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Biomedical subjects

M A Black

Publications and source records attributed to M A Black.

At least 19 recordsLinked to original sources
PubMed2000

Real-time detection of epileptiform activity in the EEG: a blinded clinical trial.

The aim of this study was to determine the performance of a PC-based system for real-time detection and topographical mapping of epileptiform activity (EA) in the EEG during routine clinical recordings. The system incorporates a mimetic stage to locate candidate spikes (including sharp-waves) followed by two expert-system-based stages, which utilize spatial and wide-temporal contextual information in deciding whether candidate events are epileptiform or not. The data comprised 521 consecutive routine clinical EEG recordings (173 hours). Performance was evaluated by comparison with three independent electroencephalographers (EEGers-I). A second group of two EEGers (EEGers-II) separately interpreted the spike topographical maps and, for EEGs categorized as containing only questionable EA by the detection system, reviewed 6 sec segments of raw EEG centered on each questionable event. Thirty-eight of the EEGs were considered to contain definite EA by at least two of EEGers-I. The false detection rate of the system was 0.41 per hour. The system was found to have a sensitivity of 76% and a selectivity of 41% for EEGs containing definite EA. However, it only missed detection of EA in 5% of the recordings. EEGers-II agreed with EEGers-I on the distribution (generalized, lateralized, focal, multifocal) of EA in 79% of cases. This is by far the largest clinical evaluation of computerized spike detection reported in the literature and the only one to apply this in routine clinical recordings. The false detection rate is the lowest ever reported, suggesting that this multi-stage rule-based system is a powerful and practical tool in clinical electroencephalography and long-term EEG monitoring.

Adolescent↗
PubMed1997

Glutamate-treated rat cortical neuronal cultures die in a way different from the classical apoptosis induced by staurosporine.

The alkaloid protein kinase inhibitor staurosporine induced neuronal cell death with both the morphological and the biochemical characteristics of apoptosis. The punctate chromatin associated with apoptosis with retention of plasma membrane integrity was observed in neurons identified by colocalization of NeuN staining. Such cells had DNA fragmentation visualized by in situ end-labeling which was seen as a laddered pattern upon gel electrophoresis. In contrast cells treated with glutamate did not exhibit either of these morphological or biochemical hallmarks of apoptosis. Instead a much smaller and more compact pyknotic structure was observed associated with smeared DNA fragmentation patterns. A confocal time-lapse study of the appearance of the morphological changes in individual nuclei after staurosporine treatment showed collapse into punctate chromatin over a period of 10 min. In contrast, the collapse into small pyknotic nuclei after glutamate treatment was at least 10 times slower. It is concluded that excitotoxicity produced by glutamate did not induce cell death by an apoptotic mechanism in cultured cortical neurons.

Animals↗
PubMed1997

Subcellular localization of G-proteins in primary-cultured mouse preadipocytes and adipocytes.

The subcellular localization of G5 alpha, Gi alpha 1&2, Gi alpha 3, and G beta was studied in primary-cultured undifferentiated and differentiated, lipid replete, adipose cells. The results show a distinct distribution for each of these G-proteins and differences between differentiated and undifferentiated cells. All the G-proteins examined had a cytoplasmic localization; only Gi alpha 1 and 2 showed a significant colocalization with the plasma membrane and this only in differentiated cells. Most studies using cells in culture have reported an intracellular localization for G-proteins, whereas in tissue sections the localization has been reported to be largely with the plasma membrane, with some intracellular localization. The results suggest that the cell-cell interactions or the specific geometry imposed by culture conditions favor the intracellular compared to peripheral localization of G-proteins. Alternately, the posttranslational modifications necessary for G-protein insertion in the plasma membrane may be deficient in cultured cells.

Adenylyl Cyclases↗
PubMed1997

Antagonism of N-methyl-D-aspartate-evoked currents in rat cortical cultures by ARL 15896AR.

