only resulted in minor changes in the plasma lipid and apolipoprotein profiles. The only significant changes were a 10% increase in HDL cholesterol and a 35% decrease in apoE. CONCLUSIONS: Gemfibrozil treatment significantly reduces both plasma lipids and apoB, apoC-III and apoE concentrations in patients with moderately advanced renal insufficiency. The results of this study indicate that gemfibrozil enhances the clearance of apoB-containing triglyceride-rich lipoproteins.

Apolipoproteins↗
PubMed1997

[Rare non-Hodgkin's lymphoma in the course of infection with human immunodeficiency virus. Two cases with bone marrow invasion].

Malignant non Hodgkin's lymphomas in patients with acquired immunodeficiency syndrome are usually of high grade and have a B-cell phenotype. We describe two cases of rare lymphomas during acquired immunodeficiency syndrome: one case of pleomorphic T cell lymphoma with medium and large cell predominance, of high grade of malignancy, according to the updated Kiel classification, involving mainly the bone-marrow, and one case of low grade monocytoid B-cell lymphoma with bone-marrow extension, which is a rare condition in this type of lymphoma. These lymphomas seem to be a casual event during acquired immunodeficiency syndrome, but the immunodeficiency can be responsible of a more aggressive behavior.

Adult↗
PubMed1997

High-dose infusional doxorubicin and cyclophosphamide: a feasibility study of tandem high-dose chemotherapy cycles without stem cell support.

The purpose of this study was to determine the maximally tolerated dose of doxorubicin administered during two cycles of intensive chemotherapy with cyclophosphamide and doxorubicin without stem cell support in patients with advanced cancer and to assess the cumulative cardiac toxicity of the regimen by noninvasive radionuclide imaging and by pre-and postchemotherapy endomyocardial biopsies. Thirty-eight patients (thirty-six with high risk or metastatic breast cancer) were treated in a dose-escalation trial using a fixed dose of i.v. cyclophosphamide (4.2 g/m2) administered over 2 h on day 5 and escalating doses of doxorubicin (50-175 mg/m2) given as a 96-h continuous i.v. infusion on days 1-4, using Filgrastim (granulocyte colony-stimulating factor) for hematological support beginning on day 6. All patients underwent pretreatment, and 28 patients underwent postchemotherapy endomyocardial biopsies. Twenty-nine of 38 patients received two cycles of treatment (median number of days between cycles, 44; range, 34-62). Twenty-one patients had received doxorubicin previously at cumulative dose levels </=150 mg/m2; all patients had pretreatment endomyocardial biopsy scores less than 1. One patient treated at the highest dose level of doxorubicin (175 mg/m2) developed symptoms of mild congestive heart failure following two cycles of chemotherapy. Pre- and posttreatment radionuclide ejection fractions were 65 and 45%, respectively; this patient had a posttreatment endomyocardial biopsy score of 1 (damage to <5% of myocytes). One additional patient at this dose level had an asymptomatic biopsy score of 1, with a decrease in ejection fraction from 62 to 43%; this recovered to 58% 5 months after completion of chemotherapy. Six additional patients treated at lower dose levels had abnormal posttreatment endomyocardial biopsies without abnormal posttreatment ejection fractions. Nine patients received only one cycle of chemotherapy: five patients due to decreased cardiac ejection fraction following cycle 1 (two of these patients had normal endomyocardial biopsies, and two patients had biopsy scores of 1); one patient secondary to tumor progression following cycle one; one patient due to persistently detectable Clostridium difficile toxin in the stool; one patient refused cycle two; and one patient died following cycle one of complications related to sepsis. A single patient experienced a grand mal seizure associated with orthostatic hypotension, which was considered the dose-limiting toxicity. The median duration (over two cycles) of granulocytopenia (absolute granulocyte count <500/microliter) at the maximally tolerated dose level of 150 mg/m2 was 8.5 days (range, 5-13 days), and the median duration of thrombocytopenia (platelets <20,000/microliter) was 2.5 days (range, 0-9 days). The median duration of hospitalization including chemotherapy administration was 23 days (range, 19-36 days). Other toxicities included stomatitis, fever, diarrhea, and emesis. One patient developed acute leukemia 54 months posttreatment. We conclude that two courses of high-dose cyclophosphamide and doxorubicin using granulocyte colony-stimulating factor are feasible and safe with tolerable myocardial toxicity as evidenced by serial endomyocardial biopsies. The dose-limiting toxicity encountered was a grand mal seizure. The recommended Phase II dose is doxorubicin 150 mg/m2 administered as a 96-h infusion on days 1-4, with cyclophosphamide 4. 2 g/m2 on day 5 and G-CSF 5 microgram/kg/day started on day 6 and administered until the total WBC is above 10,000/microliter for three consecutive days.

