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Biomedical subjects

M J McGrath

Publications and source records attributed to M J McGrath.

At least 19 recordsLinked to original sources
PubMed2001

Effects of human pregnancy on cardiac autonomic function above and below the ventilatory threshold.

This study examined the effects of human pregnancy on heart rate variability (HRV), spontaneous baroreflex (SBR) sensitivity, and plasma catecholamines at rest and during exercise. Subjects were 14 healthy, physically active pregnant women (PG; mean gestational age = 33.9 +/- 1.0 wk). Results were compared with an age-matched nonpregnant control group (NPG; n = 14) with similar characteristics. The electrocardiographic R-wave-R-wave interval and systolic blood pressure (via finger plethysmograph) were measured on a beat-to-beat basis at rest and during upright cycling at 60 and 110% of the ventilatory threshold (T(vent)). Parasympathetic nervous system (PNS) modulation (as reflected by HRV high-frequency/total power and SBR slope) was significantly reduced at rest in the PG vs. the NPG. During exercise, PNS modulation decreased significantly in both groups, but the magnitude of PNS withdrawal from rest to 110% T(vent) was smaller in the PG vs. NPG. Sympathetic nervous system (SNS) modulation (reflected by the low-frequency power-to-high-frequency power ratio) increased above resting values at 60 and 110% T(vent) in the NPG. SNS modulation at 110% T(vent) was significantly lower in the PG compared with the NPG. Plasma norepinephrine and epinephrine levels were also lower at 110% T(vent) in the PG. It was concluded that healthy pregnant women exhibit lower PNS modulation at rest and blunted SNS modulation during exercise above T(vent) in late gestation.

Adult↗
PubMed2000

Glutamatergic drugs exacerbate symptomatic behavior in a transgenic model of comorbid Tourette's syndrome and obsessive-compulsive disorder.

We previously created a transgenic mouse model of comorbid Tourette's syndrome and obsessive-compulsive disorder (TS+OCD), by expressing a neuropotentiating cholera toxin (CT) transgene in a subset of dopamine D1 receptor-expressing (D1+) neurons thought to induce cortical and amygdalar glutamate output. To test glutamate's role in the TS+OCD-like disorder of these transgenic mice (D1CT-7 line), the effects of glutamate receptor-binding drugs on their behavior were examined. MK-801, a non-competitive NMDA receptor antagonist that indirectly stimulates cortical-limbic glutamate output, aggravated a transgene-dependent abnormal behavior (repetitive climbing and leaping) in the D1CT-7 mice at doses insufficient to induce stereotypies, and more readily induced stereotypies and limbic seizure behaviors at high doses. NBQX, a seizure-inhibiting AMPA receptor antagonist, reduced only the MK-801-dependent stereotypic and limbic seizure behavior of D1CT-7 mice, but not their transgene-dependent behaviors. These data imply that TS+OCD-like behavior is mediated by cortical-limbic glutamate, but that AMPA glutamate receptors are not an essential part of this behavioral circuit. Our findings lead to the prediction that the symptoms of human Tourette's syndrome and obsessive-compulsive disorder are elicited by excessive forebrain glutamate output.

Animals↗
PubMed2000

TS+OCD-like neuropotentiated mice are supersensitive to seizure induction.

Seizures can be induced by systemic dopamine D1 receptor agonists or by cortical-limbic neurostimulation non-selectively. Seizures are also often associated with tics and compulsions, which likewise involve cortical-limbic hyperactivity. To determine if selective potentiation of cortical-limbic D1 receptor-expressing (D1+) neurons increases seizure susceptibility, we administered pentylenetetrazole (PTZ) to mice that express a neuropotentiating transgene only in a glutamatergic, cortical-limbic subset of D1+ neurons (D1CT-7 line). These mice exhibited increased PTZ-dependent seizure incidence, onset rate and intensity. Because D1CT-7 mice also exhibit tic+compulsion-like behaviors, this implies that glutamatergic hyperactivity induced by cortical-limbic D1+ neuropotentiation facilitates not only epilepsy but also tics and compulsions. This suggests a dopamine-regulated glutamatergic basis for all three states and may explain why they often co-exist in humans.

Animals↗
PubMed2000

Differing attitudes between psychiatrists and primary care providers at the interface.