The purpose of this study was to characterize the kinetics and voltage-dependence of the block of N-methyl-D-aspartate (NMDA)-induced currents in primary cultures of rat cortical neurons by the neuroprotective, low-affinity, NMDA antagonist ARL 15896AR, using whole-cell voltage-clamp techniques. ARL 15896AR caused rapid and reversible inhibition of NMDA (50 microM)-evoked currents from neurons held at -60 mV, with an IC50 of 9.8 microM. The EC50 for NMDA was not significantly affected by 10 microM ARL 15896AR (P > .05), consistent with a noncompetitive mechanism of block. ARL 15896AR antagonism was use-dependent, because application of the drug 60 sec before NMDA did not attenuate the initial NMDA-evoked current, although the block developed rapidly thereafter. Once bound, ARL 15896AR remained trapped upon removal of NMDA until subsequent NMDA re-exposure, whereupon currents recovered rapidly. The forward and reverse binding rate constants were estimated to be 2.406 x 10(4) M(-1) sec(-1) and 0.722 sec(-1), respectively. Antagonism was strongly voltage-dependent; the K(D) values at 0 and -60 mV were 60 and 11 microM, respectively. Additionally, there was a component of the block by ARL 15896AR that was voltage-insensitive. This component of the block did not act at the ligand binding site, because it was not influenced by NMDA concentration, or at the polyamine site, because it was not affected by spermine. However, there was an interaction of ARL 15896AR with the glycine regulatory site. In contrast to many uncompetitive NMDA antagonists, like MK-801, ARL 15896AR exhibited rapid kinetics. This property may result in a large margin of safety while maintaining the efficacy associated with use-dependent NMDA antagonists, making this compound an excellent candidate for clinical trials.

Animals↗
PubMed1996

The desglycinyl metabolite of remacemide hydrochloride is neuroprotective in cultured rat cortical neurons.

The neuroprotective actions of remacemide and its anticonvulsant metabolite 1,2-diphenyl-2-propylamine monohydrochloride (desglycinylremacemide; DGR) a low-affinity NMDA receptor antagonist, were investigated using primary rat cortical neuronal cultures. Exposure of cortical cultures to NMDA (100 microM) for 15 min killed 85% of the neurons during the next 24 h. This neurotoxicity was blocked in a concentration-dependent manner by adding DGR (5-20 microM), but not its remacemide precursor (10-100 microM), to the cultures during the time of NMDA exposure. This suggests that the neuroprotective, as well as the anticonvulsant, activity of remacemide is mediated by DGR. Neuroprotective concentrations of DGR also inhibited two of the principal acute effects of NMDA. DGR (5-20 microM) prevented the loss of membrane-associated protein kinase C (PKC) activity that developed by 4 h after transient exposure to 100 microM NMDA and reduced the NMDA-triggered increases in intracellular free Ca2+ concentration ([Ca2+]i) by up to 70%. By contrast, remacemide (50 and 100 microM) did not prevent the NMDA-induced loss of PKC activity or reduce the [Ca2+]i responses. These data suggest that DGR protection against NMDA-mediated toxicity in cultured cortical neurons is associated with a reduction of NMDA-triggered [Ca2+]i surges and a prevention of the loss of membrane-associated PKC activity. In addition, the inhibition of NMDA-triggered [Ca2+]i responses by DGR was qualitatively different from the inhibition of these responses by the high-affinity NMDA-receptor antagonists MK-801 and phencyclidine. This may be a consequence of DGR's lower affinity for the NMDA receptor.

Acetamides↗
PubMed1995

Growth and maturation of primary-cultured adipocytes from lean and ob/ob mice.

Stromal vascular cells from epididymal fat pads of lean and obese mice were cultured in a medium (alpha-MEM) containing fetal bovine serum (FBS) and cell replication followed for 11 days. In both types of cells, confluence occurred at 4-5 days, after which virtual growth arrest occurred in lean-mouse cells while replication continued, albeit at a slower rate in obese-mouse cells. Little or no lipid accumulation or glycerol-3-phosphate dehydrogenase (GPDH) activity was observed under these conditions. When a differentiation mixture consisting of insulin, corticosterone and isobutylmethylxanthine was added to the serum-containing alpha-MEM, a proportion of the lean-mouse cells accumulated triglycerides and GPDH activity increased significantly, indicating differentiation. By contrast, little or no differentiation occurred in obese-mouse cells. When cells grown in serum-containing alpha-MEM were transferred to a serum-free defined medium at confluence, extensive differentiation and maturation occurred in lean-mouse cells but not in obese-mouse cells. Similar experiments were conducted in cells isolated from the retroperitoneal fat pad. Although the growth pattern was similar to that of epididymal preadipocytes, the retroperitoneal lean- and obese-mouse cells differentiated more readily than epididymal cells, as shown by the GPDH specific activity. These data suggest that cells from obese mice are resistant to differentiation under conditions that support extensive differentiation in lean-mouse cells.

