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Biomedical subjects

G C Brown

Publications and source records attributed to G C Brown.

At least 127 records · Page 7Linked to original sources
PubMed1995

Rate control within the Na+/glucose cotransporter.

The intestinal Na+/glucose cotransporter has recently been cloned and expressed in Xenopus oocytes, and kinetically characterised to produce a 6-state model of the transporter. We have analyzed this model using control analysis to determine the extent to which each rate constant and step in the mechanism limits the steady-state rates under various conditions. We show that control (rate limitation) is distributed among a number of rate constants and changes with the membrane potential and the concentrations of external and internal sodium and sugar. There is no single rate-limiting step but, with saturating concentrations of external sugar and sodium and negligible internal concentrations, the sugar and sodium fluxes are limited by sodium dissociation on the inside, translocation of the unloaded carrier to the outside and translocation of the fully loaded carrier to the inside. With more physiological external and internal concentrations there is a significant leak flux, which causes the cotransporter to act as a sugar uniporter, and entails that control over the sugar flux differs from control over the sodium flux. In these conditions control is widely distributed among many of the rate constants. The analysis shows that the concept of a rate-limiting step is not generally applicable to transporters.

Animals↗
PubMed1995

Efficacy of anterior chamber paracentesis and Carbogen in treating acute nonarteritic central retinal artery occlusion.

PURPOSE: To determine whether anterior chamber paracentesis and Carbogen inhalation therapy (95% oxygen, 5% carbon dioxide) produce a significant difference in final visual acuity in eyes with acute nonarteritic central retinal artery occlusion (CRAO), compared with untreated eyes. METHODS: In this retrospective study, the records of 89 consecutive patients seen at the Retina Vascular Unit of Wills Eye Hospital with acute CRAO who received either both anterior chamber paracentesis and Carbogen therapy, or neither anterior chamber paracentesis or Carbogen therapy, were reviewed. Forty patients were treated with both therapies, whereas 49 received neither modality. Visual acuities before treatment and at subsequent follow-up visits were measured. All patients seen within 24 hours of the onset of symptoms were treated, whereas most of those seen after 24 hours were not treated. RESULTS: Stratified Wilcoxon analysis showed no statistically significant difference between the treated and untreated groups (P = 0.87) after adjusting for initial vision. A posthoc power analysis for the difference between two proportions showed that the study had adequate power (0.80) to detect a difference of the proportion of improved patients of 10% versus 25% between that treated and untreated groups. CONCLUSION: The data suggest that anterior chamber paracentesis and Carbogen therapy offer little benefit for treating acute nonarteritic CRAO.

Acute Disease↗
PubMed1995

Effect of volatile methyl jasmonate on the oxylipin pathway in tobacco, cucumber, and arabidopsis.

The effect of atmospheric methyl jasmonate on the oxylipin pathway was investigated in leaves of tobacco (Nicotiana tabacum L.), cucumber (Cucumis sativa L.), and Arabidopsis thaliana (L.). Differential sensitivities of test plants to methyl jasmonate were observed. Thus, different concentrations of methyl jasmonate were required for induction of changes in the oxylipin pathway. Arabidopsis was the least and cucumber the most sensitive to methyl jasmonate. Methyl jasmonate induced the accumulation of lipoxygenase protein and a corresponding increase in extractable lipoxygenase activity. Atmospheric methyl jasmonate additionally induced hydroperoxide lyase activity and the enhanced production of several volatile six-carbon products. It is interesting that lipid hydroperoxidase activity, which is a measure of hydroperoxide lyase plus allene oxide synthase plus possibly other lipid hydroperoxide-metabolizing activities, was not changed by methyl jasmonate treatment. Methyl jasmonate selectively altered the activity of certain enzymes of the oxylipin pathway (lipoxygenase and hydroperoxide lyase) and increased the potential of leaves for greatly enhanced six-carbon-volatile production.

Acetates↗
PubMed1995

Mild hypothermia after severe transient hypoxia-ischemia ameliorates delayed cerebral energy failure in the newborn piglet.

