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Biomedical subjects

U Brinkmann

Publications and source records attributed to U Brinkmann.

At least 91 records · Page 5Linked to original sources
PubMed1991

B3(Fv)-PE38KDEL, a single-chain immunotoxin that causes complete regression of a human carcinoma in mice.

The genes encoding the heavy- and light-chain Fv regions of the monoclonal murine antibody B3, which recognizes a carbohydrate antigen on the surface of many human carcinomas, were cloned by PCR techniques and used to generate single-chain immunotoxins containing Pseudomonas exotoxin (PE). The light and heavy chains were connected by a flexible linker to form a single-chain antigen-binding protein, B3(Fv), which was in turn fused to truncated forms of PE lacking the cell-binding domain. The single-chain Fv and two different B3(Fv) immunotoxins, B3(Fv)-PE40 and B3(Fv)-PE38KDEL, were expressed in Escherichia coli and the single-chain immunotoxins were purified to near homogeneity. Both recombinant immunotoxins were shown to be cytotoxic specifically to carcinoma cell lines that express the B3 antigen on their surface; B3(Fv)-PE38KDEL was significantly more active. Furthermore, intravenous administration of B3(Fv)-PE38KDEL caused complete regression of human epidermoid carcinomas growing subcutaneously in immunodeficient mice.

ADP Ribose Transferases↗
PubMed1991

The economic cost of malaria in Africa.

Although malaria is the major health problem in Africa, there is little research on its economic impact. This study adapts a framework for assessing the economic costs of illness to available data on malaria. Direct costs of illness are the costs of treatment and control activities, and indirect costs are the value of lost time due to morbidity and premature mortality. Direct costs were estimated by applying the average estimated health systems costs per case to the number of cases. Indirect costs were assessed by multiplying adult output per day times the estimated productive time lost through both adult and childhood cases. As data are not available to assess the economic impact of malaria in Africa as a whole, four case studies were performed on countries or regions for which needed data could be found. The four sites (Rwanda, Solenzo medical district of Burkina Faso, Mayo-Kebbi district, Chad, and Brazzaville, Congo) were chosen to illustrate the diversity in kinds of data which can be used (aggregate national health statistics versus household surveys) and in locations (urban versus rural). Costs were calculated for the recent past and were projected to 1995 based on recent epidemiological trends. Estimates for all sub-Saharan Africa were derived from the averages of these sites. In 1987, a case of malaria cost $9.84 (in 1987 US dollars)--$1.83 in direct costs and $ 8.01 in indirect costs. As the average value of goods and services produced per day in Africa was $0.82, this cost is equivalent to 12 days of output.(ABSTRACT TRUNCATED AT 250 WORDS)

Africa↗
PubMed1991

Malaria and health in Africa: the present situation and epidemiological trends.

The World Health Organization does not give any data on the malaria situation in Africa in its regular reports because of the "insufficiency and irregularity of reporting". Estimates on the total number of cases and the number of deaths vary considerably. They range from 35 million to 189 million per year depending on whose figures one uses. An intensive search of the literature using computer-based systems identified more than 1000 titles on the epidemiology of malaria. Out of them and from other sources finally 426 articles were used to describe the current malaria situation and observable trends in Africa. Major findings were that malaria is responsible for about 40% of fever cases, mortality is about 5 per 1000 per year, case fatality ranges from 2% to 24%. Admissions for malaria account for 20% to 50% of all admissions in African health services although only 8% to 25% of persons with malaria visit health services. Self-treatment is more common in urban areas (more than 60%) but an increasing number of people use some form of self protection in rural areas (2% to 25%). The resistance of malaria parasites to chloroquine and other drugs is widespread. Chloroquine resistance has reached a prevalence of about 30% at the RII level in most countries. Malaria incidence shows annual growth rates of 7.3% for Zambia, 10.4% for Togo, and 21.0% for Rwanda. The data for Burkina Faso show a downward trend of--14.7% during the years from 1973 to 1981. Since then malaria incidence is increasing at 11.0% per year. Hospital data reported from Zambia indicate that mortality is rising 5.2% per annum in children and 9.7% per annum in adults. Reasons for the increase of malaria and its role for development are discussed.

Africa↗
PubMed1991

Estimating the direct and indirect economic costs of malaria in a rural district of Burkina Faso.

Comprehensive estimates of the direct economic costs of malaria should include not only the costs of care at established health facilities, but also other expenditures, such as travel and out-of-pocket costs of drugs. They should include all episodes of illness, whether or not the patient attended a health facility. Also, the indirect economic costs, which are based on the value of time lost due to illness, consider seasonal variations in the marginal product of labor according to the agricultural season. A 1985 representative survey of 626 households in Solenzo medical district, Burkina Faso, provided household data on health service utilization, expenditures, and agricultural production with which to implement these refinements. Numbers of malaria deaths and cases were estimated by adjusting survey totals according to monthly patterns of reported malaria deaths. The marginal product of labor was valued according to typical activities in each of three agricultural seasons: brewing millet beer during the maintenance period (January-February), growing cotton during the cash crop season (March-April), and growing millet and sorghum during the food crop season (May-December). The resulting values were $0.28, $1.09, and $0.55 per day, respectively. Cost per case averaged $5.96 and cost per capita $1.15. Indirect cost due to mortality was the largest cost component ($0.79 per capita), followed by direct costs incurred by the user (e.g. transportation costs and drug purchases, $0.22 per capita). Direct costs paid by providers were small, only $0.04 per capita. A household survey provides the necessary data for more comprehensive population-based estimates of costs of malaria.

