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Biomedical subjects

L Churchill

Publications and source records attributed to L Churchill.

At least 19 recordsLinked to original sources
PubMed2004

Fos-immunoreactivity in the hypothalamus: dependency on the diurnal rhythm, sleep, gender, and estrogen.

Diurnal variations and sleep deprivation-induced changes in the number of Fos-immunoreactive (Fos-IR) neurons in various hypothalamic/preoptic nuclei were studied in the rat. The nuclei implicated in sleep regulation, the ventrolateral preoptic (VLPO), median preoptic (MnPO), and suprachiasmatic (SCN, dorsomedial subdivision) nuclei, displayed maximum c-fos expression in the rest (light) period. Sleep deprivation (S.D.) suppressed Fos-IR in the dorsomedial subdivision of SCN but failed to alter Fos in the VLPO. Fos-IR increased in the VLPO during recovery after S.D. A nocturnal rise in Fos expression was detected in the arcuate (ARC), anterodorsal preoptic (ADP) and anteroventral periventricular (AVPV) nuclei whereas the lateroanterior hypothalamic nucleus (LA) and the ventrolateral subdivision of SCN did not display diurnal variations. S.D. stimulated Fos expression in the ARC, ADP, and LA. Statistically significant, albeit modest, differences were noted in the number of Fos-IR cells between males and cycling female (estrus/diestrus) in the VLPO, MnPO, ARC, LA, and AVPV, and the female ADP did not display diurnal variations. Ovariectomy (OVX) was followed by marked reduction in Fos expression in the VLPO, SCN, and AVPV, and the diurnal rhythm decreased in the VLPO, and vanished in the dorsomedial SCN, and AVP. Estrogen administration to OVX female rats stimulated Fos expression in most nuclei, and the lost diurnal variations reoccurred. In contrast, castration of male rats had little effect on Fos expression (slight rises in diurnal Fos in the ARC and ventrolateral SCN). The results suggest that Fos expression is highly estrogen-dependent in many hypothalamic nuclei including those that have been implicated in sleep regulation.

Animals↗
PubMed2001

Sleep modifies glutamate decarboxylase mRNA within the barrel cortex of rats after a mystacial whisker trim.

STUDY OBJECTIVES: Determine the effects of time of day and sleep deprivation on glutamate decarboxylase 67,000 MW (GAD67) mRNA during cortical synaptic reorganization induced by a unilateral trimming of the mystacial vibrissae in rats. DESIGN: Two experiments were conducted--One measured GAD67 mRNA in the barrel cortex at 3 or 6 h after a unilateral whisker cut at either light or dark onset; the other measured GAD67 mRNA after a unilateral whisker cut at light onset with or without sleep deprivation. SETTING: University-based Research Laboratory. PARTICIPANTS: Sprague-Dawley rats (250-350 g). INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: The reverse transcriptase polymerase chain reaction was used to measure the time of day changes in GAD67 mRNA after a unilateral whisker cut. GAD67 mRNA decreased in the barrel cortex at 3 and 6 h after a whisker trim at dark onset when the rats were mainly awake. No changes were observed in GAD67 mRNA levels after a whisker cut at light onset, a time when the rats mainly sleep. In situ hybridization for GAD67 mRNA supported these findings; no changes in GAD mRNA occurred in layer 4 of the barrel cortex that received input from the mystacial whiskers that were trimmed at light onset. However, when the rats were sleep-deprived, GAD67 mRNA increased in the barrel cortex receiving input from the lip hairs surrounding the trimmed mystacial whiskers. CONCLUSIONS: These data imply that sleep modifies GAD67 mRNA expression and that this effect is dependent upon the nature of the ongoing synaptic reorganization. They support the notion that sleep serves a synaptic function.

Animals↗
PubMed2001

Sleep deprivation but not a whisker trim increases nerve growth factor within barrel cortical neurons.

Sleep is hypothesized to influence activity-driven changes in the brain microcircuitry. A change in the barrel cortex following the removal of the mystacial whiskers in rats is a model for synaptic plasticity. This model was combined with sleep deprivation and immunoreactivity for nerve growth factor (NGF) was determined. Sleep deprivation for 6 h after light onset significantly increased the number of NGF-immunoreactive pyramidal neurons in layer V of the barrel cortex. However, unilateral trimming of mystacial whiskers did not affect NGF immunoreactivity in the contralateral or ipsilateral barrel cortices when rats were allowed to sleep. If the rats received a unilateral whisker cut at light onset, and subsequently were deprived of sleep, increases in the NGF-immunoreactive neurons were only observed in the barrel cortex on the side that received input from the remaining intact whiskers. In contrast, NGF immunoreactivity on the side contralateral to the cut whiskers decreased in sleep-deprived animals to levels below those observed in the control animals that were allowed to sleep. These results suggest that NGF expression is influenced by the interaction of sleep, afferent input and the nature of ongoing synaptic reorganization. Further, results are consistent with the hypothesis that growth factors, such as NGF, form part of the mechanism responsible for sleep regulation and that they also form one facet of sleep-related synaptic plasticity.

Animals↗
PubMed2001

Conflict resolution at the end of life.