Severely birth-asphyxiated human infants develop delayed ("secondary") cerebral energy failure, which carries a poor prognosis, during the first few days of life. This study tested the hypothesis that mild hypothermia after severe transient cerebral hypoxia-ischemia decreases the severity of delayed energy failure in the newborn piglet. Six piglets underwent temporary occlusion of the common carotid arteries and hypoxemia. Resuscitation was started when cerebral [phosphocreatine (PCr)]/[inorganic phosphate (Pi)] as determined by phosphorus magnetic resonance spectroscopy had fallen almost to zero and [nucleotide triphosphate (NTP)]/[exchangeable phosphate pool (EPP)] had fallen below about 30% of baseline. Rectal and tympanic temperatures were then reduced to 35 degrees C for 12 h after which normothermia (38.5 degrees C) was resumed. Spectroscopy results over the next 64 h were compared with previously established data from 12 piglets similarly subjected to transient cerebral hypoxia-ischemia, but maintained normothermic, and six sham-operated controls. The mean severity of the primary insult (judged by the time integral of depletion of [NTP]/[EPP]) was similar in the hypothermic and normothermic groups. In the normothermic group, [PCr]/[Pi] and [NTP]/[EPP] recovered after the acute insult and then fell again. Minimum values for these variables observed between 24 and 48 h were significantly higher in the hypothermic group and not significantly different from the control values (p < 0.05, analysis of variance). A large reduction in secondary energy failure relative to the extent of the primary insult was shown and no further fall in either [PCr]/[Pi] or [NTP]/[EPP] took place up to 64 h in the hypothermic piglets.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Disease↗
PubMed1995

Lack of behavioral effects in non-human primates after exposure to ultrawideband electromagnetic radiation in the microwave frequency range.

The effect of acute exposure to ultrawideband (UWB) electromagnetic radiation on the Primate Equilibrium Platform (PEP) task, where the monkey's task is to manipulate a joystick control to compensate for the random perturbations in the pitch plane that are generated by a computer at unpredictable intervals, was examined. The duration of the UWB exposure was 2 min at a pulse repetition rate of 60 Hz (total of 7200 pulses). The bandwidth of the pulse was 100 MHz to 1.5 GHz (peak power between 250-500 MHz) with a peak E-field strength of 250 kV/m. Each monkey was exposed twice. The interval between exposures was 6 days. The exposure to UWB electromagnetic radiation had no effect on PEP performance when tested immediately after exposure.

Animals↗
PubMed1995

PPHP founder talks of medicine's future. Interview by Elaine S. Herrmann and Maria T. Montesano.

The Pennsylvania Medical Society's Board of Trustees in March approved a recommendation to fully support and endorse the goals of the Pennsylvania Physician Healthcare Plan, Inc. Also known as PPHP, the plan aims to be the commonwealth's first statewide, physician-owned managed care organization. Gary C. Brown, MD, a Wyndmoor ophthalmologist, is the founder and driving force of PPHP. Shortly after the board action, Dr. Brown spoke with us about the concept of physician control, his involvement with PPHP, and the organization's chances of success.

Managed Care Programs↗
PubMed1994

Nanomolar concentrations of nitric oxide reversibly inhibit synaptosomal respiration by competing with oxygen at cytochrome oxidase.

Nitric oxide (NO) reversibly inhibited oxygen consumption of brain synaptosomes. Inhibition was reversible, occurred at the level of cytochrome oxidase, and was apparently competitive with oxygen, with half-inhibition by 270 nM NO at oxygen concentrations around 145 microM and by 60 nM at around 30 microM O2. Isolated cytochrome oxidase was inhibited by similar levels of NO. These levels of NO are within the measured physiological and pathological range for a number of tissues and conditions, suggesting that NO inhibition of cytochrome oxidase and the competition with oxygen may occur in vivo.

Animals↗
PubMed1994

Brain-metabolite transverse relaxation times in magnetic resonance spectroscopy increase as adenosine triphosphate depletes during secondary energy failure following acute hypoxia-ischaemia in the newborn piglet.

The adenosine triphosphate (ATP)-dependent sodium/potassium pump extrudes intracellular sodium in exchange for extracellular potassium. Low ATP causes pump dysfunction increasing both intracellular sodium and water thereby enhancing metabolite mobility. This should be detectable by proton magnetic resonance spectroscopy (MRS) as increased metabolite transverse relaxation times (T2s). During secondary cerebral energy failure in the newborn piglet, proton and phosphorus MRS showed large increases in the T2s of choline, creatine, N-acetylaspartate, and lactate that correlated with ATP depletion. These results provide insight into factors affecting metabolite T2s and show that T2s may be useful for studying cellular oedema.

