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Biomedical subjects

J Weber

Publications and source records attributed to J Weber.

At least 199 records · Page 11Linked to original sources
PubMed1998

Serum interleukin-6 levels in metastatic renal cell carcinoma before treatment with interleukin-2 correlates with paraneoplastic syndromes but not patient survival.

PURPOSE: We sought to determine the frequency of interleukin-6 (IL-6) expression in renal cancer cell lines, the frequency of the detection of IL-6 in the serum of patients with metastatic renal cell carcinoma, whether serum IL-6 level correlates with the development of paraneoplastic syndromes and whether serum IL-6 level in patients with metastatic renal cancer correlates with response to treatment with interleukin-2 (IL-2) or patient survival. MATERIALS AND METHODS: Conditioned media from 21 cell lines from 20 patients were examined for IL-6. We identified 2 matched groups of patients with metastatic renal cancer (30 responders and 29 nonresponders) to IL-2 based immunotherapy. Stored pretreatment serum specimens were evaluated for IL-6. Medical records were reviewed to determine the presence of paraneoplastic syndromes. RESULTS: IL-6 was detected in 19 of 21 renal cancer cell lines (90%) obtained from 20 patients with metastatic renal cancer as well as in the serum of 33 of 59 patients (56%) with metastatic renal cell carcinoma. A significant association between serum IL-6 level and anemia (p = 0.0032), elevated platelet count (p = 0.01), decreased albumin (p = 0.034) and elevated alkaline phosphatase (p = 0.04) was found. A trend was noted of the association of increased serum IL-6 level and fever (p = 0.051). No correlation was found between pretreatment serum IL-6 level and survival or response to IL-2. CONCLUSIONS: IL-6 was frequently secreted by renal cancer cell lines but it was only present in the serum of approximately half of the patients with metastatic renal cancer. Elevations of serum IL-6 were associated with paraneoplastic manifestations frequently seen in patients with renal cancer, including anemia, thrombocytosis, decreased albumin and elevations of alkaline phosphatase (Stauffer's syndrome). A weak relationship was noted between serum IL-6 level and fever but none was noted between that and survival or response to IL-2.

Adult↗
PubMed1998

[Determinants for diagnostic and therapeutic co-operation between general practitioners].

In the light of new opportunities for structural arrangements in Germany calling for higher co-operation between physicians in private practice, determinants for diagnostic and therapeutic co-operation need to be examined. In the present study, 130 general practitioners were asked in regard to four typical primary care indication groups whether they prefer to diagnose and treat the patients on their own or in co-operation with colleagues. This self-assessment was validated using the data from 2,069 physician-patient contacts: physicians preferring therapy in co-operation actually referred patients three times more often. Concerning both gastro-intestinal and rheumatic disorders, physicians' preferences for diagnostic and therapeutic co-operation are highly correlated (phi = 0.491 and 0.528 respectively); preferences for diagnostic and therapeutic co-operation across indications are not as strongly correlated (phi = 0.334 and 0.397 respectively). However, there is no general indication-independent attitude towards co-operation for individual physicians: Indication and type of services are two factors which--probably in addition to others--affect co-operation independently. We confirm earlier conclusions that the detailed analysis of provider and patient characteristics together with the actual patient management on a case by case basis is a powerful tool for health services research.

Diagnostic Techniques and Procedures↗
PubMed1997

Configurations of diastereomeric hydroxyethylene isosteres strongly affect biological activities of a series of specific inhibitors of human-immunodeficiency-virus proteinase.

Human immunodeficiency virus (HIV) proteinase (PR) represents an important target for antiviral chemotherapy. We present an analysis of inhibitory activities of a series of pseudopeptide inhibitors of HIV-1 PR. All inhibitors were N-protected tetrapeptides with the scissile bond replaced by a nonhydrolysable hydroxyethylene or hydroxyethylamine isostere. To elucidate subtle structural requirements of the PR binding cleft, we synthesised inhibitors with four combinations of configurations at the asymmetric carbons of the isostere. Compounds were tested in vitro using purified recombinant enzyme and a chromogenic peptide substrate. The differences in inhibition constants between individual diastereoisomers reached three orders of magnitude. The most active hydroxyethylene-containing inhibitor possessed the 2R,4S,5S configuration at the isostere. Inhibitor activity was also tested in mammalian cell culture by analysing reduction of viral polyprotein processing and virus infectivity. The results obtained in tissue culture were generally in agreement with the in vitro data, giving a similar order of potency for the individual diastereoisomers. The most active compounds completely blocked production of infectious virus. A simulation method for interaction was employed to build a model of the inhibitors in the PR active site, to identify the interactions responsible for the differences in activities of individual stereoisomers, and to estimate the relative contribution of individual structural features to the overall inhibitory activity.