OBJECTIVE: Market forces caused by managed care are shaping practice styles for both psychiatrists and primary care physicians. This study offers a sample of the attitudes of both groups of practitioners highlighting the differences. METHOD: Forty-two psychiatrists and primary care physicians (PCP) completed surveys. The responses of each group were compared using chi square analyses. RESULTS: Psychiatrists and PCPs differed significantly on their: 1) degree of comfort in the other's traditional service domain--with PCPs more comfortable dealing with their patients' psychiatric problems than psychiatrists were dealing with their patients' medical problems, 2) perceived barriers to effective communication-psychiatrists acknowledge their own time constraints while PCPs blame their colleagues unavailability (actually an agreement that psychiatrists' availability is a limiting factor), 3) projected areas of interface in the future--with psychiatrists prioritizing collaboration on health maintenance while PCPs valued collaboration on prevention and referral as equally significant. CONCLUSIONS: Conflict between needs and expectations found in this pilot study, if shown in larger studies to be representative, will impact the success of changes in practice patterns encouraged by emerging managed care initiatives. These findings suggest that the discordant expectations between psychiatrists and PCPs about the interface of their practices deserve further study.

Communication Barriers↗
PubMed1999

Characterization of two isoforms of the skeletal muscle LIM protein 1, SLIM1. Localization of SLIM1 at focal adhesions and the isoform slimmer in the nucleus of myoblasts and cytoplasm of myotubes suggests distinct roles in the cytoskeleton and in nuclear-cytoplasmic communication.

We have cloned and characterized a novel isoform of the skeletal muscle LIM protein 1 (SLIM1), designated SLIMMER. SLIM1 contains an N-terminal single zinc finger followed by four LIM domains. SLIMMER is identical to SLIM1 over the first three LIM domains but contains a novel C-terminal 96 amino acids with three potential bipartite nuclear localization signals, a putative nuclear export sequence, and 27 amino acids identical to the RBP-J binding region of KyoT2, a murine isoform of SLIM1. SLIM1 localized to the cytosol of Sol8 myoblasts and myotubes. SLIMMER was detected in the nucleus of myoblasts and, following differentiation into myotubes, was exclusively cytosolic. Recombinant green fluorescent protein-SLIM1 localized to the cytoplasm and associated with focal adhesions and actin filaments in COS-7 cells, while green fluorescent protein-SLIMMER was predominantly nuclear. SLIMMER truncation mutants revealed that the first nuclear localization signal mediates nuclear localization. The addition of the proposed nuclear export sequence decreased the level of exclusively nuclear expression and increased cytosolic SLIMMER expression in COS-7 cells. The leucine-rich nuclear export signal was required for the export of SLIMMER from the nucleus of myoblasts to the cytoplasm of myotubes. Collectively, these results suggest distinct roles for SLIM1 and SLIMMER in focal adhesions and nuclear-cytoplasmic communication.

Alternative Splicing↗
PubMed1999

Behavioral effects of cocaine on a transgenic mouse model of cortical-limbic compulsion.

We previously created a transgenic mouse model of cortical-limbic induced compulsions in which dopamine D1 receptor-expressing (D1+) neurons in restricted regional subsets of the cortex and amygdala express a neuropotentiating cholera toxin (CT) transgene. These 'D1CT' mice engage in complex behavioral abnormalities uniquely resembling human compulsions, such as non-aggressive biting of cagemates during grooming, repeated leaping and episodes of perseverance of any and all normal behaviors. Because both compulsions and cocaine-induced behaviors may represent forms of psychomotor activation that have a shared or overlapping neurological basis, we have examined the behavioral response of these 'compulsive' mice to cocaine. In both control and D1CT mice, cocaine increased the amount of time spent engaged in typical cocaine-dependent stereotypies such as locomotion, sniffing, or gnawing, while the remainder of behaviors within their normally complete behavioral repertoires decreased. Cocaine also decreased, rather than facilitated, the incidence of D1CT transgene-induced compulsion-like behaviors such as repeated leaping and perseverance of any and all normal behaviors. The indistinguishable cocaine responses of D1CT and normal mice, as well as the masking (rather than potentiation) of D1CT mouse compulsion-like behaviors by cocaine, suggests that cortical-limbic induced compulsions are significantly different in their origin or circuitry from cocaine-induced stereotyped behaviors. Specifically, these data suggest that the motor circuits stimulated in compulsions represent only a subset of the parallel circuits stimulated by cocaine. These data are, thus, consistent with the hypothesis that topographically restricted subsets of parallel cortical-striatal-thalamic loops induce different types of compulsive behaviors.

Animals↗
PubMed1999

OCD-Like behaviors caused by a neuropotentiating transgene targeted to cortical and limbic D1+ neurons.

