Search PubMed⌕ Search

Biomedical subjects

K Winkler

Publications and source records attributed to K Winkler.

At least 109 records · Page 6Linked to original sources
PubMed1993

Structural base of the interaction of a monoclonal antibody against p24 of HIV-1 with its peptide epitope.

The interaction of a murine monoclonal antibody (CB 4-1) against the core protein p24 of HIV-1 with its peptide antigen was studied in detail. The amino acid sequence of the variable regions of the heavy and light chain as derived from DNA sequencing was used to model the structure of the antigen binding region on the basis of reported Fab structures from the Brookhaven Protein Data Base. A linear peptide epitope responsible for the p24 binding to the antibody was determined by peptide scan. Subsequent N- and C-terminal truncation of the corresponding sequence region as well as amino acid substitutions were performed to recognize the epitope and the amino acid residues critical for antibody binding. These data were used to derive a structural model of the peptide-antibody interaction.

Amino Acid Sequence↗
PubMed1993

Osteosarcoma.

Findings from molecular genetic and cytogenetic investigations suggest that mutations in suppressor genes play a key role in osteosarcoma pathogenesis. RB and p53 are frequently involved and are speculated to be indispensable components. Alterations in putative suppressor genes on chromosomes 18q and 3q additionally may be involved in various patterns. The high resolution of magnetic resonance imaging in osteosarcoma imaging is confirmed, and the validity of dynamic gadolinium-enhanced imaging for estimation of tumor response is stated. The efficacy of single-drug high-dose methotrexate convincingly is shown to be 19%. Phase II trials with nonspecific immunostimulation using a synthetic liposomal mycobacterium-derived antigen (liposomal muramyl tripeptide phosphatidylethanolamine) do not yet allow us to draw conclusions on eventual efficacy. A novel and promising approach may be intervention in the endocrine or orthocrine and paracrine tumor growth regulation. Hypophysectomy in mice dramatically reduced plasma or insulin-like growth factor and local as well as systemic growth of transplanted osteosarcoma. The close interrelation between tumor response, surgical margins, and local control is demonstrated, as well as the fatal prognosis after local failure. Also, the validity of known risk factors in patients undergoing intensive chemotherapy has been confirmed. Interestingly, dose intensity was not found to influence prognosis.

Humans↗
PubMed1993

A wound healing model with sonographic monitoring.

The methods used hitherto for quantification of skin repair processes only allow an examiner a two-dimensional assessment of superficial wound healing. With the recent advent of high frequency B-scan ultrasonography in dermatology it has become possible to follow the course of healing and evaluate the healing processes in deeper layers of the skin. In this investigation 80 patients received cryosurgery for treatment of basal cell carcinomas on the face or neck region. As the size of cryosurgical defects can be precisely controlled they are potentially useful as standardized wound healing models. The course of wound healing after cryosurgery using a digital ultrasound scanner (DUB 20, Taberna pro medicum, Lüneburg, Germany) was monitored. The usable depth of penetration of the echo signal is approximately 7 mm. The lateral resolution is approximately 200 microns, the axial resolution approximately 80 microns. The cryolesion and the repair processes were examined ultrasonographically and clinically over a period of at least 3 weeks or until the wound had completely healed. The depth of invasion and lateral extent of the basal cell carcinoma as well as the size of the induced cryolesion can be determined by ultrasound. The exudative phase after cryosurgery, with developing oedema and necrosis, can be quantified on the basis of the reduced reflectivity in the corium. The repair processes taking place in the region of necrosis can be visualized in the ultrasound scan. The ultrasonically monitored wound healing model which we have demonstrated is particularly suitable for investigating the efficacy of drugs which promote healing.

Aged↗
PubMed1993

The effect of hyperosmotic solutions on the hepatic blood flow.

The present study was undertaken in order to measure the effect of hyperosmotic solutions on portal and hepatic blood flow. In five anaesthetized pigs without arterial blood supply to the liver, portal blood flow rate was measured (electromagnetic flowmeter) during 5 min lasting intravenous infusions of hyperosmotic galactose (50%, 84-100 ml) and mannitol (25%, 100 ml), with physiological saline (100 ml) as control. Portal blood flow increased to a peak value of (39% [P = 0.06] galactose and 37%, [P = 0.06], mannitol) soon after stop of the hyperosmotic infusion. For galactose the change ended somewhat earlier than for mannitol. Saline induced a minor increase (15%). Similarly, increments of, on average, 144% of the hepatic blood flow rate was seen in six patients with cirrhosis, following infusion of hyperosmotic galactose, the increase being more pronounced than in the pigs. The causes for these osmotic effects are not known, but they have to be taken into consideration in studies of the portal and hepatic blood flow.

