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Biomedical subjects

B Wolf

Publications and source records attributed to B Wolf.

At least 145 records · Page 8Linked to original sources
PubMed1994

Human serum biotinidase. cDNA cloning, sequence, and characterization.

Biotinidase (EC 3.5.1.12) catalyzes the hydrolysis of biocytin, the product of biotin-dependent carboxylase degradation, to biotin and lysine. Biotinidase deficiency is an inherited metabolic disorder of biotin recycling that is characterized by neurological and cutaneous abnormalities, and can be successfully treated with biotin supplementation. Sequences of tryptic peptides of the purified human serum enzyme were used to design oligonucleotide primers for polymerase chain reaction amplification from human hepatic total RNA to generate putative biotinidase cDNA fragments. Sequence analysis of a cDNA isolated from a human liver library by plaque hybridization with the largest cDNA probe revealed an open reading frame of 1629 bases encoding a protein of 543 amino acid residues, including 41 amino acids of a potential signal peptide. Comparison of the open reading frame with the known biotinidase tryptic peptides and recognition of the expressed protein encoded by this cDNA by monoclonal antibodies prepared against purified biotinidase demonstrated the identity of this cDNA. Southern analyses suggested that biotinidase is a single copy gene and revealed that human cDNA probes hybridized to genomic DNA from mammals, but not from chicken or yeast. Northern analysis indicated the presence of biotinidase mRNA in human heart, brain, placenta, liver, lung, skeletal muscle, kidney, and pancreas.

Amidohydrolases↗
PubMed1994

Ising model for cooperative processing of extracellular information by protein-tyrosine kinases and cell adhesion molecules.

Activation of receptor tyrosine kinases by multiple growth (GFs) is a major process through which mitogenic information is transmitted into cells. Cell cycle progression additionally requires the coordinated interaction of cellular adhesion receptors with extracellular matrix (ECM) molecules. Recent data from several groups, which demonstrated that integrin-ECM contacts promote multiple phosphorylations of intracellular components although the integrin cytoplasmic domains do not have intrinsic protein kinase activity, support the theory that some adhesion receptor families transduce extracellular signals cooperatively with protein-tyrosine kinases (PTKs). Based on the well-established hypothesis that adhesion receptors induce an aggregation of PTKs through a rearrangement of the cytoskeleton, a mathematical minimal model for the regulation of PTKs is presented which accounts for the synergism between different environmental signals mediated by growth factors and cell adhesion molecules (CAM) or cell adhesion associated substances like carcinoembyronic antigen (CEA). The model, which is closely related to a two-dimensional Ising model describing order-disorder transitions in ferromagnetic crystals, provides evidence that a cell-type-specific pattern of cell adhesion molecules may function as a molecular amplifier which promotes the metastatic activity of malignant tumor cells through the indirect induction of intracellular PTK activity.

Animals↗
PubMed1994

pH-dependent LAK cell cytotoxicity.

In the microenvironment of many solid tumors the pH is considerably lower (mean pH between 6.6 to 7.2) than the pH in normal tissue (pH 7.0-7.5). Therefore, the influence of acidic pH on the cytotoxic activity of lymphokine-activated killer cells (LAK cells) after different culture periods was tested. K-562 human erythroleukemia cells were selected as target cells. Cell killing was measured using a two-color flow cytometric method. At physiological pH of 7.4, LAK cell-mediated cytotoxicity ranged from 15 to 48% (E:T ratio = 50:1). The specific lysis of target cells was considerably reduced (up to 70% inhibition of specific lysis) under acidic conditions (pH 6.8, 6.3, 5.8). This effect was independent of donors, duration of the culture period, and the E:T ratio in the cytotoxic assay. As pH gradients surrounding tumor cells may reach values below pH 6.0 at the cell surface, the pH-dependence of LAK cell cytotoxicity could at least partially explain the inhibition of the natural immune response in solid tumors. Therapeutic immunological strategies concerning the enhancement of the natural immune response like LAK cell and IL-2 immunotherapy including IL-2 gene therapy may only be successful if a simultaneous inhibition of the acidification process and an elevation of tumor pH is achieved.

Cell Line↗
PubMed1994

Theophylline suppresses human alveolar macrophage respiratory burst through phosphodiesterase inhibition.

