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Biomedical subjects

L Schmidt

Publications and source records attributed to L Schmidt.

At least 91 records · Page 5Linked to original sources
PubMed1994

Hereditary papillary renal cell carcinoma.

We describe a 3 generation family with members affected with papillary renal cell carcinoma, an uncommon histological type of renal cell carcinoma. Multiple tumors of varying size were present in both kidneys of affected family members. The disorder was not linked to polymorphic markers on chromosome 3p and there was no loss of heterozygosity at loci on 3p in renal tumors. The results suggest the presence of a renal cell carcinoma gene not located on 3p that predisposes to renal cell carcinoma with a distinct histological appearance. The inherited disorder in this family appears to be different from recognized hereditary cancer syndromes.

Adolescent↗
PubMed1994

Mutations of the VHL tumour suppressor gene in renal carcinoma.

Multiple, bilateral renal carcinomas are a frequent occurrence in von Hippel-Lindau (VHL) disease. To elucidate the aetiological role of the VHL gene in human kidney tumorigenesis, localized and advanced tumours from 110 patients with sporadic renal carcinoma were analysed for VHL mutations and loss of heterozygosity (LOH). VHL mutations were identified in 57% of clear cell renal carcinomas analysed and LOH was observed in 98% of those samples. Moreover, VHL was mutated and lost in a renal tumour from a patient with familial renal carcinoma carrying the constitutional translocation, t(3;8)(p14;q24). The identification of VHL mutations in a majority of localized and advanced sporadic renal carcinomas and in a second form of hereditary renal carcinoma indicates that the VHL gene plays a critical part in the origin of this malignancy.

Adenocarcinoma, Clear Cell↗
PubMed1994

Loss of heterozygosity of the human cytosolic glutathione peroxidase I gene in lung cancer.

The consistent deletion of 3p21 in lung cancer has led to intensive efforts to identify a lung tumor suppressor gene at this locus. We recently mapped the gene for the selenium-dependent drug-detoxifying enzyme glutathione peroxidase 1 (GPX1) to this location by in situ hybridization. We developed a polymerase chain reaction-based assay which demonstrated the existence of three GPX1 alleles characterized by the number of alanines in a polyalanine coding sequence in exon 1. These three alleles produced a heterozygote frequency of 70% in two separate populations: normal tissue DNA taken from Centre d'Etude du Polmorphisme Humain (CEPH) parents and normal tissue taken from cancer patients. In contrast, 10 heterozygote tumors were detected out of 64 lung cancer specimens. Linkage analysis of GPX1 to Genethon 3p markers in CEPH pedigrees demonstrated that GPX1 was located between the two microsatellite markers believed to flank the lung cancer deletion site. Nucleotide sequence analysis of GPX1 alleles did not reveal any mutations of this gene in lung tumors. However, sequence analysis did reveal that the three GPX1 alleles were characterized by three nucleotide substitutions in addition to the polyalanine polymorphism, including a substitution at codon 198 which results in either a proline or leucine at that position. Therefore, the different GPX1 alleles encode structurally different hGPx1 subunits. In addition, analysis of allele frequency suggests that the GPX1*ALA7 allele may occur less frequently in tumors with 3p21 deletions.

Alleles↗
PubMed1994

Genetically modified skin to treat disease: potential and limitations.

Molecular definition of disease at the level of the gene and advances in recombinant DNA technology suggest that many diseases are amenable to correction by genes not bearing the defective elements that result in disease. Many questions must be answered before this therapy can be used to correct chronic diseases. These questions fall into safety and efficacy categories. Experience with transplanting cellular elements of skin or skin substitutes (defined as skin that possess the cell types and a dermal structure to develop into a functioning skin) to athymic rodents is considerable and is seen as a system where these questions can be answered. This paper reviews these questions and presents our early analysis of genetically modified cells in skin substitutes in vivo and in vitro. Experimental data demonstrate that both a matrix of woven nylon, housing a fibroblast generated collage, and dead dermis can be utilized to shuttle genetically modified human fibroblasts from the laboratory to an in vivo setting. Genetically modified fibroblasts do not migrate from the shuttle to the surrounding tissue. The survival of significant numbers, approximately 70%, of genetically modified fibroblasts for at least 6 weeks in these shuttles, supports this general approach as having clinical utility. It is also concluded that skin substitute systems can be used to generate a genetically modified skin in vitro that has the capacity to develop into functional skin in vivo. Further, as genetically modified keratinocytes differentiate there is increased production by the transgene, supporting the concept that keratinocytes have true potential as shuttles for therapeutic genes. This work demonstrates that transplantation of systems containing genetically modified cells of the skin can be used to experimentally define many aspects of gene therapy using skin before this technology is taken to the clinic. Examples include determining the effect of gene transduction and expression on structure and function of the genetically modified skin as well as on distant skin and an assessment of the translational capacity of the transgene as function of time and cell number.

