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Biomedical subjects

M Brenner

Publications and source records attributed to M Brenner.

At least 199 records · Page 11Linked to original sources
PubMed1988

Role of copper and catalytic mechanism in the copper monooxygenase, dopamine beta-hydroxylase (D beta H).

Although classically characterized as a Type II copper protein, recent work has shown that D beta H requires two coppers per subunit for optimal activity. A major challenge has been to elucidate the relationship of these copper sites to one another, specifically whether there exists a single binuclear copper site or distinct metal sites catalyzing separate functions. In this paper, copper sites have been investigated by EPR techniques and rapid mixing methods to measure the rates and stoichiometries of copper reduction by ascorbate and subsequent reoxidation by tyramine. As shown, there is little or no evidence by EPR for spin coupling between metal sites in resting enzyme. Both coppers per subunit undergo reduction and reoxidation with single exponential values of 185 s-1 and 80 s-1, respectively. Significantly, the ratio of copper reoxidation to product formation in a single turnover is close to 2:1, implicating both coppers in the catalytic mechanism and ruling out any significant spin coupling in the enzyme-product complex. In contrast to single turnover experiments, rapid kinetics in the presence of excess ascorbate reveal a very low level of E-Cu (II). This result, which appears to conflict with evidence that the dominant enzyme form in the steady state is E-P, leads us to propose a reduction of enzyme at the level of E-P rather than free enzyme. Taken together with steady state kinetic parameters using alternate reductants, the data support separate binding sites for reductants and product/substrate and hence, separate functions for each copper per subunit. A detailed catalytic mechanism for D beta H is discussed in the context of a single metal site catalyzing dopamine hydroxylation.

Binding Sites↗
PubMed1988

[Intravenous and oral treatment with amantadine sulfate in Parkinson disease].

The rapid efficacy of amantadine on akinesia and rigidity in Parkinson's disease is generally known. The duration of this therapeutic result is however controversial. Some authors have reported a loss of efficacy after only a few weeks of therapy. The success of a short-term parenteral and subsequently oral long-term treatment with amantadine sulphate in 8 Parkinsonian patients was tested by means of clinical and neuropsychological examinations and by monitoring the serum concentration over the course of half a year. A ten-day intravenous treatment with amantadine sulphate (200 mg daily) led to a significant improvement in the clinical and psychological test results. This attained improvement could be maintained for 6 months with oral therapy consisting of 600 mg amantadine sulphate. There were strong interindividual variations in serum concentration.

Administration, Oral↗
PubMed1987

Pathologic findings on re-excision of the primary site in breast cancer patients considered for treatment by primary radiation therapy.

Gross excision of the tumor followed by radiotherapy is used for treatment of early breast cancer. Local recurrence after this form of treatment is uncommon except in patients with infiltrating ductal carcinoma whose excision specimens reveal an extensive intraductal component (EIC). It is unclear whether this observation is due to a qualitative difference in the response of tumors with EIC to radiation or to a quantitative difference in the tumor burden remaining after gross excision in patients with EIC. To address this question, the authors examined pathologic material in 71 patients with infiltrating ductal carcinoma treated with gross excision of the tumor and then selected for re-excision of the tumor site prior to radiotherapy because of the presence of either EIC in the primary excision specimen or microscopic tumor at or close to margins in the initial excision. Residual carcinoma was seen in 62% of all patients but was more frequent among the 25 patients with EIC than the 46 without (88% vs. 48%, P = 0.002). The nature of the residual tumor differed for patients with and without EIC in the primary excision specimen. Residual carcinoma in patients with EIC was often widespread and composed predominantly of intraductal carcinoma. In contrast, residual tumor in patients without EIC usually consisted of only scattered microscopic foci of infiltrating and/or intraductal carcinoma. The authors conclude that patients with EIC treated with gross excision of the tumor frequently have considerable residual intraductal carcinoma near the primary site. This finding may account for the increased risk of local recurrence observed in patients with EIC treated without re-excision of the tumor site before radiation therapy.

Breast Neoplasms↗
PubMed1987

Dopamine agonists related to 3-allyl-6-chloro-2,3,4,5-tetrahydro-1-(4-hydroxyphenyl)-1H-3-benzaz epi ne-7, 8-diol. 6-Position modifications.