Adult↗
PubMed1996

Prevention of autoimmune diabetes by linomide in nonobese diabetic (NOD) mice is associated with up-regulation of the TCR-mediated activation of p21(ras).

Oral therapy with linomide protects prediabetic nonobese diabetic (NOD) mice from insulin-dependent diabetes mellitus. The mechanisms by which linomide exerts its protective effect are not fully understood. A decreased TCR-mediated activity of the GTP-GDP binding p21(ras) proto-oncogene is associated with prediabetes in NOD mice. However, the role of this signal transduction defect in the pathogenesis of autoimmune diabetes is not known. The TCR-mediated and protein kinase C-induced activations of p21(ras) were determined in mononuclear cells from lymph nodes of linomide-treated and untreated prediabetic NOD mice. TCR cross-linking by Con A induced an increase of 13 +/- 6.8% and a decrease of 0.8 +/- 1.8% in p21(ras) activity in the linomide-treated group and the untreated controls, respectively. Cell stimulation with PMA resulted in a 15 +/- 2% increase in p21(ras) activity in the linomide-treated mice and a 10 +/- 11.4% decrease in the untreated mice. Protein levels of p21(ras) and its regulatory elements, the GTPase-activating protein and the guanine nucleotide-releasing factor, mSOS, were comparable in both groups. We, therefore, conclude that prevention of autoimmune diabetes by linomide is associated with up-regulation of the p21(ras) T cell signal transduction defect in NOD mice.

Adjuvants, Immunologic↗
PubMed1996

Toriello-Carey syndrome: evidence for X-linked inheritance.

Toriello-Carey syndrome is characterized by agenesis of the corpus callosum, telecanthus, short palpebral fissures, Robin sequence, abnormal ears, cardiac anomalies, and hypotonia. We describe two patients with Toriello-Carey syndrome and call attention to an unbalanced sex ratio. The first patient, a male, was born at term by Cesarean section and manifests micrognathia, cleft soft palate, hypoplastic right ear, anotia on the left side, cerebellar vermis hypoplasia, hydrocephalus, agenesis of the corpus callosum, and hypoplastic left heart. He died 2 days after birth. The second patient is the male sib of a patient reported previously [Am J Med Genet 42: 374-376; 1992]. He had large fontanelles, telecanthus, a short nose, small and malformed ears, micrognathia, a large ventricular septal defect, and pulmonary stenosis. At age 8 months he has growth retardation and developmental delay. A sister is unaffected. Review documented eight other patients with Toriello-Carey syndrome, six of whom were male. The two female patients are less severely affected and are still alive. Of the other male patients, all are deceased except one who is still alive at age 5 years; he has severe growth retardation (-3 SD), mental retardation (DQ44), severe speech delay, and characteristic anomalies. The predominance of affected males and the milder phenotype in the female patients suggests an X-linked gene or sex influenced gene.

Abnormalities, Multiple↗
PubMed1996

Genetic counseling of isolated carriers of Duchenne muscular dystrophy.

It has recently become possible to detect female carriers of Duchenne muscular dystrophy with no affected male relative in the family. These "isolated carriers" represent about 10% of women with high serum creatine phosphokinase (CPK) levels and clinical evidence of a muscle disease. Most isolated carriers ascertained by clinical and/or CPK levels and diagnosed by dystrophin immunostaining of muscle biopsy show symptoms of a muscular dystrophy, and often carry the diagnosis of recessive "limb-girdle muscular dystrophy" prior to dystrophin analysis. It has been difficult to offer genetic counseling and prenatal diagnosis for Duchenne muscular dystrophy in the families of these isolated carriers, largely due to the difficulty in determining which of the dystrophin alleles segregating in the family harbors the mutation in the heterozygote. Here we report genetic counseling of three isolated carriers and their families. In two cases, prenatal diagnosis of at-risk pregnancies was conducted. We determined X inactivation patterns and inheritance of X chromosomes in each family, and used this information to define the at-risk dystrophin gene. In all three families, the mutation was a de novo event, two in the paternal germ-line, and one in the maternal germ-line. In each case we show that sibs of the heterozygous woman are at population risk, while pregnancies of each propositus are at high risk. Our results show that accurate genetic counseling and prenatal diagnosis can be offered to these families.

Adult↗
PubMed1996

[Quality assurance in therapy of chronic pain. Results obtained by a task force of the German Section of the Association for the Study of Pain on psychological assessment of chronic pain. IX. Multidimensional instruments for the assessment of aspects relating to pain and recommendations on standard procedures for diagnosis].