1-Methyl-3-isobutylxanthine↗
PubMed1995

N-methyl-D-aspartate- or glutamate-mediated toxicity in cultured rat cortical neurons is antagonized by FPL 15896AR.

The neuroprotective action of (S)-alpha-phenyl-2-pyridineethanamine dihydrochloride (FPL 15896AR), a novel noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, was examined in primary rat cortical neuronal cultures. Exposure of cortical cultures to NMDA (50 microM) or glutamate (50 microM) for 15 min resulted in the death of 85-95% of the neurons during the next 24 h. This neurotoxicity was completely eliminated by adding FPL 15896AR (50 microM) to the cultures during the time of NMDA or glutamate exposure. Neuroprotective concentrations of FPL 15896AR also inhibited other acute effects of NMDA. FPL 15896AR (50 microM) prevented the loss of membrane-associated protein kinase C activity that developed by 4 h after transient exposure to 50 microM NMDA or 50 microM glutamate. FPL 15896AR also reduced by approximately 35% the magnitude of NMDA-triggered increases in intracellular free Ca2+ concentration in the cortical cultures. These data indicate that NMDA-mediated toxicity in cultured cortical neurons can be blocked by the NMDA antagonist FPL 15896AR.

Animals↗
PubMed1994

Insulin secretion and intracellular Ca2+ rises in monolayer cultures of neonatal rat beta-cells.

Glucose-induced insulin release, glucose-induced rises in intracellular free Ca2+ concentration ([Ca2+]i), and voltage-dependent Ca2+ channel activity were assessed in monolayer cultures of beta-cells from 3-5-day-old rats. The glucose-stimulated insulin secretory responses and [Ca2+]i rises were like those in adult rat beta-cells rather than fetal rat beta-cells. Voltage-dependent Ca2+ channel antagonists decreased glucose-induced insulin secretion, aborted the [Ca2+]i rise and, like deprivation of extracellular Ca2+, prevented the glucose-induced rise in [Ca2+]i when added before the glucose challenge. The presence of nifedipine-sensitive, voltage-dependent Ca2+ channels was demonstrated directly by measuring Ca2+ currents using the whole-cell configuration of the patch-clamp technique and indirectly by measuring [Ca2+]i after membrane depolarization by 45 mM K+ or 200 microM tolbutamide. Thus, in cultured beta-cells of 3-5-day-old rats the coupling of glucose stimulation to Ca2+ influx is essentially mature, in contrast to what has been reported for fetal or very early neonatal cells.

Age Factors↗
PubMed1992

Thyroid hormone and androgen regulation of nerve growth factor gene expression in the mouse submandibular gland.

The nerve growth factor (NGF) content of the mouse submandibular gland (SMG) is under hormonal control and is modulated by both thyroid hormones (TH) and androgens. The sexual dimorphism of the gland is well documented. In the adult male mouse, the SMG contains 10 times more NGF compared to the female. Conversely, castration of male mice reduces the SMG NGF levels to those found in control females. In order to determine the locus at which androgens and TH exert their effect on NGF gene expression in the SMG, steady-state NGF mRNA levels were determined. Daily treatment of adult female mice with TH for 1 week increased NGF mRNA levels 6-fold. Androgen treatment produced a 20-fold increase in SMG NGF mRNA, which was comparable to levels detected in the control adult male SMG. The effect of TH on NGF mRNA levels was time-dependent and coincided with the increase in NGF protein concentrations. At 48 h after a single TH injection, NGF mRNA levels (measured in SMG total RNA) increased 2-4-fold, while heteronuclear (hn) RNA levels were increased 1.5-2-fold. The NGF gene transcription rate was determined by run-on assay following TH treatment. A small but significant 2-fold induction by TH of NGF gene transcription was found at 24-48 h. Cytoplasmic RNA prepared from the same SMGs used in the run-on experiments was tested by S1 nuclease protection; NGF cytoplasmic RNA was increased 7-fold in the SMGs of females treated with TH 48 h previously. These results demonstrate that the effect of TH on NGF gene expression is due in part to an induction of NGF gene transcription. The discrepancies observed between transcription rate and mRNA levels suggest that the major effect of TH is at the post-transcriptional level, possibly mRNA stabilization. The time required to observe an induction of TH on NGF gene transcription is suggestive of an indirect effect, possibly through the induction by TH of another protein which in turn activates the NGF gene.