The N-allyl derivative (SK&F 85174) of 6-chloro-2,3,4,5-tetrahydro-1-(4-hydroxyphenyl)-1H-3-benzazepine-7,8-diol (SK&F 82526) retains the DA-1 agonist potency of the latter compound but unlike the parent also shows substantial DA-2 agonist activity. In a previous study of N-substituted benzazepines these combined agonist effects were shown to be uniquely associated with the N-allyl group. A continuation of this research has examined dependency of combined DA-2/DA-1 agonist activities on 6-position modification with the specific objective of developing an agonist with maximum effectiveness and potency at the DA-2 receptor subtype. DA-2 agonist activity was measured in a rabbit ear artery assay, and DA-1 agonist activity was determined in an adenylate cyclase assay. Replacing chloro with bromo retains the activity pattern and the potency of the chloro compound; replacement with a hydrogen causes a decrease of both DA-1 and DA-2 receptor activating potency. Introduction of a 6-methyl group causes loss of DA-2 agonist activity and reduction in DA-1 agonist potency. Substitution with a 6-fluoro provides the best balance of DA-2 and DA-1 agonist activities; this compound was moderately potent in both assays.

Adenylyl Cyclases↗
PubMed1987

Malignant lymphoma presenting as a renal mass: four cases.

Primary lymphoma of the kidney is extremely rare; most lymphomatous renal masses represent extension from adjacent sites of disease or involvement by generalized disease (4,9,12). Three men and one woman, 45 to 71 years of age, presented with solitary renal masses clinically thought to be renal cell carcinoma. Each experienced abdominal pain, one with hematuria and one with "B" symptoms. Physical examination revealed no peripheral lymphadenopathy or hepatosplenomegaly. Lactic dehydrogenase (LDH) was elevated in three cases, and blood urea nitrogen (BUN) and creatinine were slightly increased in two. Two cases were diagnosed correctly from needle biopsy, with ultrastructural confirmation in one case and marker studies, DNA flow cytometry, and cytogenetics in the other. Because of a presumptive diagnosis of renal cell carcinoma, two patients underwent nephrectomy. Three cases were large-cell lymphoma, and one, small noncleaved cell lymphoma.

Aged↗
PubMed1987

Cardiovascular effects and safety of intravenous and intramuscular pentamidine isethionate.

Intramuscular (im) pentamidine isethionate can cause substantial local pain and inflammation at the injection site. This drug is being used more frequently in recent years to treat Pneumocystis pneumonia, particularly in patients with acquired immunodeficiency syndrome. Clinicians began administering it iv despite warnings that iv administration might cause severe hypotension. We investigated the safety of im and iv pentamidine, monitoring hemodynamics after each dose in 11 patients with intra-arterial lines. Results showed only a small (but statistically significant) fall in mean arterial pressure after both im and slow (60 min) iv administration. A concomitant decrease in pulse occurred, but no change in cardiac output, pulmonary capillary occlusion pressure or systemic vascular resistance was noted. These results suggest that it may be safe to infuse pentamidine slowly intravenously. This route is more comfortable to patients than im administration.

Amidines↗
PubMed1987

Tibial fractures with infrapopliteal arterial injuries.

Tibial fractures with associated infrapopliteal arterial injuries have been inadequately documented in the literature. Eighteen patients with these injuries were admitted to Boston City Hospital during a 10-year period. Three patients required below-knee amputation, and two of these had ischemic intervals of greater than 8 h before vascular treatment. Six patients had delayed diagnoses of arterial injuries, but none required amputation. There were 15 open and three closed tibial fractures. Nine fractures were badly comminuted. Eight of the 14 viable limbs had delayed unions, but only one was associated with local vascular insufficiency. Five patients had complaints attributed to vascular insufficiency without clinical findings. Our conclusion is that the limb with an infrapopliteal arterial insult combined with a tibial fracture can survive with patency of only the anterior tibial or posterior tibial artery. Poor clinical results correlate with the severity of bony injury and not with the particular arterial injury. The incidence of below-knee amputation can best be related to delay in vascular treatment.

