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Biomedical subjects

D Garfinkel

Publications and source records attributed to D Garfinkel.

At least 55 records · Page 3Linked to original sources
PubMed1984

Computer modeling identifies glucokinase as glucose sensor of pancreatic beta-cells.

Previous work from this laboratory indicates that glucokinase serves as the glucose sensor of pancreatic islets. Here we show by nonlinear computer optimization that the kinetic properties of glucokinase (together with hexokinase, known to be present in islets) account for the observed glycolytic rates in islets as a function of glucose level. Alternative enzymes that have been suggested to perform the same function as glucokinase, N-acetyl-D-glucosamine kinase and glucose-6-phosphatase, are shown to have incompatible properties, including a poor fit, different curve shapes, and unreasonable parameter values resulting from optimization. Their activities in islets are shown to be too low to account for observed glucose usage rates. This work endorses our previous proposal that glucokinase acts as the glucose sensor in pancreatic islet cells.

Blood Glucose↗
PubMed1984

Foot problems in athletes.

The primary care physician who cares for athletes encounters a variety of foot problems from skin maladies to deformities of the bone. As foot injuries can be totally debilitating, they are of especially great consequence to competitive athletes and must be diligently investigated to reach a proper diagnosis. In most cases the proper use of tape, foam, felt, metatarsal pads, and bars can easily solve what may be a perplexing problem. Occasionally, manufactured orthotic devices may be necessary. In all instances, athletes must be carefully advised on ways to treat and, more important, prevent foot problems.

Athletic Injuries↗
PubMed1984

Nucleotide sequence and transcript mapping of the tmr gene of the pTiA6NC octopine Ti-plasmid: a bacterial gene involved in plant tumorigenesis.

The nucleotide sequence of a tumor morphology gene, tmr, from the Agrobacterium tumefaciens Ti-plasmid, pTiA6NC, and its flanking 5' region was determined by M13 "dideoxy" procedures. The DNA sequence reveals an open reading frame capable of encoding a 240 amino acid protein. We have identified the polyadenylated transcript initiation and termination sits by S1 nuclease mapping. The extent of the sequence required for transcription 5' to the start of transcription has been delimited by two transposon insertions. The first of these maps at -- 121 with respect to transcription initiation and results in the wild-type phenotype, the second insertion maps at about -85 and results in a tmr phenotype.

Arginine↗
PubMed1983

Computer modeling of muscle phosphofructokinase kinetics.

The kinetics of the phosphofructokinase reaction were studied by computer modeling. A general random order, two-state allosteric model, of which the Monod--Wyman--Changeux model is a limiting case, was found to most accurately reproduce the experimental observations of Pettigrew & Frieden (1979 a,b). A simplified model with Hill coefficients was found to fit almost as well. In these models substrates bind preferentially to and stabilize the enzyme in the R state, and ATPH3-, the inhibitory species, binds preferentially to and stabilizes the enzyme in the T state. Enzymatic activity is regulated by conversion from the R to the T state, which is effected by protonation, especially of the uncomplexed enzyme, but the experimental data are inadequate for accurate estimation of the pKa of the enzyme. Random order binding of substrates is an important cause of sigmoidal kinetics. Additional experiments that would aid in the discrimination among rival models are described.

Adenosine Triphosphate↗
PubMed1983

Computer simulation of metabolism in palmitate-perfused rat heart. II. Behavior of complete model.

Intermediary metabolism in rat hearts perfused with 11 mM glucose plus 1 mM palmitate was simulated by a computer model. Several enzyme submodels in a previous version of the isolated rat heart computer model were improved, and a new fatty acid oxidation pathway model was added. Compartmentation of metabolites in a pseudo-stationary state was calculated, and its implications are discussed, e.g., citrate level may not regulate glycolysis because it is mostly mitochondrial. Citrate synthetase, controlled largely by its inhibitors, is of key importance in regulating fatty acid metabolism. The response of aconitase to the mitochondrial Mg2+ level is of major importance in setting both the mitochondrial citrate and isocitrate levels. Pyruvate dehydrogenase is about 96% in the inactive phosphorylated form, and the active form is also 15% inhibited by products, severely limiting pyruvate oxidation and causing preferential utilization of palmitate as the metabolic fuel. The simulation is consistent with a creatine phosphate shuttle which delivers high energy phosphate to the site of its utilization for mechanical work.

Animals↗
PubMed1983

Computer simulation of metabolism in palmitate-perfused rat heart. I. Palmitate oxidation.