3T3 Cells↗
PubMed1994

Recovery of T-lymphocytes for adoptive immunotherapy by lymphapheresis of HIV-infected patients without alterations of virological, immunological or clinical parameters.

We performed repeated continuous flow cytaphereses (CFC) on 13 asymptomatic HIV-1-infected patients to study the feasibility of cell separation procedures to recover high yields of peripheral blood T-lymphocytes for adoptive immunotherapy in HIV-infected patients and to determine immunological and virological alterations following such procedures. A mean yield of 6.23 x 10(9) lymphocytes could be obtained by each cytapheresis, containing 1.82 x 10(9) CD4+, 3.23 x 10(9) CD8+ T-lymphocytes and 8.39 x 10(6) CD34+ peripheral progenitor cells. The CD4/CD8 ratio (mean 0.53, SD +/- 0.15) in the cell samples reflected the distribution of the lymphocyte subsets in vivo. Absolute lymphocyte counts decreased at a mean of 404/mm3 (25%) immediately after CFC but were replaced from the extravascular pool within 1 h. The CD4/CD8 ratios, p24-antigenaemia, HLA-DR expression and neopterin levels did not change significantly after cell separation. No alteration of the number of T-cells with integrated proviral DNA copies (1/10(3) to 1/10(6)) could be detected in peripheral T-helper cells by PCR after lymphapheresis. We conclude that high yields of peripheral T-lymphocytes can be obtained by continuous flow lymphapheresis for cell-mediated immunotherapy, without deterioration of virological or immunological parameters in HIV-infected patients. The separated T-cells are fully replaced from extravascular pools after 1 h.

CD4-CD8 Ratio↗
PubMed1994

Dose-ranging evaluation of the serotonin antagonist dolasetron mesylate in patients receiving high-dose cisplatin.

PURPOSE: This dose-ranging trial of intravenous dolasetron mesylate (MDL73,147EF) was performed to determine its adverse and antiemetic effects in patients receiving cisplatin at doses > or = 100 mg/m2. PATIENTS AND METHODS: Eighty-nine patients treated with initial cisplatin received a single intravenous dose of dolasetron mesylate administered over 20 minutes beginning 30 minutes before chemotherapy. The following four dose levels were studied: 1.8, 2.4, 3.0, and 5.0 mg/kg. Emesis and adverse effects were measured for 24 hours after cisplatin. RESULTS: All adverse effects were mild and transient including loose stools, headache, serum AST/ALT elevations, and asymptomatic prolongation of ECG intervals. Among the dose levels, no-emesis rates from 24% to 52% were observed, and the percentage of patients having zero, one, or two emetic episodes ranged from 48% to 82%. Complete control of vomiting increased as the dose was escalated to 2.4 mg/kg, but did not improve further with higher doses. CONCLUSION: Dolasetron mesylate can be administered safely at doses up to 5.0 mg/kg, with comparable complete protection rates and increased adverse effects at doses greater than 2.4 mg/kg. Antiemetic activity was seen after cisplatin. Trials comparing single infusions of dolasetron mesylate and ondansetron are under way.

Adult↗
PubMed1994

5'-Azido and 5'-fluoro alpha-nucleosides as analogues of AZT and FLT.