Adolescent↗
PubMed1987

Prognostic factors and life expectancy of patients with acquired immunodeficiency syndrome and Pneumocystis carinii pneumonia.

To assess determinants of prognosis for 43 patients with the acquired immunodeficiency syndrome (AIDS) and Pneumocystis carinii pneumonia, objective clinical and histopathologic characteristics were analyzed for acute and long-term prognostic significance. Severe abnormalities on initial chest radiographs and alveolar-arterial oxygen differences (AaPO2) greater than 30 mm Hg were associated with higher mortality during the period of treatment for the acute episode (p less than 0.05). Decreased long-term survival after the diagnosis of Pneumocystis pneumonia correlated with the severity of interstitial edema (a component of diffuse alveolar damage) on initial transbronchial biopsy and elevation of AaPO2 at the time of diagnosis (Cox proportional hazards analysis, p less than 0.05). The persistence of Pneumocystis cysts after 3 wk of therapy was associated with significantly decreased long-term survival (p less than 0.05) when follow-up biopsy was performed in 27 of the patients. Patients with a diagnosis of Pneumocystis pneumonia before July 1985 had more advanced disease at the time of diagnosis and a worse prognosis than did those in whom the diagnosis was made after July 1985 (p less than 0.05). This study demonstrates that important prognostic information can be derived from information obtained at initial presentation and follow-up bronchoscopic evaluation in patients with AIDS and Pneumocystis carinii pneumonia, and suggests that early detection and initiation of therapy may improve chances for survival.

Acquired Immunodeficiency Syndrome↗
PubMed1987

Nonspecific interstitial pneumonitis in patients with AIDS: radiologic features.

Chest radiographic abnormalities in patients with AIDS usually are associated with opportunistic infection or neoplasm. One hundred five patients with AIDS and clinical evidence of pneumonitis had chest radiographs and underwent bronchoscopy with bronchoalveolar lavage, transbronchial biopsy, or open-lung biopsy. Chest radiographs were abnormal in 73 (70%). Pneumocystis carinii pneumonia was identified at bronchoscopy or open-lung biopsy in 52 (50%). Nonspecific interstitial pneumonitis occurring in the absence of an identifiable infection was documented histologically in 36 (34%). Twenty (56%) of these 36 patients had abnormal chest radiographs. No currently recognized infectious agents were recovered from lavage fluid or were seen histopathologically in patients with nonspecific interstitial pneumonitis. The results show that nonspecific interstitial pneumonitis is clinically and radiologically indistinguishable from Pneumocystis carinii pneumonitis and should be considered in the differential diagnosis of AIDS patients with interstitial infiltrates.

Acquired Immunodeficiency Syndrome↗
PubMed1987

Nonspecific interstitial pneumonitis: a common cause of pulmonary disease in the acquired immunodeficiency syndrome.

During a 4.4-year period, nonspecific interstitial pneumonitis was seen in 41 of 110 (38%) patients with the acquired immunodeficiency syndrome and accounted for 32% (48/152) of all episodes of clinical pneumonitis. Diffuse alveolar damage was typically a feature of nonspecific interstitial pneumonitis, but neither lung biopsy nor bronchoalveolar lavage detected a pathogen. Of these 41 patients, 13 had no associated pulmonary tumor and had not been exposed to pulmonary toxins, whereas 28 patients had either concurrent pulmonary Kaposi sarcoma, previous experimental therapies, or a history of pneumocystis pneumonia or drug abuse. Of these 41, 23 had normal chest radiographs. The clinical features of patients with nonspecific interstitial pneumonitis were similar to those of patients with pneumocystis pneumonia, although histologic findings showed less severe alveolar damage in patients with nonspecific interstitial pneumonitis (p less than 0.001). Pathologic evaluation and clinical follow-up suggest that many clinical episodes of pneumonitis in patients with the acquired immunodeficiency syndrome are due to nonspecific interstitial pneumonitis of unknown cause.

Acquired Immunodeficiency Syndrome↗
PubMed1987

[Intracranial pressure-controlled treatment of brain edema with glycerin and sorbitol in intracerebral hemorrhage].