To study the behavioral role of neurons containing the D1 dopamine receptor (D1+), we have used a genetic neurostimulatory approach. We generated transgenic mice that express an intracellular form of cholera toxin (CT), a neuropotentiating enzyme that chronically activates stimulatory G-protein (Gs) signal transduction and cAMP synthesis, under the control of the D1 promoter. Because the D1 promoter, like other CNS-expressed promoters, confers transgene expression that is regionally restricted to different D1+ CNS subsets in different transgenic lines, we observed distinct but related psychomotor disorders in different D1CT-expressing founders. In a D1CT line in which transgene expression was restricted to the following D1+ CNS regions-the piriform cortex layer II, layers II-III of somatosensory cortical areas, and the intercalated nucleus of the amygdala-D1CT mice showed normal CNS and D1+ neural architecture but increased cAMP content in whole extracts of the piriform and somatosensory cortex. These mice also exhibited a constellation of compulsive behavioral abnormalities that strongly resembled human cortical-limbic-induced compulsive disorders such as obsessive-compulsive disorder (OCD). These compulsive behaviors included episodes of perseverance or repetition of any and all normal behaviors, repetitive nonaggressive biting of siblings during grooming, and repetitive leaping. These results suggest that chronic potentiation of cortical and limbic D1+ neurons thought to induce glutamatergic output to the striatum causes behaviors reminiscent of those in human cortical-limbic-induced compulsive disorders.

Aggression↗
PubMed1999

Differential response of cortical-limbic neuropotentiated compulsive mice to dopamine D1 and D2 receptor antagonists.

We previously created transgenic mice in which dopamine D1 receptor-expressing (D1+) neurons in regional subsets of the cortex and amygdala express a neuropotentiating cholera toxin (CT) transgene. These 'D1CT' mice engage in complex biting, locomotor and behavioral perseverance-repetition abnormalities that resemble symptoms of human compulsive disorders associated with cortical-limbic hyperactivity. Because excessive cortical-limbic stimulation of striatal motor pathways may play a critical role in causing compulsive disorders, we examined the responsiveness of D1CT mice to dopamine D1 and D2 receptor antagonists. D1CT mice were found to be largely resistant to the cataleptic action of the D1 receptor antagonist SCH23390. The abnormal repetitive leaping of D1CT mice was similarly unaffected by SCH23390. In contrast, the D1CT mice displayed supersensitivity to cataleptic induction by the D2 receptor antagonist sulpiride. These data are consistent with the hypothesis that complex compulsions are mediated by chronic excessive corticostriatal (and/or amygdalostriatal) glutamatergic stimulation of the striatal direct and indirect motor pathways.

Animals↗
PubMed1999

The cardiac expression of striated muscle LIM protein 1 (SLIM1) is restricted to the outflow tract of the developing heart.

LIM proteins perform critical roles in development and tissue differentiation. The skeletal muscle LIM protein 1 (SLIM1) comprises four and a half LIM domains. Northern blot analysis demonstrated high level expression of SLIM1 mRNA in adult human skeletal muscle with intermediate expression in adult heart and lower expression in other tissues. Western blot analysis using specific affinity-purified anti-SLIM1 antipeptide antibodies demonstrated a 32 kDa polypeptide in the aorta and atria of rabbit heart, but not in vena cava, interventricular septum or ventricular muscle. SLIM1 was also demonstrated in rabbit skeletal muscle. In situ hybridization of whole mouse embryos confirmed the cardiac expression of SLIM1 was restricted to the cardiac outflow tract from embryonic day 8.5-11. No expression was seen in atrial or ventricular muscle. SLIM1 mRNA was also demonstrated in the hindbrain, neural tube and somites. The localized expression of SLIM1 to the outflow tract of the embryonic heart implies an important role for the protein in the development of this region and possibly in congenital heart anomalies involving the separation and formation of the aortic and pulmonary trunks.

Adult↗
PubMed1999

The role of cognitive and affective processing in a transgenic mouse model of cortical-limbic neuropotentiated compulsive behavior.

Obsessive compulsive disorder (OCD) may involve abnormal cortical-limbic processing or responsiveness. Mice with behaviors resembling the symptoms of OCD and related disorders were made by expression of a neuropotentiating cholera toxin (CT) transgene in cortical-limbic D1 receptor-expressing neurons. Because these D1CT mice express CT in the piriform cortex and amygdala (major cognitive and affective olfactory processing areas) it was tested whether abnormal odor perception, discrimination, or responsiveness facilitates their compulsion-like behavior. The mice exhibited normal olfactory discriminative capability. An anxiogenic odor potentiated their abnormal repetitive leaping, but novel or familiar nonthreatening odors did not. These data suggest that compulsions can be triggered not by impaired cortical-limbic processing but by increased cortical-limbic responsiveness, particularly to sensory or cognitive stimuli with affective properties.