The effects of theophylline upon human alveolar macrophage function were assessed and compared with its action upon macrophage cyclic nucleotide phosphodiesterase (PDE) activity and cyclic adenosine monophosphate (cAMP) levels. In the concentration range of 10 mumol/liter to 1 mmol/liter, theophylline caused a concentration-dependent inhibition of opsonized zymosan-stimulated hydrogen peroxide (H2O2) generation and PDE-catalyzed cAMP hydrolysis and increased the cellular cAMP content. Macrophage H2O2 generation was also inhibited by forskolin, an activator of adenylyl cyclase, but whereas theophylline (1 mmol/liter) and forskolin (1 mumol/liter) exhibited a synergic elevation of macrophage cAMP, there was no synergy between the two agents in the inhibition of respiratory burst. The inhibition of H2O2 generation by theophylline was reversed by the competitive inhibitor of cAMP-dependent protein kinase, (Rp)8-bromoadenosine cyclic 3':5'-monophosphorothioate (Rp-8-Br-cAMPS; 100 mumol/liter), indicating that the functional effect of theophylline was mediated through the elevation of cAMP. The inhibition of H2O2 generation by theophylline was not affected by adenosine deaminase (0.1 U/ml), indicating that the inhibition did not involve adenosine antagonism. It is concluded that theophylline exerts a direct inhibitory action upon human alveolar macrophage function through the elevation of cAMP levels as a result of PDE inhibition, and that this effect is observed at concentrations of theophylline that may be achieved in serum during therapy.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1994

Ano-cutaneous fistula associated with Bardet-Biedl syndrome in an African child.

An ano-cutaneous fistula associated with a Bardet-Biedl syndrome in a 12-year old African boy is described. The patient presented with mental retardation, obesity, syndactyly, polydactyly, retinitis pigmentosa and hypogenitalism. Past history revealed that he had an imperforated anus with anocutaneous fistula at birth, which was repaired successfully. The the best of our knowledge, it is the first case described in the African literature.

Africa↗
PubMed1993

Combined pedigree and twin family study to determine the sources of variation in serum biotinidase activity: the usefulness of multiple study designs.

Biotinidase, the enzyme responsible for recycling the vitamin biotin, is deficient in most individuals with late-onset multiple carboxylase deficiency. Based on clinical criteria, biotinidase deficiency appears to be inherited as an autosomal recessive trait; however, the inheritance of biotinidase serum activity as a quantitative trait has not been studied previously. In this study, both segregation analysis of proband families and the analysis of twin family data were used to determine the relative contributions of a major gene, polygenes and environment to the variation in serum biotinidase activity. Segregation analysis of 24 families of biotinidase-deficient individuals indicated that serum biotinidase activity is determined by the segregation of a single codominant major gene with the variability about the mean of each major genotype attributable to environmental effects. Significant polygenic effects could not be detected by this analysis. Variance component analysis of 128 twin families, which included the twins, their spouses, and their offspring, indicated that 70% of total variance in biotinidase activity is attributable to additive genetic effects, 22% to individual environmental effects, and 8% to shared environmental effects. The model also included an age effect for females. A portion (27%) of the estimated additive variance may be attributed to the segregation of the major gene. This study emphasizes the usefulness of studying multiple data sets representing different types of family relationships.

Amidohydrolases↗
PubMed1993

Systems analysis in cell biology: from the phenomenological description towards a computer model of the intracellular signal transduction network.

In this paper we introduce a systematic approach for the modelling of complex biological systems which is especially useful for the analysis of signal transduction mechanisms in cell biology. It is shown that systems analysis in form of top-down levelled dataflow diagrams provides a powerful tool for the mathematical modelling of the system in terms of a stochastic formulation. Due to the exact formulation, the consistency of the model with the experimental results can be tested by means of a computer simulation. The method termed Structured Biological Modelling (SBM) is illustrated by modelling some aspects of the second messenger network which regulates cell proliferation. As an example for the straightforward development of a mathematical description a stochastic computer model for intracellular Ca2+ oscillations is presented.

Animals↗
PubMed1993

Oxidation resistant muteins of antileukoproteinase as potential therapeutic agents.