The continuous epidural registration of intracerebral pressure showed that the pronounced brain edema which develops during the 4th to 14th day of an intracerebral hemorrhage could lead to an increase in intracerebral pressure (ICP greater than 25 mmHg) requiring treatment. During the therapy extensive ICP crises (ICP greater than 35 mmHg), lasting for 1 to 3 days and only controllable through high doses of glycerol and sorbitol, developed. Glycerol (50 g orally) and sorbitol (50 g i.v.) lowered the pressure during this phase for approximately 3 h and 1.5 h respectively. These time intervals were in accordance with the changes in plasma osmolality through the administration of both substances. Due to its longer efficacy, glycerol provides an important supplement or alternative to sorbitol therapy, especially as the permitted maximum dosage would have to have been exceeded in a treatment consisting exclusively of sorbitol. The duration of the decrease in intracerebral pressure lasted longer during the remainder of the treatment in the case of both substances, being decisively dependent on the intracerebral pressure intensity. The relatively harmless epidural measurement of intracerebral pressure allowed an optimal control of the brain edema therapy as the dosage of the hyperosmolar substances could be given exactly in accordance with the intracerebral pressure intensity and subsequently varying efficacy.

Administration, Oral↗
PubMed1986

Dopamine receptor agonists: 3-allyl-6-chloro-2,3,4,5-tetrahydro- 1-(4-hydroxyphenyl)-1H-3-benzazepine-7,8-diol and a series of related 3-benzazepines.

The N-allyl derivative (SK&F 85174) of 6-chloro-2,3,4,5-tetrahydro-1-(4-hydroxyphenyl)-1H-3-benzazepine-7,8-dio l (SK&F 82526) not only retains the exceptional D-1 agonist potency of its parent but also displays reasonably potent D-2 agonist activity, as measured by a dopamine-sensitive adenylate cyclase test and a rabbit ear artery assay, respectively. Several additional N-substituted compounds were prepared to explore the D-2/D-1 agonist relationship. The N-methyl analogue retained good D-2 agonist potency, but this substitution converted D-1 agonist activity into antagonist activity. Most other N-substituents sharply decreased D-2 agonist potency including the N-n-propyl group. This observation was surprising since the introduction of mono- or di-N-n-propyl substituent(s) is commonly linked with retention or enhancement of D-2 agonist potency in other series of dopamine agonists. The N-(2-hydroxyethyl) analogue retains about one-fourth the D-2 potency of SK&F 85174. Several synthetic methods were used to prepare these compounds. N-Allylation of a trimethoxybenzazepine followed by cleavage of the methyl ethers with boron tribromide was the preferred method. Other methods used were direct alkylation of the trihydroxy secondary amine, i.e., SK&F 82526, and an acylation-amide reduction-cleavage method.

Alkylation↗
PubMed1986

Malignant fibrous histiocytoma associated with peripheral blood eosinophilia. In vitro studies demonstrating tumor-derived eosinophilopoietic activity.

Peripheral blood eosinophilia is a well-recognized paraneoplasia in many kinds of hematological and nonhematological malignancies. We report the case of a patient with a malignant fibrous histiocytoma. With increasing tumor burden, the patient developed a marked peripheral blood eosinophilia. Using an in vitro assay for growth of eosinophilic colonies, both the serum and the tumor of the patient proved to contain an eosinophilopoietic activity.

Cell Division↗
PubMed1985

The role of enzyme sequestration in the regulation of the adenylate cyclase of Dictyostelium discoideum.