Animals↗
PubMed1999

Socio-demographic variations in perspectives on cardiovascular disease and associated risk factors.

Coronary heart disease (CHD) rates in Ireland are very high but little is known about attitudes to the disease. Qualitative attitudinal data were collected in focus group settings from 74 individuals across socio-demographic categories in order to assess knowledge of and attitudes to CHD and associated risk factors. Focus group questions were derived from group deconstruction of constructs from the Health Belief Model, Theory of Planned Behaviour, Protection Motivation Theory and Social Learning Theory. Participants were drawn from the personnel lists of local government and a health authority hospital. Eight types of groups were constructed according to the various permutations of the three variables: age, gender and occupational group. Analyses revealed good knowledge levels about risk factors among participants. However, participants exhibited mixed loci of control and low motivation to change behaviours. Men generally were less motivated to change than women; older men thought it too late and younger ones too soon. Though white and blue collar groups' views were similar, the discussion in white collar groups was more varied. Participants were sceptical about apparently contradictory medical advice which undermined motivation to change. The data complement earlier work and suggest preventative initiatives should be more focused.

Adult↗
PubMed1999

Physical conditioning effects on fetal heart rate responses to graded maternal exercise.

PURPOSE: This study examined the effects of advancing gestational age and maternal aerobic conditioning (stationary cycling) on fetal heart rate (FHR) responses to strenuous non-steady-state maternal exercise. METHODS: Subjects chose to participate in either an exercise group (EG) or control group (CG). Fourteen healthy, previously sedentary pregnant women participated in the exercise group, and six pregnant controls remained sedentary. Stationary cycling (heart rate target: 145 beats x min(-1)) was performed 3 d x wk(-1) by the exercised group. Exercise duration was increased from 14 to 25 min x session(-1) during the second trimester and was maintained at 25 min x session(-1) throughout the third trimester. FHR was monitored before, during, and after a progressive submaximal cycle ergometer test (peak heart rate = 170 beats x min(-1)) performed at approximately 27 and 37 wk gestation. RESULTS: Mean FHR increased significantly (P < 0.05) during exercise, followed by a modest suppression and then a delayed rise during the recovery period at both observation times. Fetal bradycardia was not observed in any of the exercise tests. Effects of advancing gestational age included a lower FHR baseline both at rest and in response to maternal exercise and a lower incidence of exercise-induced tachycardia. Maternal physical conditioning did not significantly alter FHR response to maternal exercise. CONCLUSION: Our results support the hypothesis that FHR responses to strenuous exercise are altered by advancing gestational age and a brief progressive exercise test terminated at a maternal heart rate of 170 beats x min(-1) does not induce fetal distress during a healthy pregnancy.

Adult↗
PubMed1999

Anxiety in a transgenic mouse model of cortical-limbic neuro-potentiated compulsive behavior.

Anxiety and amygdalar stimulation may induce or exacerbate compulsions triggered by cortical-limbic hyperactivity, as in human obsessive-compulsive disorder (OCD). We previously created transgenic mice that exhibit OCD-like biting, movement and behavioral perseverance abnormalities. These behaviors are caused by expression of a neuro-potentiating cholera toxin (CT) transgene in dopamine D1 receptor-expressing (D1+) neurons within the amygdalar intercalated nucleus (ICN) and within cortical areas that project to orbitofrontal cortex and striatum. Here we tested whether anxiety and increased amygdalar stimulation may play a role in eliciting or exacerbating such behaviors. D1CT mice exhibited increased thigmotaxis (tendency of mice to remain along the perimeter of open areas) in the open field assay, and increased latency to first transit and reduced transit number in the light-dark assay. These studies indicate that the D1CT mice exhibit a significant increase in behavioral indicators of anxiety. Furthermore, yohimbine, a drug that induces both amygdalar stimulation and behavioral indicators of anxiety, exacerbated abnormal leaping in D1CT mice but failed to exacerbate their abnormal behavioral perseverance. These data suggest that chronic potentiation of D1+ neurons in the amygdalar ICN increases anxiety and facilitates particular compulsive behaviors.

Amygdala↗
PubMed1999

Randomised, double-blind, placebo controlled pilot study assessing nitroglycerin as a tocolytic.