Animals↗
PubMed1993

Hepatic, renal, and total body galactose elimination in the pig.

Galactose elimination capacity is used as a quantitative measure of liver function on the assumption that galactose elimination outside the liver is negligible or easily corrected for. The relationship between hepatic and extrahepatic removal of galactose was studied in anesthetized pigs during quasi-steady-state conditions by continuous infusion of galactose. The hepatic removal approximated a constant [maximal velocity = 585 +/- 41 mumol/min, Michaelis constant (Km) = 0.24 +/- 0.07 mmol/l, mean +/- SE, n = 20]. The renal removal was less than the amount filtered, showing maximal tubular reabsorption (Tm 178 +/- 3.0 mumol/min, Km 3.8 +/- 0.9 mmol/l, n = 20). Metabolic conversion of galactose in the kidney was not demonstrable. At all concentrations studied (0.4-5.8 mmol/l), total galactose elimination from the body exceeded the sum of hepatic and renal elimination by approximately 100 mumol/min, independent of the concentration. At blood concentrations usually used for clinical estimation of the galactose elimination capacity (approximately 4 mmol/l), hepatic removal in the pig accounted for 55% and renal removal for 30% of total removal; 15% of removal occurred in other organs. We conclude that estimation of the hepatic galactose elimination capacity from whole body elimination curves requires correction for renal removal of galactose.

Animals↗
PubMed1992

Treatment of soft tissue sarcoma in childhood and adolescence. A report of the German Cooperative Soft Tissue Sarcoma Study.

BACKGROUND: In the first German soft tissue sarcoma (STS) study, CWS-81, 344 patients younger than 19 years of age who had previously untreated soft tissue sarcoma were studied. For this analysis, there were 218 patients with chemosensitive STS (Group A: rhabdomyosarcoma [RMS], synovial sarcoma, extraosseous Ewing sarcoma, leiomyosarcoma, undifferentiated sarcoma, and malignant peripheral neuroectodermal tumor) who could be studied for a minimum potential follow-up time of 6 years. METHODS: A staging system based on the postoperative extent of the disease was used. The chemotherapy for Stage I-III disease consisted of vincristine, dactinomycin, cyclophosphamide, and doxorubicin (VACA). Patients with metastatic disease and patients with Stage III disease who failed to respond to VACA were given ifosfamide instead of cyclophosphamide. The definitive procedure for local tumor control (either no radiation exposure, 40 Gy, or 50 Gy) for patients with Stage II-III disease depended on the tumor status at second-look surgery after 16 weeks of chemotherapy. RESULTS: The rates of disease-free survival (DFS) and survival after 5 years was 61% +/- 4% and 57% +/- 4%, respectively, in group A; for patients with nonmetastatic tumors (Stages I-III), the rates were 69% +/- 4% and 72% +/- 4, respectively. Patients with nonmetastatic rhabdomyosarcoma had a similar prognosis: the survival rate was 73% +/- 4%, and the DFS rate was 68% +/- 4%. There was no difference in prognosis between patients with Stage I and and those with Stage II disease (DFS rate, 88% +/- 5% and 88% +/- 6%, respectively). The DFS rate for patients with Stage III disease was 54% +/- 5% and for those with Stage IV, 11% +/- 5%. Lack of local tumor control was the primary cause of therapy failure: 10% of patients with localized disease did not achieve complete remission, whereas 18% who were in complete remission experienced local relapse. The most important prognostic factors were tumor size (P = 0.005) and the degree of tumor regression after primary chemotherapy (P = 0.007). The prognosis also differed according to primary site: paratesticular tumors had the best prognosis, whereas tumors located in the parameningeal regions of the head and neck had the worst prognosis (DFS rate, 96% +/- 4% versus 49% +/- 7%, respectively). CONCLUSIONS: The following conclusions were drawn from the CWS-81 study: (1) intensive chemotherapy (VACA for 35 weeks) provides long-term control for most patients with Stage I-II disease; (2) patients with primary unresectable tumors (i.e., Stage III) who achieve complete remission with chemotherapy alone have the same prognosis as patients with postoperative disease of Stages I and II; (3) tumor size and the degree of tumor regression after primary chemotherapy influence outcome and thus can be used as a basis for risk-adapted therapy.

