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Biomedical subjects

M Brandt

Publications and source records attributed to M Brandt.

At least 109 records · Page 6Linked to original sources

Reversal of intrapulmonary shunting in cirrhosis after liver transplantation demonstrated by perfusion lung scan.

A young girl with biliary atresia leading to cirrhosis developed respiratory complications with hypoxemia. Intrapulmonary shunting was diagnosed with a 99mTc-MAA perfusion lung scan, which showed marked systemic activity. The shunting resolved after liver transplantation. The perfusion lung scan offers an efficient method to screen patients with cirrhosis in whom intrapulmonary shunts are suspected and to follow their progress.

Child↗

Studies on the mechanism of steroid 5 alpha-reductase inhibition by 3-carboxy A-ring aryl steroids.

The mechanism of interaction between two 3-carboxy A-ring aryl steroids, 17 beta-(N,N-diisopropylcarboxamide)-estra-1,3,5(10)-triene-3-carboxy lic acid (1) and 17 beta-(N-t-butylcarboxamide)-estra-1,3,5(10)-triene-3-carboxylic acid (2), with rat hepatic and human prostatic steroid 5 alpha-reductases has been investigated. Dead-end inhibition plots with 1 and 2 versus both substrates (testosterone and NADPH) were linear-uncompetitive using either enzyme, while double-inhibition analyses indicated cooperative binding to enzyme between NADP+ and 1 or 2. These results were interpreted within the ordered kinetic mechanism of steroid 5 alpha-reductase to result from the preferential association of 3-carboxy A-ring aryl steroids to the enzyme-NADP+ complex. The direct displacement by 2 of a radioligand known to associate to this same enzyme form provides further support for these conclusions.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗

Mechanistic studies with solubilized rat liver steroid 5 alpha-reductase: elucidation of the kinetic mechanism.

A solubilized preparation of steroid 5 alpha-reductase (EC 1.3.1.30) from rat liver has been used in studies focused toward an understanding of the kinetic mechanism associated with enzyme catalysis. From the results of analyses with product and dead-end inhibitors, a preferentially ordered binding of substrates and release of products from the surface of the enzyme is proposed. The observations from these experiments were identical with those using the steroid 5 alpha-reductase activity associated with rat liver microsomes. The primary isotope effects on steady-state kinetic parameters when [4S-2H]NADPH was used also were consistent with an ordered kinetic mechanism. Normal isotope effects were observed for all three kinetic parameters (Vm/Km for both testosterone and NADPH and Vm) at all substrate concentrations used experimentally. Upon extrapolation to infinite concentration of testosterone, the isotope effect on Vm/Km for NADPH approached unity, indicating that the nicotinamide dinucleotide phosphate is the first substrate binding to and the second product released from the enzyme. The isotope effects on Vm/Km for testosterone at infinite concentration of cofactor and on Vm were 3.8 +/- 0.5 and 3.3 +/- 0.4, respectively. Data from the pH profiles of these three steady-state parameters and the inhibition constants (1/Ki) of competitive inhibitors versus both substrates indicate that the binding of nicotinamide dinucleotide phosphate involves coordination of its anionic 2'-phosphate to a protonated enzyme-associated base with an apparent pK near 8.0. From these results, relative limits have been placed on several of the internal rate constants used to describe the ordered mechanism of the rat liver steroid 5 alpha-reductase.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗

Inhibition of rat liver steroid 5 alpha-reductase by 3-androstene-3-carboxylic acids: mechanism of enzyme-inhibitor interaction.

The interactions of a series of newly discovered inhibitors of delta 4-3-oxo-steroid 5 alpha-reductase (SR; EC 1.3.1.30), the 3-androstene-3-carboxylic acids (steroidal acrylates), have been studied by using a solubilized rat liver enzyme preparation. As exemplified by one member of this series, 17 beta-[N,N-diisopropyl-carbamoyl)androst-3,5-diene-3-carboxylic acid (1a), the dead-end inhibition patterns of selected compounds in this class are best evaluated by a linear uncompetitive kinetic model versus either substrate, testosterone (T) or NADPH. These results were interpreted within the context of the preferentially ordered kinetic mechanism for rat liver SR to arise from the association of inhibitor to the binary complex of enzyme and NADP+. This proposed inhibition mechanism was supported by data from double-inhibition experiments implicating the synergistic binding of steroidal acrylate and NADP+ to SR. Further evidence for the preferential formation of this ternary complex was obtained from filtration binding assays with [3H]-1a, where radioligand association to protein was greatly enhanced in the presence of NADP+. The amount of [3H]-1a binding to protein was proportional to the specific activity of SR in the enzyme preparations, and the estimated dissociation constant from binding data by Scatchard analysis (Kd = 25 nM) was comparable to the inhibition constants estimated for SR activity (Ki = 12-26 nM). From the pH profile for inhibition of the solubilized liver SR with 1a, it is proposed that the anion of the steroidal acrylate (pK1 = 4.7 +/- 0.2) is the active inhibitory species, coordinating to a protonated active site functionality (pK2 = 7.5 +/- 0.1). On the basis of data from similar experiments with structural analogues of 1a, the determinants for binding recognition and inhibitory potency are compared to structural features of the putative enzyme-bound intermediate states. These compounds represent a potential therapeutic alternative in the treatment of 5 alpha-dihydrotestosterone specific androgen dependent disease states.