Animals↗
PubMed1997

HIV-1 viral load, phenotype, and resistance in a subset of drug-naive participants from the Delta trial. The National Virology Groups. Delta Virology Working Group and Coordinating Committee.

BACKGROUND: The Delta trial showed that combination therapy (zidovudine plus didanosine and zidovudine plus zalcitabine) substantially lengthened life and reduced disease progression compared with zidovudine monotherapy. We did a nested virological study in three countries (France, the Netherlands, and the UK) to investigate changes in markers for viral load and antiretroviral-drug resistance during therapy. METHODS: 240 zidovudine-naive HIV-1-infected patients were randomly assigned zidovudine only (n = 87), zidovudine plus didanosine (n = 80), or zidovudine plus zalcitabine (n = 73). Viral load in peripheral-blood mononuclear cells and plasma was measured by quantitative culture. Plasma HIV-1 RNA was measured by reverse-transcriptase PCR amplification, and serum p24 antigen by ELISA. Resistance to antiretroviral drugs was measured phenotypically by culture and genotypically by detection and quantification of drug-related point mutations in the pol gene. Analyses were done by intention to treat. FINDINGS: The reduction in viral load was greatest 4-12 weeks after the start of therapy and was most pronounced in the combination-therapy study groups (median reductions of RNA at 4 weeks 1.58, 1.28, and 0.49 log10 copies/mL for zidovudine plus didanosine, zidovudine plus zalcitabine, and zidovudine only, respectively). RNA levels at 8 weeks were predictive of disease progression and death after allowance for baseline values. At 48 weeks, the proportion of participants with phenotypic zidovudine resistance was similar in all three groups: didanosine and zalcitabine resistance were rare; zidovudine genomic resistance correlated with phenotypic resistance (r = 0.54, p < 0.0001) and developed earlier in the combined-therapy groups. However, participants in the zidovudine monotherapy group had higher circulating loads of resistant virus than those in the combined-therapy groups. INTERPRETATION: Combined antiretroviral therapy was more efficient at lowering virus load than monotherapy. Although zidovudine resistance was common in monotherapy and combined-therapy groups, circulating concentrations of resistant virus were substantially lower in the combination groups, which is likely to be a result of the continued antiviral activity of didanosine or zalcitabine.

Anti-HIV Agents↗
PubMed1997

An HIV type 1 epidemic among injecting drug users in the former Soviet Union caused by a homogeneous subtype A strain.

Epidemiological data have demonstrated rapid growth of HIV-1 infections among injecting drug users (IDUs) in the Ukraine and Russia, during 1996. Here we describe the results of genetic analysis of isolates derived from 12 HIV-1-infected IDUs in different sites of Russia and the Ukraine. The blood samples were taken within a 1- to 2-month period after the first HIV-1-positive test. The results of the heteroduplex mobility assay as well as gag/env phylogenetic analysis reveal that all sequences belong to gag/env genetic subtype A. Moreover, interpatient genetic distances between the nucleotide sequences encompassing the C2-V3, the V4-V5, and p17-encoding regions within this group were low (the average means were 0.9, 1.3, and 0.4%, respectively). These data show a marked homogeneity of HIV-1, probably spreading during primary infection. It is possible that the current epidemic of subtype A HIV-1 among IDUs in the former Soviet Union is caused by a point source exposure.

Adolescent↗
PubMed1997

Binding of TNP-ATP and TNP-ADP to the non-catalytic sites of Escherichia coli F1-ATPase.

