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Biomedical subjects

J G Greene

Publications and source records attributed to J G Greene.

At least 19 recordsLinked to original sources
PubMed1996

ARL-15896, a novel N-methyl-D-aspartate receptor ion channel antagonist: neuroprotection against mitochondrial metabolic toxicity and regional pharmacology.

ARL-15896 [(+)-alpha-phenyl-2-pyridineethanamine], formerly known as FPL-15896, is a novel N-methyl-D-aspartate (NMDA) receptor ion channel antagonist. Using quantitative receptor autoradiography, we examined the regional binding characteristics of ARL-15896 and compared them to those of MK-801, the prototypical NMDA receptor channel blocker. The affinity of ARL-15896 was much lower (3000-fold) than that of MK-801 in all brain regions examined. In addition, in contrast to MK-801, which has a higher affinity in the forebrain than in the cerebellum (IC50 of 10 nM vs 24 nM), ARL-15896 had a higher affinity in the cerebellum than in the forebrain (IC50 of 17 microM vs 45 microM). The neuroprotective potential of ARL-15896 was investigated in a rat model of excitotoxicity, the intrastriatal injection of malonate. Malonate is a competitive inhibitor of succinate dehydrogenase, and its toxicity has been shown to be mediated largely by the NMDA receptor. Administration of ARL-15896 either intrastriatally (200 nmol) or subcutaneously (9.0 mg/kg) reduced the volume of the lesion produced by 1 mumol of malonate by 80%, a degree similar to that reported for MK-801. ARL-15896 was also protective when administered after the malonate injection. Furthermore, in contrast to MK-801, administration of ARL-15896 was not associated with any apparent behavioral side effects. This report is consistent with previous studies suggesting that drugs with regional pharmacological profiles similar to that of ARL-15896 have better clinical tolerability; it also indicates that ARL-15896 is an effective neuroprotective agent.

Animals↗
PubMed1995

Intrastriatal injections of the succinate dehydrogenase inhibitor, malonate, cause a rise in extracellular amino acids that is blocked by MK-801.

The effects of intrastriatal injections of a reversible inhibitor of succinate dehydrogenase, malonate, on the extracellular concentrations of amino acid neurotransmitters were examined using a microdialysis probe that was positioned a fixed distance from an injection cannula. Malonate (2 mumol) caused a 23 +/- 5-fold increase in extracellular glutamate (Glu), a 18 +/- 6-fold increase extracellular gamma-aminobutyric acid (GABA) and a modest increase in extracellular aspartate (Asp, 2.9 +/- 0.8-fold increase). Administration of the NMDA receptor antagonist MK-801 (5 mg/kg) prior to injection of malonate almost completely blocked these increases. This study provides direct evidence that inhibition of succinate dehydrogenase causes an increase in extracellular amino acid neurotransmitters and further evidence that bioenergetic defects may contribute to the pathogenesis of chronic neurodegenerative diseases through an excitotoxic mechanism.

Amino Acids↗
PubMed1995

Characterization of the excitotoxic potential of the reversible succinate dehydrogenase inhibitor malonate.

Although the mechanism of neuronal death in neurodegenerative diseases remains unknown, it has been hypothesized that relatively minor metabolic defects may predispose neurons to N-methyl-D-aspartate (NMDA) receptor-mediated excitotoxic damage in these disorders. To further investigate this possibility, we have characterized the excitotoxic potential of the reversible succinate dehydrogenase (SDH) inhibitor malonate. After its intrastriatal stereotaxic injection into male Sprague-Dawley rats, malonate produced a dose-dependent lesion when assessed 3 days after surgery using cytochrome oxidase histochemistry. This lesion was attenuated by coadministration of excess succinate, indicating that it was caused by specific inhibition of SDH. The lesion was also prevented by administration of the noncompetitive NMDA antagonist MK-801. MK-801 did not induce hypothermia, and hypothermia itself was not neuroprotective, suggesting that the neuroprotective effect of MK-801 was due to blockade of the NMDA receptor ion channel and not to any nonspecific effect. The competitive NMDA antagonist LY274614 and the glycine site antagonist 7-chlorokynurenate also profoundly attenuated malonate neurotoxicity, further indicating an NMDA receptor-mediated event. Finally, the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) antagonist NBQX (2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(f)-quinoxaline) was ineffective at preventing malonate toxicity at a dose that effectively reduced S-AMPA toxicity, indicating that non-NMDA receptors are involved minimally, if at all, in the production of the malonate lesion. We conclude that inhibition of SDH by malonate results in NMDA receptor-mediated excitotoxic neuronal death. If this mechanism of "secondary" or "weak" excitotoxicity plays a role in neurodegenerative disease, NMDA antagonists and other "antiexcitotoxic" strategies may have therapeutic potential for these diseases.