Native antileukoproteinase (ALP) and two oxidant resistant mutants ALP 242 and ALP 231 were synthesized by means of recombinant DNA technology. In the ALP 242 molecule the methionine residue located in the reactive centre of the binding loop is replaced by a leucine residue. In ALP 231 all four methionine residues of the second domain were substituted by leucine residues. The native inhibitor and the two oxidant resistant molecules show comparable inhibitory capacities towards human neutrophil elastase (HLE) and cathepsin G. All three inhibitors were treated with different reactive oxygen species. After incubation with chloramine T or supernatants of activated polymorphonuclear leukocytes (PMN's) a drastic drop of inhibitory capacity of the native molecule was observed. Compared to the native form of ALP the mutant ALP 242 was less inactivated, whereas ALP 231 was nearly totally resistant towards all reactive oxygen. (Heinzel-Wieland R. et al., Biomed Biochim Acta 50: 677-681 (1991)) The intratracheal administration of HLE into the lung of Syrian Hamsters induced mild to moderate emphysematous lesions. The inhibitory potencies of native ALP and the ALP mutants were determined in this animal model by means of intratracheal instillation of the different molecules one hour prior to the administration of HLE. The inhibitory effects of ALP 242 and ALP 231 towards HLE-induced emphysema were significantly better than that of the native molecule. Surprisingly no significant differences between the two mutants were observed. (Rudolphus A. et al., Clin Sci 81: 777-784 (1991)) In a second animal model the emphysema was induced by repeated intratracheal administration of lipopolysaccharides (LPS) into the hamster lungs. This model is characterized by a chronic process of inflammation probably caused by a continuous release of endogenous elastase from infiltrating PMN's. Repeated applications of 1 mg of ALP 242 reduced the LPS-induced emphysema by 70 to 80%. In contrast, equal amounts of the native molecule resulted in significantly lower inhibition of the LPS-induced emphysema, only 23-30% reduction was observed. Repeated applications of 1 mg of ALP 231 reduced the LPS-induced emphysema only about 50%. So far it is not yet clear, why the totally oxidant resistant ALP 231 was less effective than the ALP 242 molecule. (Stolk J. et al., Pulmonary Pharmacology in press (1992))

Animals↗
PubMed1993

[Importance of cell self-organization for tumor biology].

A cell is a complex system working far from thermodynamic equilibrium. The prediction of cellular functions based exclusively on the molecular basis is yet impossible because of the many degrees of freedom of the microsystem cell. In contrast, the system cell displays only a surprisingly small spectrum of macroscopic observable degrees of freedom, the number of which changes during the cell cycle and neoplastic growth. Illustrated by image analytical and cell biological data we attempt to describe these phenomena of cellular self-organization.

Animals↗
PubMed1993

Congenital neurosyphilis revisited.

The clinical symptoms, serological results and computed tomographic findings of two Zimbabwean children, one with the early meningeal and one with the late parenchymatous form of congenital neurosyphilis are reported. The paediatrician's suspicion of the existence of this condition should remain high as long as syphilis continues to flourish worldwide.

Child↗
PubMed1993

Adverse psychic reactions to psychotropic drugs--a report from the AMUP study.

The AMUP study (AMUP = Arzneimittelüberwachung in der Psychiatrie (Drug Monitoring in Psychiatry)) was conducted from 1979 to 1989 in order to provide for a systematic and standardized assessment of all adverse reactions to psychotropic drugs under the conditions of routine clinical treatment at two psychiatric hospitals. This paper presents data from the AMUP study on the type and frequency of adverse psychic reactions to psychotropic drug groups and relevant single drugs. Psychic ADR leading to drug discontinuation were observed in 4.5% of 15,264 inpatients monitored over an eight-year period. Only neurological ADR were more frequent (4.9%). Neuroleptics and antidepressants were involved with similar frequencies in ADR that were at least "probably" drug-related (3.3 and 3.5%). Lithium salts and benzodiazepines were only rarely involved in psychic ADR. Toxic delirium (1.0%), agitation (0.9%), and sedation (0.8%) were the most frequent single events, usually rated as "probably" drug-related. Depression and psychotic states were next in frequency, but judged as only "possibly" drug-related in a considerable proportion of cases. Haloperidol, the most common high-potency neuroleptic, was imputed mainly for depression, sedation, agitation, and (malignant) neuroleptic syndrome; with medium-potency perazine, toxic delirium and sedation prevailed; among the most common antidepressants, amitriptyline was above all connected with toxic delirium, while with clomipramine agitation predominated. The paper discusses the particular difficulties encountered in the field of psychic ADR in psychiatric patients regarding causality assessment, and emphasizes the need for continuous ADR assessment studies including state hospitals.

