Coupled oscillator theory of enzyme action.
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Biomedical subjects
Publications and source records attributed to J L Fox.
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Enoyl reductase in the fatty acid synthetase from brewer's yeast, a flavoenzyme function, has been used as a specific probe for one partial activity of the multi-functional enzyme. The enzyme has an absorption maximum at 460 nm with epsilon = 18600 M-1 cm-1 and A280 = 1.37 mg-1 ml. The circular dichroism spectrum shows negative peaks at 373 and 466 nm. The fluorescence maximum is at 540 nm. The apoenzyme has an absorption maximum at 279 nm and shows fluorescence at 345 nm. The association constant for the FMN is 4 X 10(7) M-1. The redox potential was determined as Eh = --0.193 V. The reductase is characterized as a 'true' transhydrogenase as no flavin free radical can be obtained by photochemical or chemical reduction or oxidation, i.e. it only functions via two-electron steps. An interpretation of the hydrophobic nature of the flavin binding site based on spectral data is presented.
The efficacy of a new remineralization system was determined in vivo by maintaining a low concentration of approximately 1 ppm fluoride for 48 hrs against a demineralized human tooth. Human subjects were selected who wore removable partial dentures containing two or more of the demineralized teeth with film system. The findings indicate levels of fluoride uptake to 500 ppm at 50 micron depths in experimental sites.
An unusual case of adenocarcinoma metastatic to the pontomedullary region of the brain stem is presented. When the floor of the 4th ventricle was exposed at operation, this intramedullary tumor was found to be cystic. The patient died of septic complications after an uneventful decompression of the cyst and a subtotal excision of the neoplasm. The rational for surgery (tissue diagnosis and decompression) in some of these cases is discussed.
A case of suprasellar arachnoid cyst and hydrocephalus diagnosed by computed tomography (CT) and positive-contrast ventriculography is presented. Transfrontal exploration of the 3rd ventricle revealed findings consistent with the cyst being, in fact, a large forward and upward diverticulum of the arachnoidal membrane of Liliequist. The authors suggest that some of the other similarly located arachnoid cysts are extensions of this membrane imperforate by previous infection, hemorrhage, or maldevelopment.
The authors present a family of 13 siblings: six are proven to have had intracranial aneurysms, five have had elective cerebral angiography with normal findings, and two have refused angiography. Of the six aneurysm cases, two had disabling and one had fatal subarachnoid hemorrhages; three underwent successful clipping of their aneurysms which were discovered by elective angiography. It is concluded that the two remaining patients who have refused angiography have a 50% statistical chance of harboring a potentially lethal aneurysm, for in this family the occurrences of six proven cases among 11 siblings studied is consistent with a dominant Mendelian inheritance.
A physical model approach to the topical delivery of a vidarabine ester prodrug was investigated. It involved modeling, theoretical simulations, experimental method development for factoring and quantifying parameters, and, finally, employment of the deduced parameters to determine the steady-state species fluxes and concentration profiles in the target tissue. The present report describes the physical modeling and theoretical simulation aspects. The physical model for the simultaneous transport and bioconversion of a topically delivered prodrug was formulated assuming homogeneous enzyme distributions and constant diffusivities in the membrane. The mathematical problem was solved, and the solution yielded concentration profiles and fluxes of all species in the biomembrane. These results provided the prevailing levels of the prodrug, the drug, and the metabolite at the target site and the transport rates of all species into the bloodstream. Computations of concentration profiles and fluxes were carried out for a reasonable range of the parameters. The relative activities of the esterase and the deaminase enzymes, as well as the stratum corneum permeabilities, were important in influencing the concentration profiles and fluxes of all species.
Results of initial studies on methods for determining various model parameters are reported. By employing excised hairless mouse skin in a diffusion cell system, numerous model parameter values were deduced. The stratum corneum permeability was estimated from steadystate fluxes with preparations of heat-separated epidermal membranes. Determinations of dermis diffusivities and enzyme rate constants in situ involved considering the simultaneous transport and the enzyme processes and factoring the diffusivities and enzyme rate constants from the overall kinetics. Dermal diffusivities were on the order of 10-6 cm2/sec for vidarabine and its 5'-valerate ester. The enzyme rate constants were 1.70 x 10-3 sec-1 for the esterase and 8.68 x 10-3 sec-1 for the deaminase.
We report 2 cases of the tethered spinal cord syndrome. Early clinical detection of this syndrome in children with bladder dysfunction should be followed by diagnostic myelography and immediate surgical release of the spinal cord. The pathophysiology of the syndrome is discussed.
The effects of topically applied hemoglobin, methemoglobin, hemin, ferrous chloride (FeCl2) and ferric chloride (FeCl3) were investigated by observation through the operating microscope to determine their effect on the normal and spastic canine basilar artery. Following transclival exposure, the artery was made spastic by puncture or topical barium chloride. No consistent changes in arterial diameter were seen with topical hemoglobin, methemoglobin, or hemin. The buffered ferrous ion (Fe++) caused marked vasodilation at concentrations of 10 microgram/ml. The buffered ferric ion (Fe++) caused mild vasoconstriction at similar concentrations. The possible role of iron (a component of hemoglobin) in vasospasm following subarachnoid hemorrhage and subsequent hemoglobin degradation is discussed.
A case of persistent meningitis following excision of a jugular foramen neurinoma is presented. A cerebrospinal fluid fistula at the mastoid region was localized by computed tomographic demonstration of air bubbles in the posterior fossa.
A case with four unusual aneurysms is presented. On the right were a ruptured small middle cerebral artery aneurysm and a giant carotid-ophthalmic artery aneurysm. On the left were two giant internal carotid artery aneurysms: one at the ophthalmic artery and one at a ventral or paraclinoid position. All four aneurysms were clipped. The patient returned to her household duties.
Internal regularities of amino acid sequences of flavodoxins, FMN-containing, low molecular weight flavoproteins, were statistically examined using the minimum mutation method. The sequence of Clostridium pasteurianum flavodoxin shows statistically significant evidence of repetitious internal gene duplications at different levels of structure. Peptide pairs with a low chance probabilitiy of occurrence were frequently observed at a shift of 5 residues. The pairs with the lowest chance probabilities are a pair of heptapeptides at positions39--45 vs. 44--50, a 5 residue shift (p = 9 x 10(-6)). Most of the related pairs are consistent and could best be explained by the repeating pentapeptide sequence: (Lys-Gly-Ala-Asp-Val-)n and appropriate gaps. Internal repetitions with longer shifts were also suggested for other flavodoxins. Repetitious gene duplication is proposed for the early stages of flavodoxin evolution.
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Three cases of subarachnoid hemorrhage from intracranial aneurysms are presented. Two of the patients survived long enough to develop delayed cerebral vasospasm. The computerized tomograms and angiograms were correlated with the clinical course. It is suggested that delayed cerebral vasospasm may be preceded by relative vasodilation, or at least inhibition of vasocontraction, and concomitant increased vascular permeability of the parent vessels diagnosed by contrast enhanced computerized tomography. This phenomenon, if confirmed in larger series of patients, may allow prediction of that patient destined for vasospasm and may suggest some of the pathophysiology of this devastating problem.
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