Adult↗
PubMed1990

The growth rate-limiting reaction in methanol-assimilating yeasts.

The maximum growth rate of methylotrophic yeasts during growth on methanol is about 0.2 h-1. Since they are able to grow faster on substrates such as glucose we tried to identify the putative limiting step in methanol metabolism within the assimilatory pathway, leading to the formation of a major precursor for biosyntheses, or within the linear dissimilatory sequence. Growth experiments with mixed substrates and determination of some kinetic parameters allowed us to restrict the number of possible pacemaker enzymes. The dissimilatory sequence does not seem to be growth-rate limiting. This also applies to transketolase, transaldolase and fructose-1,6-bisphosphatase. Surprisingly, methanol oxidase appears to be the prime candidate.

Alcohol Oxidoreductases↗
PubMed1989

High-level expression of recombinant genes in Escherichia coli is dependent on the availability of the dnaY gene product.

We have observed that proteins, such as human tissue-type plasminogen activator, pro-urokinase or gp41 of human immunodeficiency virus, which have a high content of rare codons in their respective genes, are not readily expressed in Escherichia coli. Furthermore induction of these heterologous genes leads to growth inhibition and plasmid instability. Supplementation with tRNA(AGA/AGG(Arg)) by cotransfection with the dnaY gene, which supplies this minor tRNA, resulted in high-level production with greatly improved cell viability and plasmid stability.

Base Sequence↗
PubMed1981

Epidemiological studies on the animal reservoir of gambiense sleeping sickness. Part I. Review of literature and description of the study areas.

A review of literature of the previous and recent evidence of potential animal reservoir hosts of gambiense sleeping sickness is given. A highly endemic sleeping sickness area in the Ivory Coast is described together with an area of recent low endemicity in southwestern Upper Volta. These areas were surveyed as part of a study on the significance of any potential animal reservoir of the disease. The results are described in detail in subsequent papers.

Animals↗
PubMed1981

Epidemiological studies on the animal reservoir of gambiense sleeping sickness. Part II. Parasitological and immunodiagnostic examination of the human population.

The prevalence of the disease was determined in the population (n = 3402) of a highly endemic sleeping sickness area in the Ivory Coast and an area of recent low endemicity in southwestern Upper Volta by using parasitological techniques supplemented by the determination of trypanosome specific antibodies and serum macroglobulins (IgM). 62 cases of trypanosomiasis were diagnosed parasitologically in the sleeping sickness focus in the Ivory Coast. 30 Trypanozoon stocks were established for their behavioural and biochemical characterization. The percentage of specific antibody carriers. 26% and 10% obtained with the enzyme-linked immunosorbent assay (ELISA) in both areas, respectively, was compared to that obtained for raised IgM levels. False negative diagnosis resulted in 24% with the ELISA, 12% with the indirect immunofluorescent test (IFT) and 19% with the radial immunodiffusion (RID). Considering IFT and IgM levels together, the proportion of false negative results fell to 8%. Possible reasons for low sensitivities, especially of the ELISA are discussed.

Adolescent↗
PubMed1979

Suspension culture of myocardial cells from newborn rats.

Myocardial cells from newborn rats were held in a spinner type culture for 2 days and then explanted into culture flasks. Three main cell types were observed: single multipolar cells of embryonic type, cell aggregates containing 10 to 50 connected cells, and bipolar cells retaining some adult characteristics. Except for the latter, up to 95% of intact cells settled and were beating 6 hours after explantation. The percentage of fibroblast-like cells was drastically reduced when compared with conventional cultures. Cell debris could be removed 2 hours after explantation by changing the culture medium, or more effectively by a density step centrifugation using Lymphoprep or Lymphoprep-Ficoll mixtures.

Animals↗
PubMed1978

[Lassa fever].

Explore the source record for details and available documents.

Adult↗
PubMed1975

[Lassa fever].

Explore the source record for details and available documents.

Africa, Western↗
PubMedDate not supplied

Mutations of two lysine residues in the CDR loops of a recombinant immunotoxin that reduce its sensitivity to chemical derivatization.

B3(Fv)-PE38 is a recombinant single-chain immunotoxin in which the Fv region of monoclonal antibody B3 is connected to a truncated form of Pseudomonas exotoxin. It would be desirable to use the lysine residues of the molecule for chemical modification so that it can be derivatized with poly(ethylene glycol) to achieve reduced immunogenicity or with the Bolton-Hunter reagent for biodistribution studies. We found that derivatizing lysine residues of B3(Fv)-PE38 causes a marked loss of specific target cell cytotoxicity and/or immunoreactivity. Here we show that two lysine residues in the antibody-combining region of B3(Fv)-PE38 can be replaced with arginines, with only a small loss of cytotoxicity and no change in specificity. This mutant molecule is 3-fold more resistant to inactivation by derivatization with succinimidyl 4-(N-maleimidomethyl)cyclohexane 1-carboxylate (SMCC) or Bolton-Hunter reagent.

