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Biomedical subjects

E Davidson

Publications and source records attributed to E Davidson.

At least 37 records · Page 2Linked to original sources
PubMed1997

Mitochondrial encephalomyopathy with coenzyme Q10 deficiency.

Coenzyme Q10 (CoQ10) transfers electrons from complexes I and II of the mitochondrial respiratory chain to complex III. There is one published report of human CoQ10 deficiency describing two sisters with encephalopathy, proximal weakness, myoglobinuria, and lactic acidosis. We report a patient who had delayed motor milestones, proximal weakness, premature exertional fatigue, and episodes of exercise-induced pigmenturia. She also developed partial-complex seizures. Serum creatine kinase was approximately four times the upper limit of normal and venous lactate was mildly elevated. Skeletal muscle biopsy revealed many ragged-red fibers, cytochrome c oxidase-deficient fibers, and excess lipid. In isolated muscle mitochondria, impaired oxygen consumption was corrected by the addition of decylubiquinone. During standardized exercise, ventilatory and circulatory responses were compatible with a defect of oxidation-phosphorylation, which was confirmed by near-infrared spectroscopy analysis. Biochemical analysis of muscle extracts revealed decreased activities of complexes I+II and I+III, while CoQ10 concentration was less than 25% of normal. With a brief course of CoQ10 (150 mg daily), the patient reported subjective improvement. The triad of CNS involvement, recurrent myoglobinuria, and ragged-red fibers should alert clinicians to the possibility of CoQ10 deficiency.

Adult↗
PubMed1996

Comparative biochemical studies in fibroblasts from patients with different forms of Leigh syndrome.

We have compared respiratory chain enzyme activities, ATP synthesis, and ATP hydrolysis in cultured fibroblast mitochondria from patients with Leigh syndrome (LS) due to: (i) cytochrome oxidase (COX) deficiency (#6); (ii) pyruvate dehydrogenase complex (PDHC) deficiency (#4); and (iii) maternally inherited LS (MILS) with the T8993G mutation in the ATPase 6 gene of mtDNA (#5). Enzyme activities were normal in patients with MILS and variably decreased in those with COX and PDHC deficiency. ATP hydrolysis was normal or mildly decreased in all three groups. In contrast, ATP synthesis was decreased in all patients but more markedly in those with MILS, and especially with pyruvate/malate as substrate. These studies show that impaired ATP production is the common feature of all three forms of LS, but it is both more severe and more specific in MILS, consistent with the genetic defect.

Adenosine Triphosphatases↗
PubMed1996

Structure-based design of parasitic protease inhibitors.

To streamline the preclinical phase of pharmaceutical development, we have explored the utility of structural data on the molecular target and synergy between computational and medicinal chemistry. We have concentrated on parasitic infectious diseases with a particular emphasis on the development of specific noncovalent inhibitors of proteases that play a key role in the parasites' life cycles. Frequently, the structure of the enzyme target of pharmaceutical interest is not available. In this setting we have modeled the structure of the relevant enzyme by virtue of its sequence similarity with proteins of known structure. For example, we have constructed a homology-based model of falcipain, the trophozoite cysteine protease, and used the computational ligand identification algorithm DOCK to identify in compuo enzyme inhibitors including oxalic bis(2-hydroxy-1-naphthyl-methylene)hydrazide (1) [Ring, C. S.; Sun, E.; McKerow, J. H.; Lee, G.; Rosenthal, P. J., Kuntz, I. D.; Cohen, F. E., Proc. Natl Acad. Sci. U.S.A. 1993, 90, 3583]. Compound 1 inhibits falcipain (IC50 6 microM) and the organism in vitro as judged by hypoxanthine uptake (IC50 7 microM). Following this lead, to date, we have identified potent bis arylacylhydrazides (IC50 150 nM) and chalcones (IC50 200 nM) that are active against both chloroquine-sensitive and chloroquine-resistant strains of malaria. In a second example, cruzain, the crystallographically determined structure of a papain-like cysteine protease, resolved to 2.35 A, was available. Aided by DOCK, we have identified a family of bis-arylacylhydrazides that are potent inhibitors of cruzain (IC50 600 microM). These compounds represent useful leads for pharmaceutical development over strict enzyme inhibition criteria in a structure-based design program.

Aldehydes↗
PubMed1996

Hepatitis A transmission by factor IX concentrates.