5-alpha Reductase Inhibitors↗

Malignant thymoma in children: a 20-year review.

Malignant thymomas are extremely rare in children, with only 27 cases reported thus far in the pediatric surgical literature. We report four additional cases diagnosed at this institution over the past 20 years (ages 3 to 14 years). Clinical presentations included superior vena cava syndrome, cough, dyspnea, cyanosis, enlarging mediastinal mass, spontaneous pneumothorax, and pleuropericardial effusion. Three patients underwent incomplete resection of the mass or biopsy because of "unresectability" and were treated with radiotherapy and adjunctive chemotherapy. One patient underwent near complete macroscopic resection as well as radiotherapy and chemotherapy. All patients died at intervals ranging from 6 months to 2 1/2 years after diagnosis. Three patients were found to have metastatic disease prior to death or at autopsy. In one case, the initial pathological diagnosis was lymphocytic thymoma. After ultrastructural studies were performed, the diagnosis was changed to thymic T-cell lymphoma. This patient subsequently developed acute lymphoblastic leukemia 3 months after surgical resection followed by radiotherapy. Malignant thymomas are highly aggressive tumors in children. A radical surgical approach with complete excision of the tumor and contiguous structures in continuity, with adjunctive radiotherapy and chemotherapy remains the only hope for survival in children with these rare lesions.

Adolescent↗

Steroidal A ring aryl carboxylic acids: a new class of steroid 5 alpha-reductase inhibitors.

A series of 17 beta-carbamoyl-1,3,5(10)-estratriene-3-carboxylic acids has been prepared and evaluated in vitro as inhibitors of human and rat prostatic steroid 5 alpha-reductase (EC 1.3.1.30). Potent inhibition of the human enzyme, in particular, was observed and preliminary studies using rat enzyme suggest that the inhibition results from the formation of an enzyme-NADP(+)-inhibitor complex. The compounds were synthesized from estrone, generally employing a differentiated bis-triflate carbonylation strategy.

5-alpha Reductase Inhibitors↗

Inhibition of steroid 5 alpha-reductase by unsaturated 3-carboxysteroids.

A series of unsaturated steroids bearing a 3-carboxy substituent has been prepared and assayed in vitro as inhibitors of human and rat prostatic steroid 5 alpha-reductase (EC 1.3.1.30). It is proposed that the observed tight binding of the 3-androstene-3-carboxylic acids is due to mimicry of a putative, high-energy, enzyme-bound enolate intermediate formed during the NADPH-dependent conjugate reduction of testosterone by steroid 5 alpha-reductase. These compounds were prepared through palladium(0)-catalyzed carbomethoxylations of enol (trifluoromethyl)sulfonates derived from 3-keto precursors. Modification of A and B ring unsaturation and substitution at C-3, -4, -6, and -11 was explored. Mono- and dialkylcarboxamides were employed as 17 beta side chains to enhance inhibitory activity with the human enzyme.

5-alpha Reductase Inhibitors↗

The secretory erythropoietin response in patients with multiple myeloma and Waldenström's macroglobulinaemia.

Immunoreactive levels of serum erythropoietin (EPO) have been measured in 95 patients with multiple myeloma (MM) and 12 patients with Waldenström's macroglobulinaemia (MW). Of the MM patients 23% were uraemic (mostly light and moderate renal failure) and 61.7% were anaemic. In the anaemic nonuraemic MM patients the mean serum EPO titre was 106.8 +/- 30.4 mU/ml which, when related to the extent of anaemia, was found to be appropriately elevated for the degree of anaemia (the mean haemoglobin (B-HGB) concentration was 6.66 +/- 1.31 mmol/l). The mean serum EPO concentration in uraemic and anaemic MM patients was 39.2 +/- 9.2 mU/ml, which was markedly lower than serum EPO levels in the non-uraemic MM patients, but still higher than in nonanaemic control subjects (22.5 +/- 8.5 mU/ml). The mean B-HGB concentration in uraemic MM patients was 6.04 mmol/l. In the anaemic MM patients with severe renal failure (S-creatinine levels greater than 400 mumol/l) the compensatory secretion of EPO was inadequate in relation to the degree of anaemia. The data indicate that unless the hypoproliferative anaemia of MM is accompanied by considerable renal failure the anaemia does not appear to be associated with a deficient biogenesis of EPO. Likewise the anaemia found in patients with MW also seems, generally, to elicit an appropriate increase in EPO secretion. Reasonably clinically stable MM patients with anaemia and uraemia may be candidates for replacement therapy with recombinant human erythropoietin (rhEPO).