Thirty-three women in preterm labour were randomised in a double-blind fashion to receive either transdermal nitroglycerin (n = 17) or placebo (n = 16). Both groups had significant (P < 0.001) change in the cervix prior to randomisation. The primary outcome measure was delivery within 48 hours of randomisation. Fewer women randomised to nitroglycerin treatment (6/17) were delivered within 48 hours, compared with the placebo treatment (10/16) (RR 0.56, 95% CI 0.27 to 1.19). This pilot study lends support to two case series published that suggest that transdermal nitroglycerin may be promising as a safe, effective means for tocolysis.

Administration, Cutaneous↗
PubMed1999

Effects of pregnancy and chronic exercise on maternal cardiac structure and function.

This study examined the interactive effects of pregnancy and aerobic conditioning on maternal cardiac structure and function. Effects of closely monitored cycle ergometer conditioning were studied during the second (TM2) and third trimesters (TM3) in 22 previously sedentary pregnant women (exercised group, EG) and a nonexercising pregnant control group with similar characteristics (CG, n = 19). Subjects were studied in the resting state by two-dimensional echocardiography and during cycle ergometer exercise at three steady-state power outputs at the start of TM2 (ENTRY), at the end of TM2 and TM3 (postconditioning), and 3-4 months postpartum (NPR, nonpregnant reference, CG only). Aerobic conditioning did not increase left ventricular dimensions beyond those attributable to pregnancy itself. In addition, in contrast with previous studies of nonpregnant women, physical conditioning during pregnancy did not reduce heart rate (HR) in the resting state. During exercise, the slope of the HR versus oxygen uptake (VO2) regression decreased significantly between preconditioning and the end of TM3 in the EG, suggesting that training-induced reductions in HR become more evident with increasing exercise intensity. Also, significant reductions in oxygen pulse (VO2/HR) were observed at all three work rates in the CG, but not in the EG. These findings support the hypothesis that the cardiovascular effects of aerobic conditioning are obscured by more powerful effects of pregnancy in the resting state but become "unmasked" during strenuous exercise.

Adult↗
PubMed1998

Detecting subtle differences in behavior using waveform display analysis.

We have devised a method, behavioral waveform display analysis, to analyze complex ethological information by measuring behavior in real time and visualizing it as a time-dependent, multistate waveform. To facilitate the generation and statistical analysis of behavioral waveform displays, we have designed a simple Macintosh-based software program. When keystrokes coded to particular behavioral states are entered in real time, this software measures and collates the time, frequency, and duration of each behavioral state. These data can then be displayed either in a tabular format for statistical analysis of behavioral duration and frequency or as graphical coordinates for creating waveform displays by direct importing into graphing programs. An illustration of the use of waveform display analysis to detect anomalous behaviors in cocaine- and amphetamine-treated mice, some of which are not detectable by a standard time-sampling assay, is shown. Both waveform display and time-sampling analysis detected drug-induced changes in sniffing, bar hanging, digging, and rearing. However, unlike time-sampling analysis, waveform display analysis also detected changes in the total duration, frequency, and average duration of these behaviors as well as additional changes in gnawing and locomotion. Additionally, visual scanning of behavioral waveform displays detected drug-induced changes in the patterns of behavior not detectable by time-sampling, including 1) a staged progression to a limited behavioral repertoire consisting of sniffing, locomotion, and rearing; 2) rapid switching between these remaining few behaviors; 3) a delayed onset of postinjection rearing relative to sniffing and locomotion; and 4) the absence of other transient stereotypies during the onset of drug action. These data indicate that behavioral waveform display provides an approach for the detection, visualization, and statistical analysis of aspects of complex behavior not amenable to detection by time-sampling methods.

Amphetamine↗
PubMed1997

Voltammetric detection for capillary electrophoresis.

Several approaches to implementing amperometric detection for capillary electrophoresis have been reported. This report describes the development of a voltammetric detector for CE. The detector is designed to minimize distortion of the voltammetry due to ohmic potential drop. This was accomplished by using a cast Nafion detection cell at the end of the separation capillary. The cast Nafion detection cell provided a low-dead-volume, low-resistance cell that minimized ohmic potential drop and peak band broadening. The ability to detect the current due to oxidation of analytes superimposed on a large background current was also improved. A dynamic background subtraction scheme was used in which a second working electrode, positioned in the electrochemical cell but outside of the detection cell, was used to compensate for the background current in real time. The output of the compensating working electrode was subtracted from the output of the detecting working electrode prior to analog-to-digital conversion. Postexperimental digital background subtraction was also implemented. This approach provided optimal elimination of the background current with maximal detection of the analytical signal. The voltammetric detector developed produced high-quality voltammetric response of analytes with injected concentrations as low as 0.20 microM. The system was evaluated by obtaining CE voltammograms of a mixture of eight test phenolic acids.

Electrodes↗