Although the adenylate cyclase of Dictyostelium discoideum cannot be activated by its cAMP agonist in vitro, its in vivo activation can be demonstrated by rapidly breaking and assaying the cells, over 10-fold higher activity being observed for stimulated cells than for basal cells. We report here that when basal cells are broken in the presence of labeled ATP and then rapidly assayed, they display 8-fold more adenylate cyclase activity than cells broken in the presence of unlabeled ATP. This suggests that a significant amount of the enzyme in extracts of basal cells is sequestered within vesicles that can be loaded with substrate at the time of cell lysis, but then rapidly seal. In contrast to the results obtained with basal cells, when cells activated in vivo are broken in the presence of labeled ATP, there is less than 2-fold increase in adenylate cyclase activity. Thus, a much smaller percentage of the observed adenylate cyclase activity of stimulated cells appears to be due to sequestered enzyme than of basal cells. Two models are discussed that account for these observations. One model envisions that roughly equal populations of sequestered and nonsequestered enzyme are produced upon breakage of both basal and activated cells, but that sequestered enzyme in basal extracts becomes uniquely activated in vitro. The other model proposes that the differences in observed activity are due directly to differences in sequestration. According to this latter model, nearly all of the -fold activation previously observed for the D. discoideum adenylate cyclase can be accounted for by a change in sequestration of the enzyme rather than by an intrinsic alteration in the enzyme per se. It therefore suggests a novel mode of regulation whereby an enzyme may be packaged within vesicles and its activity controlled by modulating the permeability of the vesicles to its substrate or effectors.

Adenosine Triphosphate↗
PubMed1985

Ileal conduit calculi from stapler anastomosis: a long-term complication?

A long-term review of 24 patients in whom ileal conduit diversions were constructed using surgical staples has shown calculi developing as a result of the staples in only 1 patient (4.2%). Experience suggests that calculi usually form within fourteen months of surgery, pass spontaneously, and produce minimal symptoms.

Adolescent↗
PubMed1984

Evidence for two copper atoms/subunit in dopamine beta-monooxygenase catalysis.

The stoichiometry of the copper requirement for the dopamine beta-monooxygenase-catalyzed conversion of dopamine to norepinephrine has been investigated by rapid chemical-quench techniques. This approach, which employs concentrated samples of enzyme, overcomes ambiguities of interpretation arising from levels of trace copper in excess of enzyme concentrations normally added to steady state kinetic assays. Low turnover numbers are observed when rapid quench kinetic studies are performed under conditions in which enzyme concentrations (2.5-7.1 microM) are in excess over trace copper levels (about 0.7 microM). The addition of exogenous Cu(II) results in full restoration of activity, which is maximal at a stoichiometry of 2 mol of copper/mol of enzyme subunit. From the dependence of catalytic activity on copper levels we conclude that both coppers are required for catalysis. No stimulation of activity was observed upon addition of the following metal ions: Ni(II), Co(II), Mn(II), Fe(III), and Zn(II). In addition, the magnitude of the tritium isotope effect for [2-3H]dopamine hydroxylation is invariant over a large range of enzyme activities accompanying changes in the ratio of copper to enzyme concentration. These results appear to rule out an effector role for the second mole of copper/subunit, implicating both copper atoms in active site redox chemistry.

Animals↗
PubMed1984

Studies of the guanylate cyclase of the social amoeba Dictyostelium discoideum.

Observations on the properties of the guanylate cyclase (GTP pyrophosphate-lyase (cyclizing), EC 4.6.1.2) of the social amoeba Dictyostelium discoideum are reported. On the basis of similarities in kinetic and fractionation properties, it is shown that the activity from vegetative cells and the sixfold higher activity from starved cells appear to be due to the same enzyme. Most of the activity is found to be soluble, and by gel exclusion chromatography a molecular weight of 250,000 has been estimated for this form. As the enzyme shows considerably more activity with Mn+2 than Mg+2, the Km for Mn+2 activation was determined (700 microM), and compared to the levels of total cell Mn+2 (10 microM) and Mg+2 (3mM). These data suggest that Mg+2 is probably the physiological cofactor. A previous report [J. M. Mato, (1979) Biochem. Biophys. Res. Commun. 88, 569-574] that the enzyme is activated about twofold by ATP was confirmed; but contrary to that report, activation by the ATP analog 5'-adenylyl-imidodiphosphate was also obtained. Since this analog does not donate its phosphate in kinase reactions, it is likely that ATP activates the guanylate cyclase by direct binding rather than by phosphorylation. The known in vivo agonist of the guanylate cyclase, cAMP, did not activate the enzyme in vitro, either alone or in various combinations with calcium, calmodulin, ATP, and phospholipids.

Adenosine Triphosphate↗