Anabolic Agents↗
PubMed1992

Thyroid hormones precociously increase nerve growth factor gene expression in the submandibular gland of neonatal mice.

The developmental regulation of the expression of nerve growth factor (NGF) was studied in the mouse submandibular gland (SMG). Having demonstrated that, in the neonatal mouse, maturation of the SMG can be accelerated by treatment with thyroid hormones, with the resulting induction in SMG content of NGF, studies were undertaken to further examine the locus of thyroid hormone action. Because of the sexual dimorphism of the SMG, both male and female neonatal mice were used. NGF messenger RNA levels were undetectable in SMGs from untreated immature mice, while hybridization to total RNA from T4-treated mice was easily observable for NGF complementary DNA. Treatment for 14 days compared to 7 days resulted in a 7-fold increase in SMG NGF mRNA levels. A signal was obtained in 21-day-old control mice using S1 nuclease protection analysis; T4 increased NGF mRNA levels by 100-fold in both male and female immature mice. Heteronuclear RNA levels were induced 20-fold by T4. No sex differences were readily observable. Determination of the effect of thyroid hormone treatment on SMG NGF gene expression by nuclear run-on assay demonstrated a significant transcriptional effect of T4. Initial experiments using the pmngf6 vector, which is a pBR322-derived probe containing the full length NGF cDNA, showed a 2.5-fold induction of gene transcription. When an internal fragment of pmngf6 was subcloned into pTZ18R, thus removing the dC/dG tails contained in pmngf6, the background hybridization was considerably reduced and a 12.5-fold induction in NGF gene transcription was obtained after T4 treatment of neonatal mice. The results show that thyroid hormones increase NGF gene expression in the SMG of the immature male and female mouse. This effect is due in part to a significantly enhanced rate of gene transcription.

Animals↗
PubMed1988

Different insulin-secretory responses to calcium-channel blockers in islets of lean and obese (ob/ob) mice.

The purpose of these experiments was to determine whether the activity of the voltage-dependent Ca2+ channel was modulated in the same manner in islets of the ob/ob mouse as in islets of homozygous lean mice of the same strain. The effect of agents that are known to alter the concentrations and movements of intracellular Ca2+ were investigated in relation to glucose-stimulated insulin secretion and in relation to the effect of forskolin. In islets of obese mice, verapamil and nifedipine both inhibited glucose-induced insulin release, nifedipine being the more potent inhibitor. Forskolin-stimulated secretion was inhibited either not at all (verapamil) or much less (nifedipine) in islets of the ob/ob mouse compared with those of lean mice. At basal glucose concentrations, verapamil initiated insulin secretion in islets of the ob/ob mouse and acted synergistically with forskolin to evoke a secretory activity that was 3-fold greater than that evoked by 20 mM-glucose. Nifedipine also initiated secretion at basal glucose concentrations and acted synergistically with forskolin, but its effect was considerably smaller than that of verapamil. A comparison of the effect of forskolin in the presence of Ca2+-channel blockers and in the absence of Ca2+ suggests that, in the obese mouse, the operation of the voltage-dependent Ca2+ channel is impaired.

Animals↗
PubMed1988

Abnormal regulation of cAMP accumulation in pancreatic islets of obese mice.

The present study was undertaken 1) to determine whether a defect in the regulation of adenosine 3',5'-cyclic monophosphate (cAMP) accumulation was present in the beta-cell of the ob/ob mouse, 2) to determine how such a defect, if present, would alter the regulation of insulin secretion in these islets, and 3) to find out if epinephrine had similar effects on insulin secretion and cAMP production in islets of lean and obese mice. In the obese mouse, inhibitory modulators neither inhibited cAMP accumulation in intact islets nor adenylate cyclase activity in islet homogenates. These anomalies in the modulation of cAMP accumulation were not correlated with a failure to inhibit insulin secretion. It is concluded that, first, a defect in cAMP modulation is present in the islets of Langerhans of the obese mouse; second, epinephrine produces its effects on insulin secretion and cAMP accumulation via distinct mediators; and third, an anomaly in the adenylate cyclase system is unlikely to be the cause of the exaggerated insulin secretion in the islet of the ob/ob mouse. It is more likely that the exaggerated insulin secretion is due to a faulty cation gating mechanism that, in turn, may contribute to the impaired ability of the islet to accumulate cAMP.

