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Biomedical subjects

W Bernhardt

Publications and source records attributed to W Bernhardt.

At least 19 recordsLinked to original sources
PubMed2006

Hypoxia-inducible factors and tubular cell survival in isolated perfused kidneys.

Adaptation to hypoxic environment is conferred through hypoxia-inducible transcription factors (HIFs). We have previously shown that the HIF system is transiently activated in vivo in radiocontrast-induced acute renal failure, associated with profound hypoxia in the renal medulla. Medullary thick ascending limbs (mTALs), the most affected nephron segments in this model, were virtually unable to mount an adaptive HIF response. Here, we study correlations between oxygenation, HIF activation, and cell viability in a related ex vivo model, the isolated perfused rat kidney (IPK). In IPKs perfused with cell-free oxygenated medium, severe medullary hypoxic damage developed, affecting 42+/-9% of mTALs in the mid-inner stripe. HIF-1alpha tubular immunostaining was noted with a zonal and tubular pattern largely similar to our findings in vivo: in 34+/-3% of collecting ducts (CDs) within the mid-inner stripe and extensively in the papillary tip, whereas mTALs were all HIF-negative. In IPKs supplemented with RBCs (improved oxygen supply), mTAL damage was totally prevented and CDs' HIF expression was attenuated (22+/-4%). By contrast, although measures designed to reduce medullary hypoxia by decreasing tubular reabsorptive activity (furosemide, ouabain, or high-albumin-non-filtering system) reduced mTAL damage, all paradoxically resulted in increased HIF expression in CDs (51+/-4%), and 17+/-3% of mTALs became immunostained as well. Our data confirm that CDs and mTALs have markedly different HIF responses, which correlate with their viability under hypoxic stress. mTALs transcriptional adaptation occurs within a narrow hypoxic range, and it appears that workload reduction can shift mTALs into this window of opportunity for HIF activation and survival.

Animals↗
PubMed2001

Genomic plasticity and melanoma formation in the fish Xiphophorus.

Melanoma formation in certain interspecific hybrids of the genus Xiphophorus (Teleostei: Poeciliidae) is associated with the overexpression of the Xmrk receptor tyrosine kinase oncogene. The Xmrk oncogene arose by duplication of the pre-existing Xmrk protooncogene in a highly unstable subtelomeric region of the X and Y sex chromosomes undergoing frequent rearrangements including duplications, deletions, amplifications, and transpositions. Some of these rearrangements are likely to be responsible for the overexpression of the Xmrk oncogene in melanoma. The oncogene itself is very unstable in Xiphophorus and is frequently removed by deletion or disrupted by transposable elements. The Xmrk oncogene region displays a high concentration of retroelements not observed in the corresponding Xmrk protooncogene region. Particularly, a retrovirus long terminal repeat-like sequence was amplified in the proximity of the Xmrk oncogene. Additional genes, some of them also duplicated copies, were detected in this region and might be involved in modulating the melanoma's phenotype.

Journal Article↗
PubMed1999

Proliferation and survival of mammary carcinoma cells are influenced by culture conditions used for ex vivo expansion of CD34(+) blood progenitor cells.

Malignant cell contamination in autologous transplants is a potential origin of tumor relapse. Ex vivo expansion of CD34(+) blood progenitor cells (BPC) has been proposed as a tool to eliminate tumor cells from autografts. To characterize the influence of culture conditions on survival, growth, and clonogenicity of malignant cells, we isolated primary mammary carcinoma cells from pleural effusions and ascites of patients with metastatic breast cancer and cultured them in the presence of stem cell factor (SCF), interleukin-1beta (IL-1beta), IL-3, IL-6, and erythropoietin (EPO), ie, conditions previously shown to allow efficient ex vivo expansion of CD34(+) BPC. In the presence of serum, tumor cells proliferated during a 7-day culture period and no significant growth-modulatory effect was attributable to the presence of hematopoietic growth factors. When transforming growth factor-beta1 (TGF-beta1) was added to these cultures, proliferation of breast cancer cells was reduced. Expansion of clonogenic tumor cells was seen in the presence of SCF + IL-1beta + IL-3 + IL-6 + EPO, but was suppressed by TGF-beta1. Cocultures of tumor cells in direct cellular contact with hematopoietic cells showed that tumor cell growth could be stimulated by ex vivo expanded hematopoietic cells at high cell densities (5 x 10(5)/mL). In contrast, culture under serum-free conditions resulted in death of greater than 90% of breast cancer cells within 7 days and a further decrease in tumor cell numbers thereafter. In the serum-free cultures, hematopoietic cytokines and cellular contact with CD34(+) BPC could not protect the tumor cells from death. Therefore, ex vivo expansion of CD34(+) BPC in serum-free medium provides an environment for efficient purging of contaminating mammary carcinoma cells. These results have clinical significance for future protocols in autologous progenitor cell transplantation in cancer patients.