Amino Acid Sequence↗
PubMedDate not supplied

Recombinant antibody fragments and immunotoxin fusions for cancer therapy.

Recombinant immunotoxins consist of Fv regions of cancer specific antibodies fused to truncated bacterial toxins. Many recombinant immunotoxins contain a truncated version of Pseudomonas Exotoxin as a toxic moiety. This toxin is modified in such a manner that by itself it does not bind to normal human cells, but it retains all other functions of cytotoxicity. The recombinant antibody fragments target the modified toxin to cancer cells which are killed, either by direct inhibition of protein synthesis, or by concomitant induction of apoptosis. Cells that are not recognized by the antibody fragment, because they do not carry the cancer antigen, are spared. Many factors influence the in vivo anti-tumor activity of recombinant immunotoxins. Among them are considerations of which types of cancer and at what stages may be the best targets for immunotoxin therapy and tumor specificity of the antigen that is targeted by the recombinant antibody. Also the affinity of immunotoxins and their ability to enter and penetrate into tissues and tumors, which in turn is dependent on the size of the protein. And, because one very important factor is the stability of immunotoxins, a great deal of protein-engineering is required to stabilize the recombinant antibody moiety of immunotoxins. Excellent activity and specificity can be observed for many recombinant immunotoxins in in vitro assays using cultured cancer cells as well as in animal tumor models. Ongoing clinical trials provide examples where the promising preclinical data correlate with successful results in experimental cancer therapy.

Bacterial Toxins↗
PubMedDate not supplied

Prognostic significance of newly defined ploidy related parameters in melanoma.

5c exceeding rate is the parameter, most frequently showing prognostic impact. The CAS200 image analyzer makes possible the measurement of additional parameters defining single subfractions of cells, as for example the ratios of diploid, aneuploid, tetraploid, octaploid and 16-ploid cells. The main objective of this study was to define the prognostic significance of these new parameters in 106 primary melanomas with known survival time. 29 out of 106 melanomas were euploid. 77 out of 106 showed an aneuploid histogram. Multivariate analysis with Cox regression demonstrated that the percentage of aneuploid cells between 2c and 4c and the percentage of aneuploid cells between 4c and 8c, but not 5c exceeding rate, were able to influence survival time.

Adolescent↗
PubMedDate not supplied

Proliferative activity in the progression of pigmented skin lesions, diagnostic and prognostic significance.

Proliferative compartments of a tumour can be determined cytophotometrically, by in situ hybridisation or by immunohistochemical detection of Ki67 antigen. The main objective of this study was to analyse the proliferative activity during the progression of pigmented skin lesions with respect to differential diagnostic and prognostic applications. The material investigated consisted of 209 pigmented skin lesions (31 naevi, 30 dysplastic naevi, 106 primary melanomas, 20 lymphatic and 22 organ melanoma metastases). Comparison of the ratios of cells in the S-phase gained by two different methods (cytometry, in situ hybridisation) did not show any significant differences. The correlations between Ki67 and S-phase indices in every diagnostic group were highly significant. The results of forward and backward Cox regression were identical and only Ki67 showed an independent prognostic influence (p < 0.001, coefficient in regression 0.02) with change in risk 2% and confidence limit ranging between 1.1% and 2.9%.

Adolescent↗
PubMedDate not supplied

Implication of the proliferation and apoptosis associated CSE1L/CAS gene for breast cancer development.

The CSEIL/CAS protein (CAS) is a Ran-binding protein with a function as a nuclear transport (export) factor. CSEIL/CAS, similar to Ran and other ran-binding proteins, plays at the same time an important role in the mitotic spindle checkpoint, which assures genomic stability during cell division. This checkpoint is frequently disturbed in neoplasms of various origin, including breast, hepatic and colonic tumors. CAS is located on chromosome 20ql3 and amplified in several cell lines, including breast, colon and bladder cancer. MEKl phosphorylation is known to be a reason for different CAS localization and activity. We evaluated the expression of CAS in 50 benign and malignant tumors of the breast by immunohistochemistry. Benign lesions of the breast (n=13) revealed a weak, predominantly cytoplasmatic CAS positivity. In ductal and lobular in situ carcinomas (n=17), 70-90% of the tumor cells were positive for anti-CAS staining which was predominantly cytoplasmatic. In invasive ductal and lobular carcinomas (n =20), 70-90% of the tumor cells stained positive with anti-CAS in a predominantly nuclear pattern. Different localization of CAS might affect its role not only for chromosome segregation, proliferation and apoptosis, but also its function in nuclear transport of proteins like retinoblastoma-gene-product, p53 and BRCAl. A different regulation in this checkpoint might contribute to the invasive potential in malignant carcinomas of the breast. Alteration of CAS-activity, possibly via MEKl-inhibition, might therefore be a possible option for breast cancer therapy.

Antibodies, Monoclonal↗