Adenosine Triphosphate↗
PubMed1994

Rate limitation within a single enzyme is directly related to enzyme intermediate levels.

The extents to which different rate constants limit the steady-state rate of an isolated enzyme can be quantified as the control coefficients of those constants and elemental steps. We have found that the sum of the control coefficients of rate constants characterising unidirectional rates depleting a particular enzyme intermediate is equal to the concentration of that enzyme intermediate as a fraction of the total enzyme concentration. Together with simple measurements this powerful relation may be used (i) to estimate certain enzyme intermediate levels, in particular the free enzyme concentration, and (ii) to estimate the control coefficients of rate constants and steps.

Enzymes↗
PubMed1994

The analysis of rate limitation within enzymes: relations between flux control coefficients of rate constants and unidirectional rates, rate constants and thermodynamic parameters of single isolated enzymes.

The extent to which a rate constant or step within an enzyme mechanism limits the net enzyme rate in a particular condition can be quantified as a flux control coefficient. We derive here a number of relations between the control coefficients and the unidirectional rates, rate constants, and thermodynamic parameters of the enzyme. These and other relations are used to suggest a number of methods for experimentally measuring control coefficients within enzymes.

Enzymes↗
PubMed1994

Combined central retinal vein occlusion and cilioretinal artery occlusion associated with prolonged retinal arterial filling.

We examined four healthy men who developed cilioretinal artery occlusion associated with central retinal vein occlusion. Unlike previously reported patients with this clinical entity, there appeared to be abnormal central retinal artery inflow, as evidenced by prolonged, irregular filling of the branch retinal arteries with intravenous fluorescein angiography. The patients were treated with systemic corticosteroids. All of the patients had initial improvement in vision. However, three of the four patients had recurrent episodes of visual loss. The final visual acuity was 20/40 or better in three of the four patients.

Adult↗
PubMed1994

Control analysis applied to the whole body: control by body organs over plasma concentrations and organ fluxes of substances in the blood.

Metabolic control analysis is adapted as a method for describing and analysing the control by organs in the body over the fluxes and concentrations of substances carried in the blood. This physiological control analysis can most usefully be applied to substances with fluxes into and out of organs that are uniquely dependent only on their plasma concentrations. The organ flux of a substance is defined as the steady-state net flux of a substance into a particular organ. The organ flux control coefficients quantify the extent to which a particular organ controls the flux of a substance into the same or another particular organ. Organ concentration control coefficients quantify the extent to which an organ controls the steady-state concentration of a substance in the blood. The control coefficients are additive and obey summation, connectivity and branching theorems. Thus the control coefficients can be determined experimentally by measuring the sensitivities (elasticities) of organ fluxes to the plasma concentration of the substance. As an example of the application of these concepts, the control of ketone-body metabolism in vivo is analysed using data from the literature.

Abdomen↗
PubMed1994

Acute behavioral toxicity of pyridostigmine or soman in primates.

Effects of a peripherally active carbamate (pyridostigmine bromide) and a centrally active organophosphate (OP) nerve agent (soman) on performance by rhesus monkeys of a compensatory tracking (primate equilibrium platform, or PEP) task were measured using a balanced Latin-square design to determine the ED50 for pyridostigmine (0.66 mg/kg) and the up-and-down (titration) method to determine the ED50 for soman (2.50 micrograms/kg). We concluded that the PEP performance model is a sensitive and reliable indicator of anticholinesterase (anti-ChE) behavioral toxicity. We also found that soman, an irreversible inhibitor of acetylcholinesterase (AChE), is more than 100 times more behaviorally disruptive than the reversible peripheral inhibitor pyridostigmine, as indicated by the difference in ED50 doses expressed in molar terms. Soman's behavioral toxicity is severe at levels of serum cholinesterase inhibition (70-80%) at which pyridostigmine does not significantly affect performance. As a prophylactic treatment for OP agent poisoning, pyridostigmine has a substantial safety factor, since behavioral toxicity becomes significant only at approximately four times the proposed therapeutic dose.

Animals↗
PubMed1994

Primate performance decrements following acute soman exposure: failure of chemical countermeasures.