Antigens, CD34↗
PubMed1998

Purging of mammary carcinoma cells during ex vivo culture of CD34+ hematopoietic progenitor cells with recombinant immunotoxins.

Tumor cells have been found in autologous hematopoietic cell transplants used after high-dose chemotherapy. To specifically eliminate contaminating mammary tumor cells during ex vivo expansion of CD34+ hematopoietic progenitor cells, we used recombinant immunotoxins (ITs) directed against cell-surface antigens expressed on mammary carcinoma cells. ITs were expressed from fusion cDNAs combining a single-chain antibody fragment (scFv) directed against the Erb-B2 or epidermal growth factor (EGF) receptors with a truncated Pseudomonas exotoxin A fragment devoid of its cell-binding domain. CD34+ hematopoietic progenitor cells did not express Erb-B2 and EGF receptors as detected by Western blotting. Ex vivo expansion of total hematopoietic cells or of colony-forming cells from CD34+ progenitors in the presence of stem-cell factor (SCF), interleukin-1 (IL-1), IL-3, IL-6, and erythropoietin (Epo) was not affected when ITs were added to the cultures. In contrast, MDA-MB 453 and MCF-7 mammary carcinoma cells were depleted in a dose- and time-dependent manner by more than 3 log in coculture with CD34+ cells over a period of 7 days in the presence of 100 to 1,000 ng/mL of anti-Erb-B2 IT. This included elimination of the subpopulations with regrowth potential. Similarly, addition of either anti-Erb-B2 or anti-EGF receptor ITs to primary breast cancer cells isolated from patients with metastatic disease resulted in elimination of cytokeratin-positive cells in seven of seven samples. ITs are highly efficient and convenient to use for the depletion of mammary tumor cells during ex vivo expansion of hematopoietic progenitor-cell autografts.

ADP Ribose Transferases↗
PubMed1998

Minimal residual disease in autologous hematopoietic harvests from breast cancer patients.

The increasing use of high-dose chemotherapy with autologous hematopoietic transplantation for the treatment of solid malignancies has raised concern about the role of tumor cells contaminating the grafts. Minimal residual disease (MRD) in autologous grafts has became a dynamic and intensively studied field in oncology. This review discusses the current status of MRD in breast cancer autografts and presents existing data on detection methodology, clinical relevance, biologic characteristics and purging techniques.

Antineoplastic Agents↗
PubMed1990

[Measuring microhardness of laser exposed tooth surface].

In principle it is possible to homogenize the enamel surface by melting structural elements with the continuous wave CO2 laser. Using the precision instrument NEOPHOT 2 (Carl Zeiss JENA) the microhardness of extracted laserexposed premolares were tested so as to clarify the functional strain capasity and the mechanical characteristics of laserexposed regions of enamel surfaces. The proven higher hardness in the centre of the laserinduced fusing zones (in comparison with adjacent enamel) objectify an attainable refining of the enamel surface that probably causes an increase in the caries-preventive resistance.

Dental Enamel↗
PubMed1984

Excretion of total and muscular N tau-methylhistidine and creatinine in muscle diseases.

The daily urinary excretions of N tau-methylhistidine and creatinine from 52 adult patients were measured under standardized conditions. The ratio of N tau-methylhistidine to creatinine excretion was calculated on the basis of the total and muscle-specific excretion rates and correlated to the clinical status of the patients. In patients with muscular diseases and in those with diseases of the central nervous system, the total daily excretion of both metabolites was about 30% lower than in controls. The muscle-specific ratio in patients with diseases of the central nervous system and patients with muscular diseases was not different from that observed in controls. Only in patients with neurogenic atrophies was the ratio elevated, so that it was more than twice the control value. The ratio of excreted N tau-methylhistidine/creatinine is only valid as an indicator of myofibrillar protein breakdown after correction for the contribution of nonskeletal muscle tissues to the urinary excretion.

Adolescent↗
PubMed1981

Quantitative importance of non-skeletal-muscle N tau-methylhistidine and creatine in human urine.