5-Azido-2,5-dideoxy-beta-D-erythro-pentofuranosyl nucleosides 10 and their corresponding alpha-anomers 11 have been synthesized by condensation of methyl 3-O-acetyl-5-azido-2,5-dideoxy-beta-D-erythro-pentofuranoside (7) with silylated nucleobases followed by deprotection with methanolic ammonia. Reaction of silylated thymine (19) with methyl 2,3-di-O-benzoyl-5-deoxy-5-fluoro-D-arabino-pentofuranoside (15) and methyl 5-azido-2,3-di-O-benzoyl-5-deoxy-alpha-D-arabino-pentofuranoside (17 alpha) afforded a mixture of the alpha-nucleosides 20 and the acyclo nucleosides 5-fluoro- and 5-azido-2,3-O-dibenzoyl-5-deoxy-1-O-methyl-1-(thymin-1-yl)-D -arabinitol (22). Compounds 20 and 22 were deprotected with methanolic ammonia to give the acyclic nucleosides 21 and 23, respectively. The new nucleosides were inactive against HSV-1 and HIV-1.

Animals↗
PubMed1993

[Lymph drainage from the breast to the parasternal lymph nodes].

Breast lymphography revealed linkage between the axillary and parasternal lymph nodes in three out of 55 patients with breast cancer. In all the cases the efferent lymph vessels outlined laterally and, according to Berg's scheme, lymph node groups I, II and III were filled. Lymph vessel responsible for the filling of the parasternal lymph nodes branched from the area of group I lymph nodes. In two out of the 3 cases axillary metastasis was detected in one case, however, the axillary was found unaffected. The lymph vessel linkage observed doesn't seem to support the widely accepted concept, according to which there are only direct efferent lymph vessels running from the breast to the parasternal lymph nodes. This finding also explains why the incidence of parasternal metastases in the breast is higher in the case of tumorous obstruction of the axillary lymph nodes.

Axilla↗
PubMed1993

[Evaluation of home pregnancy tests].

Three home pregnancy tests, Clearblue (Tjellesen), Clearblue one step (Tjellesen) and Predictor (Organon), were tested and compared with respect to sensitivity, specificity, prozone-phenomenon and convenience for use. In addition, they were compared with two well-known pregnancy tests, HCG-Novoclone (Novo) and HCG-Nostick (Organon), which are used in several hospitals and drugstores. All three home pregnancy tests were found to be in agreement with the instructions for use with regard to sensitivity and prozone phenomenon. One test, Clearblue one step, showed false positive results when LH was added. Clearblue was found to be laborious and unhygienic in performance. Predictor seems to be the test of choice.

Evaluation Studies as Topic↗
PubMed1993

von Hippel-Lindau syndrome: cloning and identification of the plasma membrane Ca(++)-transporting ATPase isoform 2 gene that resides in the von Hippel-Lindau gene region.

We have isolated and analyzed full-length complementary DNA clones encoded by a 200-kilobase gene encompassing the D3S601 locus that resides in the von Hippel-Lindau (VHL) gene region. The deduced amino acid sequence shows 99% identity with the published sequence of the rat plasma membrane Ca(++)-transporting ATPase isoform 2 complementary DNA, implying that we have cloned and positioned the human plasma membrane Ca(++)-transporting ATPase isoform 2 gene within the VHL critical region. The gene is expressed in VHL target tissues and should be considered a potential candidate gene for the VHL disease.

Amino Acid Sequence↗
PubMed1993

Developments in alcoholism treatment.

Alcohol treatment systems expanded and diversified considerably over the past decade. This reflects adaptation to a variety of forces, including developments in national health care financing and policy, changes in other health care systems with which alcohol treatment had strong ties, the more diffuse effects of social movements and a "drying trend" in American public opinion, as well as agitation by advocacy and provider groups within the alcohol field. Drawing on national monitoring data, this chapter reviews developments at the levels of financing policy, organizations, client populations, and treatment modalities, documenting expansion in private sector alcohol treatment units, a growing emphasis on providing outpatient treatment, a merger between services for alcohol and drugs at the organizational and conceptual levels, increases in service delivery to coerced populations, as well as demographic change in alcohol treatment caseloads during the 1980s.

Adult↗
PubMed1993

Pharmacokinetics of etoposide: correlation of pharmacokinetic parameters with clinical conditions.