Factor IX concentrates unlike factor VIII concentrates have not to date been associated with the transmission of hepatitis A virus (HAV). A retrospective study by reverse transcriptase polymerase chain reaction on a batch of factor IX concentrate used to treat two haemophilia B patients who developed jaundice and IgM anti-HAV antibodies within 50 days of factor IX administration in 1985 revealed the presence of HAV RNA. These findings indicate that factor IX concentrates can transmit HAV and that appropriate viral inactivation steps to inactivate nonenveloped viruses as well as enveloped viruses are necessary to ensure the safety of factor IX concentrates.

Adult↗
PubMed1995

In vitro antimalarial activity of chalcones and their derivatives.

A series of chalcones and their derivatives have been synthesized and identified as novel potential antimalarials using both molecular modeling and in vitro testing against the intact parasite. A large number of chalcones and their derivatives were prepared using one-step Claisen-Schmidt condensations of aldehydes with methyl ketones. These condensates were screened in vitro against both chloroquine-sensitive and chloroquine-resistant strains of Plasmodium falciparum and shown to be active at concentrations in the nanomolar range. The most active chalcone derivative, 1-(2,5-dichlorophenyl)-3-(4-quinolinyl)-2-propen-1-one (7), had an IC50 value of 200 nM against both a chloroquine-resistant strain (W2) and a chloroquine-sensitive strain (D6). The resistance indexes for all compounds were substantially lower than for chloroquine, suggesting that this series will be active against chloroquine-resistant malaria. Structure-activity relationships (SAR) of the chalcones in the context of a homology-based model structure of the malaria trophozoite cysteine protease, the most likely target enzyme, are presented.

Animals↗
PubMed1994

Comparison between intranasal and intravenous midazolam sedation (with or without patient control) in a dental phobia clinic.

Two new modes of sedation; patient-controlled sedation (PCS) and intranasal sedation (INS) were compared with the traditional bolus intravenous sedation (BIVS) while delivering dental care to apprehensive patients in a specialized dental fear clinic. Effective sedation was evaluated in a randomized, prospective study in 42 ASA 1 and 2 patients, in a factorial design. Eighteen patients were sedated with .5% midazolam INS. Ten patients received intravenous PCS via a patient-controlled analgesia pump containing midazolam, and 14 patients received intermittent intravenous boluses of 1 mg midazolam given as needed (BIVS). Appropriate local anesthetic nerve blocks with 2% lidocaine with 1:100,000 epinephrine, and supplementary inhalation of nitrous oxide and oxygen via a nasal mask, were also given to all patients in the study. The dosage requirement with PCS was higher than that found with INS or BIVS. However, PCS produced some anxiety reduction when compared with INS and BIVS. It also reduced interfering movements during treatment more effectively than the other sedation modes. No complications were detected in any of the patients and they were able to leave the clinic within 1 hour after completion of treatment.

Administration, Intranasal↗
PubMed1994

Anti-malarial drug development using models of enzyme structure.

BACKGROUND: The trophozoite stage of the malaria parasite infects red blood cells. During this phase of their life-cycle, the parasites use hemoglobin as their principal source of amino acids, using a cysteine protease to degrade it. We have previously reported a three-dimensional model of this cysteine protease, based on the structures of homologous proteases, and the use of the program DOCK to identify a ligand for the malaria protease. RESULTS: Here we describe the design of improved ligands starting from this lead. Ligand design was based on the predicted configuration of the lead compound docked to the model three-dimensional structure of the protease. The lead compound has an IC50 of 6 microM, and our design/synthesis strategy has resulted in increasingly potent derivatives that block the ability of the parasites to infect and/or mature in red blood cells. The two best derivatives to date have IC50(s) of 450 nM and 150 nM. CONCLUSIONS: A new class of anti-malarial chemotherapeutics has resulted from a computational search that was based on a model of the target protease. Despite the lack of a detailed experimental structure of the target enzyme or the enzyme-inhibitor complex, we have been able to identify compounds with increased potency. These compounds approach the activity of chloroquine (IC50 = 20 nM), but have a distinct mechanism of action. This series of compounds could thus lead to new therapies for chloroquine-resistant malaria.

Animals↗
PubMed1994

African-American physicians' views on health reform: results of a survey.

Little is known about African-American physicians' health system experience or their opinions on health reform. In an attempt to obtain socioculturally relevant data quantifying these experiences and opinions, the National Medical Association administered a 38-question, 80-item survey instrument in August 1993. The questionnaire was completed by 236 physicians. The results indicate that African-American physicians feel health care is a right and that the health system needs fundamental change. Although there was no consensus on the type of health reform needed, approximately 35% cited availability and access to care to be the greatest problem facing the system with high costs of care (18.2%) ranking second. Unique findings in the survey indicated respondents felt that the needs and concerns of most African Americans will not be fairly addressed in the reform of the health-care system, that African-African physicians are not included in the formation of health-care policies, and that African-American physicians are facing high levels of professional and healthcare system racial discrimination. More than 99% of African-American physicians reported some degree of racial discrimination in the practice of medicine including peer review, obtaining practice privileges at hospitals, hospital staff promotions, Medicaid and Medicare reimbursements, malpractice suits, private insurance oversight and reimbursements, and referral practices of white colleagues. These findings have profound health policy, health financing, and health service delivery implications and should be included in debates and deliberations on health reform.