Animals↗
PubMed1995

Exacerbation of NMDA, AMPA, and L-glutamate excitotoxicity by the succinate dehydrogenase inhibitor malonate.

We report that a subtoxic dose of the succinate dehydrogenase (SDH) inhibitor malonate greatly enhances the neurotoxicity of three different excitatory amino acid agonists: N-methyl-D-aspartate (NMDA), S-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (S-AMPA), and L-glutamate. In male Sprague-Dawley rats, intrastriatal stereotaxic injection of malonate alone (0.6 mumol), NMDA alone (15 nmol), S-AMPA alone (1 nmol), or glutamate alone (0.6 mumol) produced negligible toxicity as assessed by measurement of lesion volume. Coinjection of subtoxic malonate with NMDA produced a large lesion (15.2 +/- 1.4 mm3), as did coinjection of malonate with S-AMPA (11.0 +/- 1.0 mm3) or glutamate (12.8 +/- 0.7 mm3). Administration of the noncompetitive NMDA antagonist MK-801 (5 mg/kg i.p.) completely blocked the toxicity of malonate plus NMDA (0.5 +/- 0.3 mm3). This dose of MK-801 had little effect on the lesion produced by malonate plus S-AMPA (9.0 +/- 0.7 mm3), but it attenuated the toxicity of malonate plus glutamate by approximately 40% (7.5 +/- 0.9 mm3). Coinjection of the AMPA antagonist 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(f)-quinoxaline (NBQX; 2 nmol) had no effect on malonate plus NMDA or malonate plus glutamate toxicity (12.3 +/- 1.8 and 14.0 +/- 0.9 mm3, respectively) but greatly attenuated malonate plus S-AMPA toxicity (1.5 +/- 0.9 mm3). Combination of the two antagonists conferred no additional neuroprotection in any paradigm. These results indicate that metabolic inhibition exacerbates both NMDA receptor- and non-NMDA receptor-mediated excitotoxicity.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Pulmonary scar carcinoma: report of three cases and review of the literature.

Pulmonary scar carcinoma was described as a distinct clinicopathological entity over 50 years ago. There are many theories on the formation of this entity. We present three cases of pulmonary scar carcinoma with a high ratio of adenocarcinoma. One patient had a favorable postoperative course despite a 14-month delay in treatment. Necropsy specimen of another patient showed two primary scar carcinomas unrelated to each other. Literature review and discussion of etiology, diagnosis, and treatment modalities of pulmonary scar carcinoma were done. Pathogenesis and prognosis of the neoplasms associated with apical scars are not clearly understood.

Adenocarcinoma↗
PubMed1994

The endogenous cofactors, thioctic acid and dihydrolipoic acid, are neuroprotective against NMDA and malonic acid lesions of striatum.

Thioctic acid (alpha-lipoic acid) and dihydrolipoic acid are endogenous, interconvertible cofactors of the mitochondrial pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase complexes. These compounds help to maintain glutathione and alpha-tocopherol in their reduced states, and they possess intrinsic free radical scavenging properties. We examined whether systemic treatment with thioctic acid or dihydrolipoic acid is protective against direct- and indirect-acting excitotoxins. Adult rats were treated for 10 days with intraperitoneal injections of vehicle, thioctic acid or dihydrolipoic acid, and on day 7 of treatment animals received unilateral stereotaxic injections of NMDA or malonic acid into the striatum. Histological assessment 3 days after the stereotaxic injections revealed a marked reduction in lesion volume in animals treated with thioctic acid or dihydrolipoic acid. We conclude that thioctic acid and dihydrolipoic acid are neuroprotective against direct and indirect excitotoxic insults.

Animals↗
PubMed1994

Polysynaptic regulation of glutamate receptors and mitochondrial enzyme activities in the basal ganglia of rats with unilateral dopamine depletion.