The pharmacokinetic parameters of etoposide were established in 35 patients receiving the drug parenterally within the framework of different polychemotherapy protocols. A total of 62 data for 24-h kinetics were analysed. After sample extraction and high-performance liquid chromatography (HPLC) or thin-layer chromatographic (TLC) separation, etoposide was measured by means of [252Cf]-plasma desorption mass spectrometry (PDMS). This highly specific detection system proved to be very practicable and reproducible. The present study comprised two parts that were absolutely comparable in terms of clinical and pharmacokinetic parameters. In part II of the study, sensitivity was improved by modifying the analytical technique. After the exclusion of patients who had previously been given cisplatin or who exhibited renal impairment and of one patient who showed extremely high levels of alkaline phosphatase, gamma-GT and SGPT, the mean values calculated for the pharmacokinetic parameters evaluated were: beta-elimination half-life (t 1/2 beta), 4.9 +/- 1.2 h; mean residence time (MRT), 6.7 +/- 1.4 h; area under the concentration-time curve (AUC), 5.43 +/- 1.74 mg min ml-1; volume of distribution at steady state (Vdss), 6.8 +/- 2.7 l/m2; and clearance (Cl), 18.8 +/- 5.3 ml min-1 m-2. The pharmacokinetic parameters were correlated with 12 different demographic or biochemical conditions. Impaired renal function, previous application of cisplatin and the age of patients were found to influence etoposide disposition to a statistically significant extent. We suggest that the dose of etoposide should be reduced in elderly patients and/or in individuals with impaired renal function, especially in those exhibiting general risk factors such as reduced liver function with regard to the polychemotherapy.

Adult↗
PubMed1993

Phototransformation of monovinyl and divinyl protochlorophyllide by NADPH:protochlorophyllide oxidoreductase of barley expressed in Escherichia coli.

The chlorophyll precursors monovinyl protochlorophyllide (MV-PChlide) and divinyl protochlorophyllide (DV-PChlide) were extracted from mutant C-2A' of the unicellular green alga Scenedesmus obliquus which accumulates both protochlorophyllide derivatives in the dark. The two pigments were characterized by absorption and fluorescence spectroscopy and by plasma desorption mass spectrometry. The molecular masses of MV-PChlide and DV-PChlide were determined as 612 and 610 atomic mass units (amu) respectively. Both MV-PChlide and DV-PChlide were accepted as substrates and photoconverted to chlorophyllides in vitro by NADPH:protochlorophyllide oxidoreductase of barley expressed in Escherichia coli.

Chlorophyta↗
PubMed1993

Neutrophil platelet-activating factor in normal and hypertensive pregnancy and in pregnancy-induced hypertension.

1. Platelet-activating factor is a phospholipid with potent vasodilator and platelet-activating properties. To test the hypothesis that a generalized change in cellular platelet-activating factor metabolism may be involved in the systemic vasodilatation of normal pregnancy or pregnancy-induced hypertension, we studied platelet-activating factor and eicosanoid synthesis in isolated leucocytes obtained from pregnant women before and after delivery compared with age-matched non-pregnant control subjects. Parallel observations were carried out in age- and gestation-matched women with uncomplicated hypertension in pregnancy and in women with pregnancy-induced hypertension and a further set of normotensive pregnant control subjects. 2. Leucocyte counts were higher in all pregnant groups compared with non-pregnant control subjects. Neutrophil production of platelet-activating factor and metabolites of prostacyclin, prostaglandin E2 and thromboxane in response to calcium ionophore stimulation were all lower in pregnant women compared with non-pregnant control subjects, but returned to similar levels 6 weeks post partum. There was no significant difference between essential hypertensive and normotensive groups. When women with pregnancy-induced hypertension were a priori sub-divided into those with or without proteinuria, subjects with proteinuria showed significantly lower levels of neutrophil platelet-activating factor synthesis. 3. Plasma levels of the platelet-activating factor metabolite (lyso-platelet-activating factor) were also lower in pregnancy, suggesting alterations in the activity of enzymes controlling synthesis or degradation of this phospholipid in pregnancy. In pregnancy-induced hypertension the levels of plasma lyso-platelet-activating factor were higher than in normal pregnancy.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