Adolescent↗
PubMed1992

Immunoglobulin V regions and epitope mapping of a murine monoclonal antibody against p24 core protein of HIV-1.

The nucleotide sequence of a murine monoclonal antibody (CB-mab-p24/13-5) against p24 core protein of the human immunodeficiency virus (HIV-1) was determined for variable regions of the heavy and light chain, respectively. Genetic elements encoding the VDJH- and VJL-regions of the antibody were generated from RNA by the polymerase chain reaction, cloned into the vector pICEM 19R and sequenced. Synthetic peptides, 10 amino acids overlapping served for the localization of the epitope. The residues 152-156 within the p24 sequence contain the epitope.

Amino Acid Sequence↗
PubMed1992

[Public health and citizen involvement--guidelines and general practice in Herne].

Health problems cannot be solved only by expanding medical and other systems of service. Limitations of these services are not only set by costs, but also by the disease patterns themselves. The traditional role of the patient must be redefined. It is necessary to develop personal health-coping strategies outside medical care, and for the citizen to participate in improving conditions of health in general. The public health system has the specific duty of initiating and establishing these new approaches to health promotion and coping with disease. A model for these new municipal health policies is presented with reference to medical practice in the city of Herne in the Ruhr area of Germany.

Community Participation↗
PubMed1991

Metabolic regulation of the trehalose content of vegetative yeast.

We have investigated the mechanism by which heat shock conditions lead to a reversible accumulation of trehalose in growing yeast. When cells of S. cerevisiae M1 growing exponentially at 30 degrees C were shifted to 45 degrees C for 20 min, or to 39 degrees C for 40 min, the concentration of trehalose increased by about 25-fold; an effect reversed upon lowering the temperature to 30 degrees C. This was compared to the more than 50-fold rise in trehalose levels obtained upon transition from the exponential to the stationary growth phase. Whereas the latter was paralleled by a 12-fold increase in the activity of trehalose-6-phosphate synthase, no significant change in the activities of trehalose-synthesizing and -degrading enzymes was measured under heat shock conditions. Accordingly, cycloheximide did not prevent the heat-induced accumulation of trehalose. However, the concentrations of the substrates for trehalose-6-phosphate synthase, i.e. glucose-6-phosphate and UDP-glucose, were found to rise during heat shock by about 5-10-fold. Since the elevated levels of both sugars are still well below the Km-values determined for trehalose-6-phosphate synthase in vitro, they are likely to contribute to the increase in trehalose under heat shock conditions. A similar increase in the steady-state levels was obtained for other intermediates of the glycolytic pathway between glucose and triosephosphate, including ATP. This suggests that temperature-dependent changes in the kinetic parameters of glycolytic enzymes vary in steady-state levels of intermediates of sugar metabolism, including an increase of those that are required for trehalose synthesis. Trehalose, glucose-6-phosphate, UDP-glucose, and ATP, were all found to increase during the 40 min heat treatment at 39 degrees C. Since this also occurs in a mutant lacking the heat shock-induced protein HSP104 (delta hsp104), this protein cannot be involved in the accumulation of trehalose under these heat shock conditions. However, mutant delta hsp104, in contrast to the parental wild-type, was sensitive towards a 20 min incubation at 50 degrees C. Since this mutant also accumulated normal levels of trehalose, we conclude that HSP104 function, and not towards a 20 min incubation at 50 degrees C. Since this mutant also accumulated normal levels of trehalose, we conclude that HSP104 function, and not the accumulation of trehalose, protects S. cerevisiae from the damage caused by a 50 degrees C treatment.

Glucose-6-Phosphate↗
PubMed1991

Local control and survival from the Cooperative Osteosarcoma Study Group studies of the German Society of Pediatric Oncology and the Vienna Bone Tumor Registry.

The use of aggressive chemotherapy undoubtedly has brought about a dramatic increase in the cure rate of osteosarcoma. The authors' investigations have increased the authors' knowledge of chemotherapy for osteosarcoma, the differential efficacy of currently used agents, and the pronounced schedule dependency and relative route independency of their efficiency. The authors were able to confirm the prognostic significance of tumor response after preoperative chemotherapy. Preoperative chemotherapy in itself has facilitated and promoted limb-salvage surgery. Also, more patients can be cured today by use of aggressive thoracic surgery in case of primary or secondary pulmonary metastases. The authors' efforts to steadily increase metastasis-free survival rates by intensifying chemotherapy in this series of studies, however, have been only moderately successful. Still, chemotherapy-related acute toxicity is considerable and increases with aggressiveness of treatment, and the manifestations of late toxicity may continue to increase with follow-up time. Future trials should be targeted toward exploration of the minimum indispensable amount of toxic treatment yielding comparable or even better results than those currently attainable.