Anemia↗

3 Beta-hydroxy-delta 5-steroid dehydrogenase/3-keto-delta 5-steroid isomerase from bovine adrenals: mechanism of inhibition by 3-oxo-4-aza steroids and kinetic mechanism of the dehydrogenase.

Several 3-oxo-4-aza steroids (1) have been identified as inhibitors of the 3 beta-hydroxy-delta 5-steroid dehydrogenase/3-keto-delta 5-steroid isomerase catalyzed conversion of pregnenolone to progesterone. By kinetically decoupling the two enzyme activities isolated from bovine adrenal cortex, it has been demonstrated that inhibition by 1 occurs through interference of both activities. A preferred ordered association of substrates to the 3 beta-hydroxy-delta 5-steroid dehydrogenase in which the cofactor binds prior to steroid was determined by isotope exchange at equilibrium. With this result, the dead-end inhibition patterns of 1 with the dehydrogenase were interpreted to originate from a preferred association of inhibitor within an enzyme ternate containing NADH; this proposal is supported by data from multiple inhibition analysis indicating synergistic binding of NADH and 1. Similarly, inhibition of the 3-keto-delta 5-steroid isomerase by the 3-oxo-4-aza steroids was enhanced in the presence of the positive effector NADH. On the basis of pH profiles upon Vm, Vm/Km, and 1/Ki for both enzyme activities, inhibition is proposed to result from the structural similarity of 1 to intermediate states formed upon enzyme catalysis.

3-Hydroxysteroid Dehydrogenases↗

Interaction between rat prostatic steroid 5 alpha-reductase and 3-carboxy-17 beta-substituted steroids: novel mechanism of enzyme inhibition.

Efforts to identify novel compounds capable of blocking the steroid 5 alpha-reductase (SR) catalyzed conversion of testosterone (T) to 5 alpha-dihydrotestosterone have resulted in the development of 17 beta-substituted-3-androstene-3-carboxylic acids as potent inhibitors of the rat prostatic enzyme. The dead-end inhibition patterns of one of these steroidal acrylates, 17 beta-N-(2-methyl-2-propyl)-carbamoyl-androst-3,5-diene-3-carboxylic acid were best evaluated with a linear uncompetitive kinetic model vs both T (Kii = 11 +/- 1 nM) and NADPH (Kii = 22 +/- 2 nM). To interpret these observations, the kinetic mechanism of the rat prostatic SR was shown to involve the binding of NADPH prior to that of T through a series of dead-end and product inhibition experiments. Within the context of this preferentially ordered kinetic mechanism, it is proposed that the uncompetitive inhibition patterns result from the association of the steroidal acrylate to an enzyme complex containing NADP+ in formation of a dead-end ternary complex of enzyme, NADP+, and inhibitor.

5-alpha Reductase Inhibitors↗

Ruminal degradability of crude protein from different treated soybean meals in lactating cows.

Ruminal crude protein (CP) degradability of four commercially available soybean meal (SBM) types--untoasted (U), toasted (T), heat-treated (H) and formaldehyde-treated (F)--was studied by the use of in sacco and in vivo techniques with lactating German Friesian cows cannulated in the rumen, duodenum and ileum. In two in sacco experiments three cows were fed a diet based either on grass hay plus ear-maize silage or on barley whole plant silage. Ruminal degradation rate of CP was estimated as percent nitrogen (N) disappearance from polyester bags incubated in the rumen for 2, 4, 6, 8, 12 and 24 h. Ruminal degradation rate of CP varied among the four SBM types as well as between the two basal diets. N disappearance from the bags after 12 h of incubation averaged 96, 67, 37, and 23% for the U, T, H, and F SBM types, respectively, in the cows fed the hay/ear-maize silage diet vs 99, 86, 58 and 41% for the four SBM types, respectively, in the cows fed the barley whole plant silage diet. In the in vivo experiment, four cows were fed diets based on meadow hay and ear-maize silage in a 4 x 4 Latin square design. The effect of SBM treatment on the flow rate of non-ammonia N (NAN) into the duodenum, and its relationship with the ruminal degradation rate of CP of the four SBM types, was studied. Formaldehyde treatment increased the amount of NAN entering the duodenum (P less than .05): 485 g cow-1 day-1 compared to 383, 418 and 428 g for U, T and H, respectively. Calculated ruminal CP degradabilities were 93, 75, 71 and 38% for SBM types U, T, H and F, respectively.

Animal Feed↗

B lymphocyte function in multiple myeloma: analysis of T cell- and monocyte-dependent antibody production.