Using site-directed-tryptophan fluorescence, parameters for equilibrium binding of (Mg)TNP-ATP and (Mg)TNP-ADP to non-catalytic sites of Escherichia coli F1-ATPase were determined. All three non-catalytic sites showed the same affinity for MgTNP-ATP (Kd = 0.2 microM) or MgTNP-ADP (Kd = 6.5 microM) whereas even at concentrations of 100 microM no binding of uncomplexed TNP-ATP or TNP-ADP was observed. The results demonstrate that the three non-catalytic sites bind TNP-nucleotides non-cooperatively, and emphasize the importance of Mg2+ for non-catalytic-site nucleotide binding. Parameters for binding of (Mg)TNP-ADP to the three catalytic sites were also determined, and showed marked cooperativity. This work completes the set of thermodynamic parameters for equilibrium binding of (Mg)TNP-ATP and (Mg)TNP-ADP to all six nucleotide sites of F1, providing essential information to fully exploit the potential of these nucleotide analogs in studies of F1-ATPase.

Adenosine Diphosphate↗
PubMed1997

Potency comparison of peptidomimetic inhibitors against HIV-1 and HIV-2 proteinases: design of equipotent lead compounds.

HIV-1 and HIV-2 proteinases (PR) are responsible for the processing of viral polyproteins, a step that is crucial for the formation of infectious virus particles. PR represents one of the most important targets for antiviral chemotherapy. Inhibitors of HIV-1 PR usually exhibit a 10- to 100-fold weaker affinity for HIV-2 PR. In order to design subnanomolar inhibitors for both HIV-1 and HIV-2 PRs, we prepared a series of compounds varying in the type of scissile bond replacement as well as in the P1, P1', and P2' side chains. While inhibitors containing reduced amide, hydroxyethylamine and statine isosteres had Ki values in the range of 10(-10)-10(-9) M against HIV-1 PR; their activities against HIV-2 PR were several orders of magnitude lower. Glutamic acid was identified to be the optimal P2' residue for both PRs. HIV-2 PR was shown to be more sensitive to P2' Glu-->Gln replacement. Using this data set we were able to design and prepare hydroxyethylene isostere containing inhibitors that were equipotent against both PRs.

Aspartic Acid Endopeptidases↗
PubMed1997

Catalytic mechanism of F1-ATPase.

The structure of the core catalytic unit of ATP synthase, alpha 3 beta 3 gamma, has been determined by X-ray crystallography, revealing a roughly symmetrical arrangement of alternating alpha and beta subunits around a central cavity in which helical portions of gamma are found. A low-resolution structural model of F0, based on electron spectroscopic imaging, locates subunit a and the two copies of subunit b outside of a subunit c oligomer. The structures of individual subunits epsilon and c (largely) have been solved by NMR spectroscopy, but the oligomeric structure of c is still unknown. The structures of subunits a and delta remain undefined, that of b has not yet been defined but biochemical evidence indicates a credible model. Subunits gamma, epsilon, b, and delta are at the interface between F1 and F0; gamma epsilon complex forms one element of the stalk, interacting with c at the base and alpha and beta at the top. The locations of b and delta are less clear. Elucidation of the structure F0, of the stalk, and of the entire F1F0 remains a challenging goal.

Adenosine Diphosphate↗
PubMed1997

Nucleotide occupancy of F1-ATPase catalytic sites under crystallization conditions.

Using site-directed tryptophan fluorescence we studied nucleotide occupancy of the catalytic sites of Escherichia coli F1-ATPase, under conditions used previously for crystallization and X-ray structure analysis of the bovine mitochondrial enzyme [Abrahams et al. (1994) Nature 370, 621-628]. We found that only two of the three catalytic sites were filled in the E. coli enzyme under these conditions (250 microM MgAMPPNP plus 5 microM MgADP), consistent with what was reported in the bovine F1 X-ray structure. However, subsequent addition of a physiological concentration of MgATP readily filled the third catalytic site. Therefore the enzyme form seen in the X-ray structure results from the fact that it is obtained under sub-saturating nucleotide conditions. The data show that the X-ray structure is compatible with a catalytic mechanism in which all three F1-ATPase catalytic sites must fill with MgATP to initiate steady-state hydrolysis [e.g. Weber and Senior (1996) Biochim. Biophys. Acta 1275, 101-104]. The data further demonstrate that the site-directed tryptophan fluorescence technique can provide valuable support for F1 crystallography studies.

Adenosine Triphosphate↗
PubMed1997

A placebo-controlled, double-blind prospective study in healthy female volunteers of dextrin sulphate gel: a novel potential intravaginal virucide.