The excretion of N tau-methylhistidine and creatinine was determined in a totally paralysed patient wih neither macroscopic nor microscopic detectable skeletal-muscle tissue. In this subject, it was possible for the first time to measure the basal non-skeletal-muscle-dependent excretion of N tau-methylhistidine and creatinine per 24 h and per kg of non-muscular body weight, 1.15 mumol (N tau-methylhistidine) and 35 mumol (creatinine) respectively. For the calculation of myofibrillar protein breakdown and skeletal-muscle mass on the basis of N tau-methylhistidine and creatinine excretion, the values have to be corrected for non-muscular sources. Our data show that skeletal-muscle tissue is the major contributor of N tau-methylhistidine in urine, since it contributes as much as 75% to the urinary excretion.

Creatine↗
PubMed1981

[Diabetic amyotrophy--a polygenetic syndrome (author's transl)].

Detailed clinical and biochemical investigations were done in 14 patients with the syndrome of diabetic amyotrophy. Three patients suffered from manifest insulin-dependent diabetes, five had only diminished glucose tolerance. Simultaneously, excretion of creatinine was reduced indicating reduction of healthy muscle mass. In these cases disturbance of glucose tolerance must be considered symptom and not cause of amyotrophy. Further investigations revealed neoplasia (n = 2), generalised amyloidosis (n = 3), polycythaemia vera (n = 1), chronic infectious disease (n = 3), and motor neuron degeneration (n = 3). The attribute "diabetic" must not bea considered representing a single cause in this connection. With treatment aimed at more than one factor, satisfactory results of therapy may be expected in the majority of cases.

Adult↗
PubMed1980

[Muscular lesion due to insertion of needle (author's transl)].

The influence of insertion of a needle into muscle on the activity of creatine kinase and fructose-1,6-diphosphate aldolase in serum was measured in 23 patients undergoing electromyography because of suspected neurogenic (n = 18) or myogenic (n = 5) muscular atrophy. Myogenically atrophied muscle was easily vulnerable. In neurogenic atrophy and in healthy muscle the lesion was demonstrable in enzyme changes only when muscular work followed the insertion of the needle. Activity of so-called muscle enzymes is not only changed after intramuscular injections but also due to insertions of thin electrodes (electromyography). The vulnerability of muscules may provide information on the activity of an atrophying process.

Adult↗
PubMed1979

[Glucose tolerance and muscular efficiency (author's transl)].

Glucose tolerance and insulin secretion were studied in 15 male patients suffering from muscular dystrophies. Creatinine excretion was used as a measure of functioning muscle mass. The decrease in glucose tolerance correlated significantly with the injury of muscular efficiency. Despite impaired glucose tolerance, very high levels of circulating insulin were reached, as in obese diabetics. The observations do not simply reflect the decrease in distribution volume of glucose. They can be explained by an altered proportion of muscle mass to adipose and connective tissue. Decreased glucose tolerance may signalize the myopathic reaction following an endocrine disorder or a malignant disease.

Adolescent↗
PubMed1979

Primidone metabolism in renal insufficiency and acute intoxication.

Primidone (PRIM) is metabolized into phenobarbital (PB) and phenylethylmalonamide (PEMA). During anticonvulsant therapy with PRIM under normal conditions PB represents by fat the largest portion of the total concentration of all three components (PRIM + PB + PEMA). In combined therapy with diphenylhydantoin (DPH), and during chronic PRIM overdosage, the relative concentration of PB is even higher. A case of renal insufficiency while on PRIM therapy and a case of acute PRIM intoxication are presented. In both cases PRIM and PEMA are elevated while PB is relatively low. The mechanisms involved in this phenomenon are discussed. Excluding young children with chronic PRIM overdosage, and the endogenous and exogenous intoxication described here, a relative PB concentration below 40% indicates a lack of patient compliance if a steady treatment schedule has been maintained for at least 3 weeks.

Acute Disease↗
PubMed1979

Antiepileptic therapy with phenytoin: which is the optimum serum level?

114 patients suffering from generalized grand mal seizures were treated with phenytoin only. Serum-phenytoin was monitored, and its relation to the frequency of attacks was established in each case, observing steady state periods of at least 3 months' duration. In a group of 44 patients the reduction in pretreatment frequency of attacks was used to evaluate the drug effect. The probability of attacks followed an exponential function of serum-phenytoin. Curves of equal probability for further attacks were plotted: they may assist in determining the initial regimen. However, the high variability in responsiveness during a serum-phenytoin below 10 mg/l suggested that the effective level has to be determined separately and repeatedly for every single patient.

Adolescent↗