Adult↗
PubMed1993

The bc1 complexes of Rhodobacter sphaeroides and Rhodobacter capsulatus.

Photosynthetic bacteria offer excellent experimental opportunities to explore both the structure and function of the ubiquinol-cytochrome c oxidoreductase (bc1 complex). In both Rhodobacter sphaeroides and Rhodobacter capsulatus, the bc1 complex functions in both the aerobic respiratory chain and as an essential component of the photosynthetic electron transport chain. Because the bc1 complex in these organisms can be functionally coupled to the photosynthetic reaction center, flash photolysis can be used to study electron flow through the enzyme and to examine the effects of various amino acid substitutions. During the past several years, numerous mutations have been generated in the cytochrome b subunit, in the Rieske iron-sulfur subunit, and in the cytochrome c1 subunit. Both site-directed and random mutagenesis procedures have been utilized. Studies of these mutations have identified amino acid residues that are metal ligands, as well as those residues that are at or near either the quinol oxidase (Qo) site or the quinol reductase (Qi) site. The postulate that these two Q-sites are located on opposite sides of the membrane is supported by these studies. Current research is directed at exploring the details of the catalytic mechanism, the nature of the subunit interactions, and the assembly of this enzyme.

Amino Acid Sequence↗
PubMed1992

Mutagenesis of methionine-183 drastically affects the physicochemical properties of cytochrome c1 of the bc1 complex of Rhodobacter capsulatus.

Site-directed mutagenesis was used to investigate which of the highly conserved methionine residues (M183 and M205) provides the sixth axial ligand to the heme Fe in the cyt c1 subunit of the bc1 complex from the bacterium Rhodobacter capsulatus. These residues were changed to leucine (cM183L) and valine (cM205V). Two additional mutants were constructed, 1 in which a stop codon was inserted at M205 (cM205*) and the second in which 127 amino acids were deleted between the signal sequence and the putative C-terminal transmembrane alpha-helix (c delta SfuI). Only cM205V grew photosynthetically, and membranes isolated from this strain catalyzed quinol-dependent reduction of cyt c in amounts similar to that in a wild-type strain. Even though cM183L could not grow photosynthetically, it contained all the appropriate polypeptides and cofactors of the bc1 complex, as shown by SDS-PAGE and optical difference spectroscopy of intact membrane particles. Neither of the two deletion mutants contained a stable complex. Flash absorption spectroscopy using chromatophores showed no cytochrome c rereduction after oxidation by the reaction center in cM183L. The bc1 complex from each strain was isolated and characterized. Oxidation reduction midpoint potential titrations revealed that cyt c1 from cM183L had a dramatically shifted Em value (delta Em = -390 mV) compared with wild type and cM205V. While the optical absorption spectrum of cyt c1 from cM183L suggested that the c-type heme was low-spin, nonetheless it was able to react with the exogenous ligand carbon monoxide. The overall data support that M183, and not M205, is the sixth ligand to the heme Fe of cyt c1 of the bc1 complex.

Amino Acid Sequence↗
PubMed1992

Circulating aggregated platelets, number of platelets per aggregate, and platelet size during acute myocardial infarction.

Circulating aggregated platelets (total, reversibly and irreversibly aggregated), the number of platelets per aggregate and "big" platelets were measured by a modification of the Wu and Hoak method in 42 patients on the first, second and fifth day of acute myocardial infarction (AMI). Among them, 30 had an uncomplicated course and 12 patients had complications that occurred between the 5th and 10th day of hospitalization (7 patients had reinfarction and 5 died). In all patients the measured parameters were elevated compared with those of control subjects. There was a significant increase, especially after the first observation day, in the values of total aggregated platelets (37 +/- 11% vs 26 +/- 12%, p < 0.001), reversibly aggregated platelets (27 +/- 9% vs 17 +/- 8%, p < 0.001) and the average platelets per aggregate (8.6 +/- 0.3 vs. 2.3 +/- 0.4) in patients with versus without complications. In considering the role of platelets in the development of AMI, these findings may add information to the role of platelets in determining the course of AMI.

Blood Platelets↗