After nigrostriatal dopaminergic denervation, the output nuclei of the basal ganglia, the medial globus pallidus and substantia nigra pars reticulata (Snr), become overactive, in part, because of increased activity of excitatory afferents from the subthalamic nucleus (STN). Because STN uses glutamate as a transmitter, we examined whether there are regulatory changes in glutamate receptor binding in the basal ganglia. Rats received unilateral 6-hydroxydopamine lesions of the medial forebrain bundle and substantia nigra pars compacta that were confirmed by apomorphine-induced rotation and 3H-GBR-12935 binding. As an indirect index of relative synaptic activity, succinate dehydrogenase and cytochrome oxidase activities were assayed histochemically in sections adjacent to those used for receptor binding. There were increases in enzymatic activity in entopeduncular nucleus (EP; the rodent homolog of medial globus pallidus), SNr, and globus pallidus (GP, the rodent homolog of lateral globus pallidus) in the lesioned hemisphere, suggesting increased synaptic activity, perhaps due to increased firing of the STN. Ipsilateral to the lesion, and postsynaptic to the STN, there were profound decreases in the binding of 3H-AMPA (alpha-amino-3-hydroxy-5-methylisoxazole propionic acid) in EP and SNr (45% and 30%, respectively); there were no alterations in the striatum, globus pallidus, or STN, and binding throughout the unlesioned hemisphere was equivalent to that in unlesioned control animals. In contrast, 3H-MK-801 binding to the NMDA receptor ion channel was not reduced in SNr, and was too low to be measured reliably in EP and STN. 3H-MK-801 binding was reduced by 6% in striatum and 39% in globus pallidus.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Inhibition of succinate dehydrogenase by malonic acid produces an "excitotoxic" lesion in rat striatum.

Excitotoxicity and defects in neuronal energy metabolism have both been implicated in the pathogenesis of neurodegenerative disease. These two mechanisms may be linked through the NMDA receptor, activation of which is dependent on neuronal membrane potential. Because the ability to maintain membrane potential is dependent on neuronal energy metabolism, bioenergetic defects may affect NMDA receptor-mediated excitotoxicity. We now report that reversible inhibition of succinate dehydrogenase (SDH), an enzyme central to both the tricarboxylic acid cycle and the electron transport chain, produces an "excitotoxic" lesion in rat striatum that can be blocked by the NMDA antagonist MK-801. Male Sprague-Dawley rats received intrastriatal stereotaxic injections of the SDH inhibitor malonic acid (1 or 2 mumol) in combination with intraperitoneal injections of vehicle or MK-801 (5 mg/kg) 30 min before and 210 min after malonic acid. Animals were killed 72 h after surgery, and brains were processed for histology, cytochrome oxidase activity, and [3H]MK-801 and [3H]AMPA autoradiography. The higher dose of malonic acid (2 mumol) produced large lesions that were markedly attenuated by treatment with MK-801 (28.1 +/- 3.6 vs. 4.7 +/- 2.6 mm3; p < 0.001). [3H]MK-801 and [3H]AMPA binding were reduced in the lesions by 60 and 63%, respectively. One micromole of malonic acid produced smaller lesions that were almost completely blocked by MK-801 treatment (9.6 +/- 1.3 vs. 0.06 +/- 0.04 mm3; p < 0.0001). The toxic effects of malonic acid were due specifically to inhibition of SDH inasmuch as coinjection of a threefold excess of succinate with the malonic acid blocked the striatal lesions (p < 0.002).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

The cross-sectional legacy: an introduction to longitudinal studies of the climacteric.

Hitherto the bulk of psychosocial and sociological research on the menopause has been based on cross-sectional studies, in which the research strategy has been to compare women of different ages and/or different menopausal status by reference to various parameters. This paper summarizes the main findings of these studies, which relate to a variety of countries. A consistent finding has been that much of the variance in the symptoms and complaints reported by women during the climacteric can in fact be accounted for by a number of different adverse sociodemographic and psychosocial factors. It is postulated that the mechanism whereby these factors exercise their effect can best be conceptualized in terms of a vulnerability model. Although cross-sectional studies, have obvious limitations, their findings have now been complemented by those from a number of ongoing longitudinal studies in which the same cohort of women is being followed through this transitional period of their lives.

Climacteric↗
PubMed1990

Endobronchial epithelial papilloma associated with a foreign body.