Adult↗
PubMed1993

Reversal of brain atrophy with biotin treatment in biotinidase deficiency.

Two children with biotinidase deficiency presented with seizures at 2 months of age. The first child had a fluctuating course with continual developmental progress and cessation of seizures despite symptoms of chronic neurologic dysfunction until he was diagnosed at 17 months. The second child had a progressive course with uncontrolled seizures leading to an unresponsive state until she was diagnosed at 6 1/2 months. Neither child had dermatologic symptoms until shortly before the time of diagnosis. Both children improved markedly with biotin treatment. Serial CT-scan and MRI studies of the brain showed a distinct pattern of changes. Shortly after initial presentation, diffuse low attenuation of the white matter was seen followed by progressive marked cerebral atrophy, which was reversed following biotin treatment. Because this is a reversible condition, clinicians should screen for biotinidase deficiency in all children with symptoms of chronic neurologic dysfunction, especially when radiologic findings of low attenuation of the white matter are followed by cerebral atrophy.

Amidohydrolases↗
PubMed1993

Emergence of self-organization in tumor cells: relevance for diagnosis and therapy.

The cell is a complex system functioning outside a thermodynamic equilibrium. The prediction of cellular functions based exclusively on molecular evidence is still impossible because of the large number of interacting molecules and the nonlinear interactions between cellular subsystems. The system cell displays a surprisingly small spectrum of macroscopically observable degrees of freedom. Their number and characteristics, however, are different in normal and neoplastic growth. As illustrated by image analytical, microanalytical and other cell biological data we demonstrate that certain cellular observables--termed order parameters--may serve as indicators for normal and neoplastic growth. The data indicate that the transition between normal and neoplastic growth can be understood as a phase transition of the mitogenic signalling network. In this interpretation, the order parameters of normal and neoplastic cells are the result of cellular self-organization.

Cell Communication↗
PubMed1993

Ophthalmologic findings in biotinidase deficiency.

Biotinidase deficiency is an autosomal recessively inherited metabolic disorder characterized by neurological and cutaneous manifestations and metabolic abnormalities. We studied 78 symptomatic children and found that 51% had ophthalmologic abnormalities. These include infections (30%), optic neuropathies and visual disturbances (13%), motility disturbances (13%), retinal pigment changes (4%) and pupillary findings (1%). The most commonly reported findings are optic atrophy and keratoconjunctivities. Although the disorder can be effectively treated with biotin therapy, untreated children are at risk of developing permanent neuro-ophthalmic damage.

Amidohydrolases↗
PubMed1993

Characterization of seizures associated with biotinidase deficiency.

Biotinidase deficiency is an autosomal recessively inherited disorder that is often characterized by neurologic abnormalities. We reviewed the clinical features of 78 symptomatic children, 11 new patients and 67 previously reported cases, to determine the frequency, type, age at onset, and the responsiveness of seizures to antiepileptic drugs and biotin therapy. Forty-three of the 78 (55%) symptomatic children had seizures, and seizures were the presenting symptom in 38% of the enzyme-deficient patients and 70% of those who had had seizures at some time. EEGs were available for 21 of these children. Sixteen were abnormal. The initially abnormal EEGs in eight of 12 infants became normal or improved with biotin therapy, whereas four continued to be abnormal. In 21 (49%) patients, the seizures were not well controlled with antiepileptic drugs. Biotin therapy stopped the seizures within 24 hours in 12 of 16 (75%) of those whose seizures were uncontrolled by anticonvulsants (five children died prior to diagnosis). Although the metabolic and cutaneous abnormalities were corrected in the remaining four children, they continued to have neurologic abnormalities. Biotinidase deficiency and a trial of biotin (5 to 10 mg) should be considered in infants less than 1 year of age with poorly controlled seizures, and biotinidase deficiency should be included in the differential diagnosis of an infant or child with unexplained seizures.

Amidohydrolases↗