Adenylate Cyclase Toxin↗
PubMed1985

Intravenous streptokinase in acute myocardial infarction.

Intravenous (IV) fibrinolytic therapy, a recent area of research, has a great deal of applicability in emergency medicine. We report our experience with 30 patients treated with this method. Thirty consecutive patients in the early stages of acute evolving myocardial infarction (AMI) were assigned to receive high-dose IV streptokinase, 1.5 million units over a 30-minute period. Patients presented to the treating hospital at a mean time of 1.21 +/- 1.08 hours, and treatment commenced at a mean time of 2.77 +/- 1.31 hours after the onset of symptoms. Using standard clinical criteria, 86.7% (n = 26) of the patients reperfused initially. Two, however, reoccluded within the first 48 hours, and their clinical symptoms of myocardial infarction reappeared. By clinical observation 80% (n = 24) of the patients reperfused, and myocardial salvage was observed. Twenty-four patients with clinical reperfusion and one additional patient had patency of the affected artery, yielding a reperfusion rate of 83.3% (n = 25) as judged by angiography within one week of AMI. Both patients who had reoccluded clinically also were found to be occluded on angiography. Clinical and angiographic methods yield very similar results for the judgment of reperfusion (80% vs 83%, respectively, with no significant difference, P not significant). The results of our study tend to confirm the efficacy of IV streptokinase as a valuable management tool for early myocardial infarction.

Aged↗
PubMed1984

The incidence of acute brain injury and serious impairment in a defined population.

Studies on the incidence and epidemiologic features of brain injury and the immediate medical outcomes are few, and published results have serious methodological inconsistencies which prohibit comparisons. This study provides incidence rates of brain injury among the residents of San Diego, California. Cases had clinical confirmation and onset of injury occurred during 1981. The 3358 cases identified represent a rate of 180/100,000 with males having a 2.2 times higher rate than females. Rates were highest for males aged 15-24 years and, for both genders, those over age 70. Forty-eight per cent of all cases were from transport-related causes, followed by falls (21%) and assaults (12%). Over 11% were dead-on-arrival, and 16% were classified as having moderate or severe brain damage on admission to a hospital. Age- and sex-specific incidence rates varied according to external cause of injury. For example, for most subcategories of motor vehicle crashes and for assaults, the incidence rate was highest among males aged 15-24, while for brain injuries from falls or firearms, highest incidence rates were observed in older age groups. Almost 7% of all cases discharged alive from an acute care hospital had significant neurologic sequelae. The impact of brain injury is discussed as a major unresolved public health problem.

Accidents, Traffic↗
PubMed1975

Pediatric interviewing skills taught by nonphysicians.

We cannot assume that medical students develop, through unstructured educational happenings, the skills of interviewing a mother about her child. Teaching these skills requires extensive one-to-one faculty-student involvement, which is almost prohibitive if pediatricians are expected to do this teaching. This article describes (1) a current pediatric interviewing teaching program that uses nonphysicians as teachers; (2) the selection and training of nonphysicians to teach the skill of pediatric interviewing to third-year medical students; and (3) an assessment of these teachers by comparing their techniques with those of three pediatric faculty members. The nonphysician teachers fared most favorably when their teaching methods were compared with those of three pediatricians. Acceptance of the program by the students, faculty, and administration has been most encouraging.

Education, Medical, Undergraduate↗
PubMed1975

A comparison of pediatric interviewing skills using real and simulated mothers.

In order to allay concerns about using simulators as opposed to real mothers for teaching and evaluating interviewing skills, a study was designed to test for differences in students' approaches when interviewing simulated and real mothers. Three mothers were trained to give their own children's histories consistently and two mothers trained to simulate a history. Thirty third-year medical students conducted two interviews which were audiotaped. Students were told the nature of the study and whether the mother was real or simulated. One half of the time the mothers were presented as simulators and one half of the time the simulators were presented as mothers. The variable of order was controlled. An objective checklist containing 70 to 80 bits of organic and personal data per case and an interaction analysis (with an average of 285 interactions per interview) were utilized to measure the content material gathered and the approach used by the students. The data were analyzed using an analysis of variance (ANOVA) technique. All but 1 of the 55 null hypotheses were accepted, i.e., no significant differences were found. The Use of Simulation for Teaching and Evaluating Interviewing Skills Provides a Valid Experience.

Child↗