T-cell and B-cell functions were studied in 35 patients with untreated multiple myeloma (MM) and in 16 patients with MM treated with prednisolone, melphalan and vincristine. The numbers of CD4+ T cells were normal in untreated MM patients, but markedly decreased in treated patients, whereas CD8+ cell numbers were normal in untreated and treated patients. Mitogen-induced as well as antigen-induced lymphocyte proliferative responses were reduced, but not further affected by treatment. The antigen-induced proliferative responses by lymphocytes of treated, but not of untreated patients, correlated positively to the proportions of CD4+ cells among MNC. Taken together, the findings suggest selective loss of CD4+ subpopulations during cytotoxic treatment. Pokeweed mitogen (PWM)-induced Ig production was generally low, but significantly reduced Ig production was only seen in experiments employing MM B cells and monocytes co-cultured with irradiated T-enriched cells. Irradiated MM T cells displayed normal helper function when co-cultured with normal B cells stimulated with PWM. MM B cells and monocytes cultured with irradiated normal T cells produced little Ig; however, MM monocytes were not suppressive. In 2 of 3 patients with either IgG-kappa or IgA-kappa myeloma, the numbers of PWM-stimulated B cells that produced kappa chains were somewhat higher than those found among normal MNC. The impaired ability of antibody production by B cells from untreated MM patients seems to relate to intrinsic B cell defect(s) rather than to abnormal regulation by T cells or monocytes. However, disturbances in the functions of CD4+ cells may be observed in treated MM.

Aged↗

[Brain abscess and subdural empyema from the bacteriologic viewpoint].

The bacteriology has changed since beginning of antibiotic therapy. Reports of literature and the dates of patients treated in Neurosurgical Clinic of Münster are analyzed. The improvement of microbiological technique leads to the evidence of a greater role of anaerobics and of a smaller part of sterile cultures. The success of therapy depends on the early beginning of specific therapy. The poor prognosis of the sterile inflammations is caused by inefficiency of unspecific therapy.

Bacteria↗

[An extended health surveillance program for mentally stressed employees--results and experiences].

One-week physical and psychic fitness training courses are held for nomenclature and management personal annually. Undergoing exercise bouts, they are tested for their cardiocirculatory capacity and given specific information on the type of continuous physical endurance training they should carry out. A follow-up course one year later reviews the level of fitness reached. The follow-up course focuses on a psychologically oriented manager training group talks and concentrative relaxation. Other groups of working people, including shift workers and mothers with several children are given the opportunity to undergo a four-week physical fitness training during preventive spa treatment courses. 140 persons attend this type of treatment every year. For the purpose of objectifying treatment results and reviewing the cardiocirculatory capacity random samples were taken of 20 persons exercising on a fitness machine before, immediately after and six months after the treatment course. Biochemical parameters were also determined. Physical fitness was up between 25 and 50 watts in 72 per cent of the test persons. Under exercise, the blood pressure and the heart rate fell significantly. The LPTT, cholesterol and uric-acid levels in serum were below the initial values. The improved fitness persisted only in 27 per cent of the test persons after six months, with the biochemical parameters equalling the initial values. Preventive measures in the form of physical fitness should be extended at enterprise and local levels. However, working people should be more aware of the possibilities available for physical fitness training.

Humans↗

Cavernous hemangiomas in children.

Cavernous angiomas are histologically benign hamartomas, showing no potential for metastasis. Clinically, patients present with convulsions, hemorrhage, or signs of mass effect. Although many cases exhibit ossification on X-ray, the main means of diagnosis is computed tomography. This, in turn, has led to earlier diagnoses being made in much younger patients. Early diagnosis is a matter of urgency as patients are otherwise exposed to the continuing threat of rupture. As cavernous angiomas are operable, the prognosis is usually good.

Adolescent↗

Surgical strategies for combined intraorbital and intracranial tumors.

Three unusual cases of combined intraorbital-intracranial tumors of various types which were chosen from cases treated in the Clinic and Polyclinic of Neurosurgery of the University of Münster, to demonstrate the problems of surgical therapy. A list of indications for the various accesses to the orbita is worked out. Close co-operation among the neurosurgeon, the ophtalmologist, the oto-rhino-laryngologist and the maxillofacial surgeon is necessary. All facets of the patient's condition and situation must be taken into consideration when planning therapy.

Adenoma↗

Orbital cavernous hemangiomas.

Cavernous hemangiomas are the most frequently found primary tumors in the orbital region. They normally appear in adults. Diagnostic features in the majority of cases include protrusio bulbi and orbital enlargement. B-Scan and computed tomography/MRI are the prime diagnostic aids. We recommend surgical removal of these tumors, at least in cases with marked orbital protrusion or significant optic nerve compression. The prognosis is usually good.

Adolescent↗