A double-blind, placebo-controlled study was designed to evaluate the safety and tolerability of intravaginal dextrin sulphate (D2S) gel to assess its preliminary suitability as a potential vaginal virucide. Tolerability was assessed by questionnaire and patient interview. Colposcopy with vaginal biopsy was performed to assess the macroscopic and microscopic evidence of inflammation. The potential impact of the gel on normal vaginal flora was examined by quantitative lactobacilli culture with assessment of the ratio of peroxide to nonperoxide-producing organisms. Colposcopy revealed mild erythema in five of 24 subjects receiving active gel and in none of the 12 placebo recipients, but histology in all subjects revealed no evidence of inflammation. No impact on vaginal lactobacilli was found. We conclude that D2S gel is safe and well tolerated intravaginally at the dosing schedule used in this study.

Administration, Intravaginal↗
PubMed1997

F1-ATPase, roles of three catalytic site residues.

Three critical residues, beta-Lys-155, beta-Asp-242, and beta-Glu-181, situated close to the gamma-phosphate of MgATP in F1-ATPase catalytic sites, were investigated. The mutations betaK155Q, betaD242N, and betaE181Q were each combined with the betaY331W mutation; the fluorescence signal of beta-Trp-331 was used to determine MgATP, MgADP, ATP, and ADP binding parameters for the three catalytic sites of the enzyme. The quantitative contribution of side chains to binding energy at all three catalytic sites was calculated. The following conclusions were made. The major functional interaction of beta-Lys-155 is with the gamma-phosphate of MgATP and is of primary importance at site 1 (the site of highest affinity) and site 2. Release of MgATP during oxidative phosphorylation requires conformational re-positioning of this residue. The major functional interaction of beta-Asp-242 is with the magnesium of the magnesium nucleotide at site 1; it has little or no influence at site 2 or 3. In steady-state turnover, the MgATP hydrolysis reaction occurs at site 1. beta-Glu-181 contributes little to nucleotide binding; its major catalytic effect derives apparently from a role in reaction chemistry per se. This work also emphasizes that nucleotide binding cooperativity shown by the three catalytic sites toward MgATP and MgADP is absolutely dependent on the presence of magnesium.

Adenosine Diphosphate↗
PubMed1997

[Qualitative and quantitative determination of regional myocardial perfusion with magnetic resonance tomography].

PURPOSE: Purpose of this study was to test a triple slice saturation recovery turbo FLASH sequence for myocardial perfusion imaging. In addition data-evaluation-tools for qualitative and quantitative perfusion parameters are presented and preliminary tested. MATERIAL AND METHODS: We examined 8 healthy volunteers and 4 patients with myocardial infarction. Parameters of the saturation recovery turbo FLASH sequence were as follows: TR = 2.5 msec, TE = 1.2 msec, alpha = 8 degrees, 3 slices, thickness 10 mm. For data analysis signal-intensity time curves were calculated pixel by pixel and evaluated for signal-intensity-increase over baseline and signal-intensity-upslope. Images were displayed color-coded. For quantitative data analysis we used the indicator dilution theory and developed a deconvolution algorithm which takes the arterial input function into account to calculate the myocardial mean transit time (MTT). RESULTS: The color-coded parametermaps showed uniform conditions in normal myocardium of volunteers, but reduced signal-intensity-increase over baseline and signal-intensity-upslope for infarcted areas in patients. The MTTs calculated using our algorithm were significantly shorter than those assessed with previous methods and matched better with values derived from literature. Infarcted areas show prolonged MTTs in comparison to normal myocardium. CONCLUSION: A triple slice saturation recovery turbo FLASH sequence is suitable for myocardial perfusion imaging. Color-coded parametermaps can visualize hypoperfused areas. For calculating myocardial MTTs using indicator dilution therapy a deconvolution algorithm is necessary.

Adult↗
PubMed1997

Internal anal sphincter repair.

The results of repair to the internal and sphincter alone has been evaluated in five patients with persistent anal incontinence following surgery which affected the internal anal sphincter. All had passive incontinence for solid or liquid stool. Symptoms, anorectal manometry, and anal endosonography were evaluated before and after surgery. After surgery three patients felt improved but had still persistent symptoms, and no patients achieved full continence. Three patients showed an increased maximal and resting pressure, but only one of them was within the normal range. Post operatively, all the anal ultrasound scans showed a persistent internal sphincter defect, and two showed an unsuspected external anal sphincter defect. Although some patients felt symptomatically improved, the overall clinical, manometric and radiological findings after internal and sphincter repair were disappointing.

Adult↗