Noninvasive papillary endobronchial lesions are among the least common of pulmonary neoplasms. We describe the occurrence of a papillary squamous tumor surrounding an aspirated sunflower seed foreign body, and briefly review the subject of endobronchial papilloma. This tumor should be a red flag for the presence of a foreign body, and foreign body removal may obviate the need for thoracotomy.

Bronchi↗
PubMed1990

Design of an optimal ventilator.

When a patient is incapable of adequate ventilation by natural processes, mechanical assistance must be provided. Ventilation assures sufficient Oxygen delivery to the organs and tissues of the body and excessive amounts of Carbon Dioxide are not permitted to accumulate. Ventilators are employed continuously or intermittently to improve the ventilation of the lungs. The present work involves design of a ventilator that virtually eliminates any work done by the patients in their breathing process. Presently available ventilators approach this level of performance but they have a few reported shortcomings. These limitations include insufficiency of inspiratory airflow and rigidity of operating cycles. The new ventilator is built around an optimal controller and its performance is based on computational capability of microprocessors. Real time measurements of volume, flow rates and pressure are managed and processed by these devices for optimal determination of controlled parameters of the ensuing respiratory cycle. These measured parameters are used for estimating the lung characteristics such as lung compliance and airway resistance. An independent microprocessor system incorporating data acquisition and processing features with scope for a number of additional capabilities such as graphic output, database and communications functions can prove very useful in health care institutions.

Biomechanical Phenomena↗
PubMed1989

Effects of alprazolam on respiratory drive, anxiety, and dyspnea in chronic airflow obstruction: a case study.

Alprazolam, an anxiolytic benzodiazepine, has a pharmacologic profile similar to that of diazepam. An intermediate half-life of 10-12 hours and a comparatively brief duration of activity relative to other anxiolytic benzodiazepines justified evaluation of a 0.5-mg test dose in an anxious patient with chronic obstructive lung disease. Subjective indexes, breath-by-breath respiratory drive response to hypercapnia, and blood alprazolam concentrations were determined before and after dosing. Subjective testing included a visual analog dyspnea scale, the state anxiety inventory, and subjective feelings visual analog scales (represented by alertness, calmness, and level of contentment). After dosing, the patient was better able to tolerate the rebreathing study technique. Statistically significant improvements in dyspnea (t - 10.20; p 0.0005), anxiety (t - 45.85; p less than 0.0001), alertness (t - 13.04; p less than 0.0001), cententedness (t - 12.27; p less than 0.0001), and calmness (t - 8.05; p less than 0.0001) occurred after alprazolam administration. Drive to breathe, as determined by mouth occlusion pressure and minute ventilation, was not statistically different before and after dosing. No adverse effects were reported or observed. Further study is warranted.

Alprazolam↗
PubMed1989

The Scottish first episode schizophrenia study. VII. Two-year follow-up. Scottish Schizophrenia Research Group.

Of 49 schizophrenic patients followed up 2 years after their first admission to hospital, 37% were well, 47% had been readmitted to hospital at some time over the 2 years, and 38% showed schizophrenic symptoms at follow-up. A poor outcome at 2 years was associated with male sex, poor outcome after the first 5 weeks of the first admission, negative schizophrenic symptoms on first admission, and a diagnosis of definite or probable schizophrenia using the Feighner criteria. Only 23% were in employment. A small double-blind discontinuation study of maintenance antipsychotic medication during the second year found more relapses in those switched to placebo medication. Repeat psychometric assessment at 2 years confirmed modest improvements found at 12 months; that is, there was no evidence of intellectual decline. Relatives showed no more psychosocial distress than that found in a normal community sample; what distress there was correlated with patients' schizophrenic symptoms.

Clinical Trials as Topic↗
PubMed1989

A comparison of esophageal and chest electrodes in studying the diaphragmatic EMG.

In exploring respiratory fatigue detection using the electromyograph (EMG), two EMG signals may be collected. One resulting from skin electrodes placed on the outside of the chest and the other from an esophageal electrode. The current trend in respiratory muscle fatigue detection is to use skin electrodes as the recipients of the diaphragmatic EMG signal. This eliminates the need of subjecting the person to a nasally inserted EMG electrode. Although it is more convenient to use this type of electrode, it does have several distinct disadvantages that must be overcome if accurate analysis is to take place. This paper compares the advantages and disadvantages of the two electromyograph detection methods and addresses the appropriate use of both.

Diaphragm↗