Four multidimensional inventories used as instruments for the assessment of pain are examined: "Fragebogen zur Erfassung der Schmerzverarbeitung' [Questionnaire for Assessment of Level of Coping with Pain], "Kieler Schmerzverarbeitungs-Inventar' [Kiel Inventory of Coping with Pain], "Fragebogen zur Schmerzregulation' [Questionnaire on Pain Regulation], and the German version of the "Multidimensional Pain Inventory'. None of these questionnaires assesses all domains that are important in chronic pain. The recommended standardized assessment routine for pain centres includes the use of a diary, the rating of actual, average and maximum pain intensity, the application of the PDI, a measure of disability, and the FESV, which records cognitive processing and coping. As measures of general psychological dysfunction the ADS for the assessment of depression and the B-L, a symptom checklist, are suggested as instruments suitable for routine use in diagnosis and evaluation.

English Abstract↗
PubMed1996

The HBV-producing cell line HepG2-4A5: a new in vitro system for studying the regulation of HBV replication and for screening anti-hepatitis B virus drugs.

All tissue culture systems for propagating HBV employed so far make use of tandemly arranged HBV genomes usually under the control of strong foreign promoters. Thus these systems are helpful for virus production but are of limited value in the investigation of the regulation of HBV replication or of the extent to which the expression of viral genes might be influenced by cellular signal transduction pathways. To overcome this barrier we established an HBV-producing cell line (HepG2-4A5) by stably transfecting HepG2 cells with a replication-competent, terminally redundant HBV plasmid (pSPT1.2 xHBV) that contains each of the four major HBV-ORFs only once and exclusively under the control of their own regulatory elements. HepG2-4A5 cells contain a single, nonrearranged, chromosomally integrated, replication-competent HBV genome. In the cytoplasm of HepG2-4A5 cells, all typical viral mRNAs were detectable, but no other viral transcripts were found. Furthermore, all viral gene products are synthesized in a balanced ratio, as close as possible to that found in an in vivo infection. Dane-like particles released from HepG2-4A5 cells were indistinguishable from virions synthesized in vivo, by all physical (electron microscopy, buoyant density) and biochemical (endogenous polymerase reaction, immunogenic behaviour) criteria. Because of the autologous genome organization in this system, the HepG2-4A5 cell line allows studies on the function of the HBV gene products with respect to their involvement in regulating HBV replication under conditions imitating as closely as possible the situation in vivo. Furthermore, this cell line might be a helpful tool in screening antiviral drugs and in studying their effect on regulating HBV replication.

Antiviral Agents↗
PubMed1996

Metastatic inefficiency: intravascular and intraperitoneal implantation of cancer cells.

The term metastatic inefficiency reflects the fact that most of the cancer cells entering the metastatic process are killed; some of the evidence for this is reviewed in the case of renal and colorectal carcinomas. Although much emphasis has been placed on the rapid intravascular death of cancer cells during hematogenous metastasis, much less is known about the inefficiency associated with peritoneal carcinomatosis, and up to the present no systematic and direct numerical studies have been reported of the relative metastatic inefficiencies associated with seeding of cancer cells by intraperitoneal, vascular, and lymphatic routes. However, studies on people and laboratory animals indicate that most of the cancer cells released into the peritoneal cavity are killed. Some of the mechanisms involved in killing constitute part of cellular defense operating through the release of toxic free radicals. One of these, hydrogen peroxide, given by intraperitoneal injection, has been shown to retard the development of malignant ascites in mice previously given intraperitoneal injections of cancer cells. It is suggested that local irrigation with hydrogen peroxide during surgery for abdominal tumors may be effective in inhibiting the development of peritoneal carcinomatosis.

Animals↗
PubMed1996

Induction of graft versus leukemia effects by cell-mediated lymphokine-activated immunotherapy after syngeneic bone marrow transplantation in murine B cell leukemia.

The feasibility of inducing graft versus leukemia (GVL) effects with allogeneic T cells in recipients of autologous bone marrow transplantation (BMT) was studied in a murine model (BCL 1) of human B cell leukemia/ lymphoma. Allogeneic cell therapy, induced by infusion with peripheral blood lymphocytes, a mixture of allogeneic spleen and lymph node cells and allogeneic activated cell therapy, induced by in vitro recombinant-interleukin-2(rIL-2)-activated allogeneic bone marrow cells in tumor-bearing mice, prevented disease development in adoptive BALB/c recipients. Concomitant in vivo activation of allogeneic lymphocytes with rIL-2 suppressed even more effectively the development of leukemia in secondary adoptive recipients of spleen cells obtained from treated mice. In contrast, in vivo administration of rIL-2 after syngeneic BMT, with or without equal numbers of syngeneic lymphocytes, led to disease development in secondary recipients. Our data suggest that effective cell therapy can be achieved after SBMT by allogeneic but not syngeneic lymphocytes and that anti-leukemic effects induced by allogeneic lymphocytes can be further enhanced by in vitro or in vivo activation of allogeneic effector cells with rIL-2. Therefore, cell therapy by allogeneic lymphocytes following autologous BMT could become an effective method for inducing GVL-like effects on minimal residual disease provided that graft versus host disease can be prevented or adequately controlled.

Adjuvants, Immunologic↗