A computer model of the fatty acid oxidation pathway in perfused rat heart was constructed. It includes uptake, activation, and beta-oxidation of fatty acids, triglyceride synthesis and hydrolysis, and carnitine-dependent transport of acyl groups across the mitochondrial membrane under pseudosteady state conditions. Fatty acid utilization may be limited by beta-oxidation in hypoxia or ischemia but probably not in aerobic conditions. Nonesterified fatty acids bound to proteins are found to be metabolically available. The model predicts that stearate, but not palmitate, can support the highest observed respiration rate for perfused rat heart without supplementation by other substrates. Fatty acids are preferentially oxidized rather than being stored as triglycerides because the cystosolic acyl CoA level is lower than the Km for triglyceride synthesis. It is suggested that feedback inhibition of triglyceride lipase regulates utilization of triglycerides as fuel in aerobic hearts.

3-Hydroxyacyl CoA Dehydrogenases↗
PubMed1983

Life-threatening theophylline intoxication in a hypothyroid patient.

In a hypothyroid patient who suffered also from chronic obstructive lung disease and mild congestive heart failure, treatment with 1 g/day theophylline administered orally, was followed by a life-threatening theophylline intoxication manifested by repeated epileptic fits and ventricular fibrillation, successfully reverted to sinus rhythm. The plasma theophylline was 34.7 micrograms/ml when the life-threatening arrhythmia occurred. Pharmacokinetic studies conducted during the hypothyroid state revealed a markedly prolonged theophylline plasma half-life of 29.5 h. 2 months later, after reestablishment of an euthyroid state, theophylline plasma half-life was shortened to normal, i.e. 5.7 h and the theophylline plasma level was 13.5 micrograms/ml, while the daily intake was 1 g. We conclude that hypothyroidism may predispose to theophylline intoxication, probably because of the decreased activity of the hepatic microsomal drug-metabolizing enzymes, responsible for the degradation of theophylline.

Aged↗
PubMed1982

Absence of predictive parameters for CNS involvement in adult non-lymphocytic leukaemia at time of diagnosis.

13 patients with adult non-lymphocytic leukemia (ANLL) who developed central nervous system (CNS) involvement during the course of their illness are reported and compared with a control group of 26 ANLL patients without CNS involvement. The incidence of CNS involvement was 13/510 patients (2.5%). Initial symptoms and signs and routine laboratory data were not helpful in predicting which patients would ultimately develop CNS involvement. Almost 1/2 of the patients were in clinical and haematological remission at the time of the diagnosis of CNS involvement. Specific treatment to the CNS including intrathecal cytotoxic drugs and/or radiotherapy failed to increase the survival rate significantly. Whether the establishment of an early diagnosis of CNS involvement and the institution of appropriate treatment may improve the prognosis of this complication is a question which presently remains unanswered.

Adult↗
PubMed1982

Computer simulation of energy metabolism in acidotic cardiac ischemia.

Construction and fit to experimental data of a computer model of glycolysis, the tricarboxylic acid cycle, and related metabolism in the perfused rat heart involving 63 enzyme submodels is described. The experimental preparation simulated is a rat heart perfused with Krebs bicarbonate solution containing glucose and insulin whose pH was lowered to 6.6 by equilibration with 35% CO2-65% O2. The glycolytic rate falls sharply and ischemia results, becoming apparent after 3.5 min. The model initially ascribes the fall in glycolysis largely to inhibition of hexokinase by accumulated glucose 6-phosphate and inactivation of phosphofructokinase by the low pH and subsequently to cytoplasmic glucose depletion owing to limitation of glucose uptake by the external acidosis. At the same time there is insufficiently deep hypoxia to trigger substantial mobilization of endogenous fuels (e.g., glycogenolysis or fatty acid mobilization, so that these hearts become ischemic primarily owing to a shortage of metabolic fuel.

Acidosis↗
PubMed1982

Computer simulation of metabolism of glucose-perfused rat heart in a work-jump.

A computer model of glycolysis, the tricarboxylic acid cycle, and related amino acid metabolism, is described for a glucose-perfused experimental rat heart preparation suddenly switched from low work load (Langendorff perfusion) to high work load (left atrial perfusion). Glycolytic intermediate measurements suggest activation of phosphofructokinase within a few seconds. This activation, and also that of other glycolytic enzymes, is calculated as due to a sharp increase in cytoplasmic Mg2+ level, which overcomes the inhibitory effects of a rapid fall in cytoplasmic pH to 6.77 (calculated from a rapid fall in creatine phosphate). Increased glycolytic substrate is initially supplied by glycogenolysis mediated by phosphorylase b (activated by an early rise in cytoplasmic AMP), followed by increased glucose uptake from the perfusate. Testable predictions are made by the model, especially that lactate production rate should peak early. Additional experiments are described that verify these predictions and fill gaps in the original measurements. The role of modeling in interpreting such experiments is discussed.

Amino Acids↗