Three experiments are reported: 1) a feasibility study on using laboratory primates repeatedly in behavioral toxicity studies of organophosphate (OP) agents or of chemical countermeasures against OPs; 2) a study of the efficacy of pyridostigmine pretreatment and 2-PAM therapy; and 3) a study to determine the effects of these treatments on soman-induced cholinesterase (ChE) inhibition and its recovery. In rhesus monkeys, three repeated acute low-dose (2.1 to 2.8 micrograms/kg) soman exposures, separated by intervals > 5 weeks, did not change baseline compensatory tracking performance or the soman ED50. Atropine therapy (97 micrograms/kg) alone had no effect on soman ED50. Addition of pyridostigmine pretreatment (150 micrograms/kg) and 2-PAM therapy (17 mg/kg) to atropine therapy increased the soman ED50 for a performance decrement from 2.27 micrograms/kg to 2.58 micrograms/kg, an insignificant protective effect. At the soman ED50 for behavioral decrements, pyridostigmine pretreatment increased the inhibition of serum ChE observed immediately after soman exposure, but reduced the extent of permanent inhibition. The 2-PAM therapy reduced serum ChE inhibition from about 80% to less than 70%. These effects on the time course of ChE inhibition following soman exposure appear to combine additively. These chemical countermeasures do not prevent soman-induced performance decrements, even though they are effective in protecting lives after much higher doses. The soman doses used produce only small, transient performance decrements; animals so exposed can, thus, be used repeatedly in such studies.

Animals↗
PubMed1994

Behavioral toxicity of anticholinesterases in primates: effects of daily repeated soman exposure.

The effects of repeated daily exposure to soman, an organophosphate nerve agent, on the performance of a well-learned, compensatory tracking task were tested in rhesus monkeys. The ED50 daily exposure required to produce a performance decrement on or before the fifth daily exposure (0.97 microgram/kg) was about 40% of the acute dose required to produce a similar performance decrement. After repeated, low-dose exposures, performance decrements appeared when serum cholinesterase (ChE) activity was inhibited 85-90%. Acute exposures that produced similar performance effects were associated with lower levels of ChE inhibition (65-70%), suggesting that repeated daily exposure may lead to the development of a tolerance (physiological or behavioral) to low levels of ChE activity.

Animals↗
PubMed1994

Color Doppler imaging of arterial blood flow in central retinal vein occlusion.

PURPOSE: The hemodynamics of the retrobulbar arterial circulation of patients with central retinal vein occlusion were evaluated in order to better understand the pathophysiology of this disease. METHODS: Color Doppler imaging was used to measure the peak systolic velocity and vascular resistance (pulsatility index) in the retrobulbar arteries of involved eyes and clinically healthy fellow eyes of patients with central retinal vein occlusion and in the control eyes of age- and sex-matched healthy volunteers. RESULTS: Average peak systolic velocity was significantly lower and average vascular resistance was significantly higher in the central retinal artery of involved eyes of patients with central retinal vein occlusion compared with clinically healthy fellow eyes and compared with control eyes. There also was a trend toward higher vascular resistance in the central retinal artery of clinically healthy fellow eyes of patients with central retinal vein occlusion compared with control eyes. In the ophthalmic arteries and short posterior ciliary arteries, vascular resistance was significantly higher in both the involved eyes and clinically healthy fellow eyes of patients with central retinal vein occlusion compared with control eyes. CONCLUSION: Color Doppler imaging parameters of the central retinal artery circulation were abnormal in eyes with central retinal vein occlusion, suggesting impaired arterial blood flow associated with this disease. The high vascular resistance in the central retinal arteries, ophthalmic arteries, and short posterior ciliary arteries of both involved and clinically healthy fellow eyes of patients with central retinal vein occlusion suggests that diffuse small vessel disease may predate and contribute to the development of central retinal vein occlusion.

Blood Flow Velocity↗
PubMed1993

Control analysis applied to single enzymes: can an isolated enzyme have a unique rate-limiting step?

Control analysis is used to analyse and quantify the concept of a rate-limiting step within an enzyme. The extent to which each rate constant within the enzyme limits the steady-state rate of the enzyme and the levels of enzyme intermediate species are quantified as flux and concentration control coefficients. These coefficients are additive and obey summation theorems. The control coefficients of triose phosphate isomerase, carbamate kinase and lactate dehydrogenase are calculated from literature values of the rate constants. It is shown that, contrary to previous assumption, these enzymes do not have a unique rate-limiting step, but rather flux control is shared by several rate constants and varies with substrate, product and effector concentrations, and with the direction of the reaction. Thus the general assumption that an enzyme will have a unique rate-limiting step is unjustified.

Enzymes↗