Adolescent↗
PubMed1991

A reappraisal of Poulsen's disease (hepatic zone 1 sinusoidal dilatation).

The possible cause and pathogenesis of this disease are reviewed. The condition is rare, and there are only few reports which throw some light on this remarkable morphology. It is hypothesized that metabolic zonation in the functional liver acinus may be the basis of these changes, but lack of experimental and clinical studies still makes it enigmatic.

Contraceptives, Oral↗
PubMed1990

Effect of intraarterial versus intravenous cisplatin in addition to systemic doxorubicin, high-dose methotrexate, and ifosfamide on histologic tumor response in osteosarcoma (study COSS-86).

In osteosarcoma, intraarterial (IA) administration of systemic treatment has been advocated to improve local tumor response preparing for, or even obviating, definitive surgery. Because data from the literature did not unequivocally support the local superiority of IA infusion, a comparative study was started in 1986. Preoperative chemotherapy consisted of 45 mg/m2 of doxorubicin on days 1 and 2; 12 g/m2 of high-dose methotrexate on days 15 and 22; and 3 g/m2 of ifosfamide on days 29, 30, 50, and 51 followed on days 31 and 52 by intravenous (IV) versus IA tourniquet infusion of cisplatin (DDP). A strict randomization of patients was not feasible. A balanced distribution of risk factors was strived for by stratifying and allocating the appropriate patients centrally. The infusion time was prolonged from 1 to 5 hours in the IV group, and the DDP dose was reduced from 150 to 120 mg/m2 in both arms when intolerable ototoxicity became apparent. A multivariate analysis was performed to exclude a bias on the response rates from risk factor distribution and from modifications of DDP infusion time and dosage. The overall fraction of histologic good responders (greater than 90% necrosis) was not found to be different after IA versus IV treatment (34/50 [68%] vs. 41/59 [69%]). Intraarterial instead of IV use of DDP within an aggressive systemic treatment does not seem to improve the local tumor response.

Adolescent↗
PubMed1990

Scintigraphic evaluation of tumor regression during preoperative chemotherapy of osteosarcoma. Correlation of 99mTc-methylene diphosphonate parametric imaging with surgical histopathology.

The effect of preoperative chemotherapy (PCT) on the uptake of 99mTc-labeled diphosphonates into tumor bone was quantitatively assessed from serial scan studies of 30 osteosarcomas and correlated with the histomorphological changes determined from the surgical specimens. The parametric images of the tumor blood pool and labeled methylene diphosphonate (99mTc-MDP) plasma clearance by the tumor bone enabled a sensitive distinction to be made preoperatively between a good (greater than 90% tumor cell destruction) and a poor (less than 90% tumor cell destruction) tumor response. Overall accuracy in presurgical prediction of tumor regression was found to be 88% and 96% for the blood pool and 99mTc-MDP clearance measurements, respectively (P less than or equal to 0.0004). In addition, it proved possible to localize resisting areas of viable tumor up to 1.0 cm in diameter. Even at the half-way stage of PCT, a poor response could be reliably predicted (overall accuracy 91% and 100%, respectively; P less than or equal to 0.011). Therefore, 99mTc-MDP parametric imaging is a highly sensitive and specific modality for an objective and accurate assessment of tumor regression during PCT of osteosarcoma.

Adolescent↗
PubMed1990

Homozygous deletion within the retinoblastoma gene in a native osteosarcoma specimen of a patient cured of a retinoblastoma of both eyes.

In a native osteosarcoma specimen from a patient cured of bilateral retinoblastoma eight years ago, we found a deletion of a 7.5 kb HindIII fragment within the retinoblastoma gene. Our results contribute further evidence that the 7.5 kb fragment harbors a Breakpoint Cluster Region (BCR) in osteosarcoma. In tumor tissue of another osteosarcoma patient the retinoblastoma gene did not reveal any defect on DNA or mRNA level, suggesting different transforming events in this patient.

Adult↗