OBJECTIVE: Limited empirical research has examined how decisions are made when the preferences of terminally ill patients conflict with physicians' recommendations. This study sought to investigate physicians' strategies for resolving conflicts with dying patients. DESIGN: Cross-sectional, qualitative interviews. SUBJECTS: Subjects were 158 physicians caring for at least one terminally ill patient. SETTING: University medical center. MEASUREMENTS AND MAIN RESULTS: We analyzed physicians' responses to the open-ended interview questions, "How do you handle a situation when a patient wants a treatment that you believe does not provide any benefit?" and "How do you handle a situation when a patient does not want a treatment you think would be beneficial?" For patient requests of nonbeneficial treatments, physicians reported the following as important: negotiating with and educating patients (71%), deferring to patient requests for benign or uncomplicated treatments (34%), convincing patients to forgo treatments (33%), refusing patient requests for nonbeneficial treatment (22%), using family influence (16%), not offering futile treatments (13%), and referring to other physicians for disputed care (9%). Potential harm (23%) and cost of treatment (18%) were reasons cited for withholding treatments. In response to patient refusals of beneficial treatments, physicians report the following as important: negotiating with patients (59%), convincing patients to receive treatment (41%), assessing patient competence (32%), using family influence (27%), and referring to other physicians (21%). CONCLUSIONS: Physicians vary in the communication and negotiation strategies they use when their medical judgment conflicts with dying patients' preferences. Medical ethicists could play a greater role in teaching ethically important communication skills. Physicians providing care at the end of life report strategies for respecting patients that reflect graduated degrees of accommodation tailored to the costliness and riskiness of requests; they are most accepting of patient requests for benign, technically easy, inexpensive, and medically effective treatments.

Adult↗
PubMed1999

Involvement of the pallidal-thalamocortical circuit in adaptive behavior.

Interconnections among the ventral mesencephalon, nucleus accumbens, and ventral pallidum are critical in the initiation of adaptive behavioral responses to environmental stimuli. Within this circuit are two highly topographically organized subcircuits that are differentially interconnected with limbic and motor circuitry in the brain. However, there is not a great deal of anatomical interconnection between the limbic and motor subcircuits. A polysynaptic connection between the two subcircuits involves projections from the limbic ventral pallidum to the mediodorsal thalamus to the prefrontal cortex back to the motor regions of the nucleus accumbens. In the present report we show that this connection is critical in the expression of motor behavior elicited by opioids and the capacity of a rat to perform in a task requiring spatial working memory.

Adaptation, Psychological↗
PubMed1999

The involvement of the mediodorsal nucleus of the thalamus and the midbrain extrapyramidal area in locomotion elicited from the ventral pallidum.

Motor activity is regulated by projections from the nucleus accumbens to the ventral pallidum, but it is unclear which efferents regulate behavioral output from the ventral pallidum. Motor activity was elicited pharmacologically by microinjecting either the mu opioid receptor agonist, Tyr-D-Ala-Gly-NmePhe-Gly-OH (DAMGO) or the glutamate receptor agonist, alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionate (AMPA) into the ventral pallidum. The involvement of efferent projections was determined by microinjecting the local anesthetic procaine into the mediodorsal nucleus of the thalamus (MD) or the midbrain extrapyramidal area (MEA) prior to administering DAMGO or AMPA into the ventral pallidum. The motor activity induced by DAMGO was blocked by procaine microinjected into either the MD or the MEA. In contrast, procaine microinjected into the MD did not block motor activity elicited by AMPA while procaine into the MEA abolished the behavioral activation. These data indicate that the involvement of efferent projections from the ventral pallidum to either the MD or MEA in motor activation depends upon the type of receptor stimulated in the ventral pallidum.

Analgesics, Opioid↗
PubMed1999

Repeated cocaine alters glutamate receptor subunit levels in the nucleus accumbens and ventral tegmental area of rats that develop behavioral sensitization.

Increased glutamate transmission in the nucleus accumbens and ventral tegmental area has been proposed as a mechanism underlying sensitized behavioral responses to repeated cocaine administration. GluR1, GluR2/3, and NMDAR1 subunits of glutamate receptors were quantified from immunoblots in these brain nuclei in rats at 24 h and 3 weeks after discontinuing 1 week of daily cocaine injections. Motor behavior was monitored after the first and last injections of daily cocaine, and those rats that showed >20% increase in motor activity after the last compared with the first injection were considered to have developed behavioral sensitization. The subjects that developed behavioral sensitization showed a significant increase in GluR1 levels in the nucleus accumbens at 3 weeks but not at 24 h of withdrawal. Conversely, sensitized animals showed a significant increase in NMDAR1 and GluR1 levels in the ventral tegmental area at 1 day but not at 3 weeks of withdrawal. None of these increases occurred in the rats exposed to daily cocaine that did not develop behavioral sensitization (<20% increase in motor activity), and no changes were measured in the level of GluR2/3 in any treatment group. The functional importance of the increases in glutamate receptor subunit levels is suggested by the fact that the changes were present only in rats that developed behavioral sensitization to repeated cocaine administration.

Animals↗
PubMed1998

Dopamine depletion reorganizes projections from the nucleus accumbens and ventral pallidum that mediate opioid-induced motor activity.

Motor activity elicited pharmacologically from the nucleus accumbens by the mu-opioid receptor agonist D-Ala-Tyr-Gly-NMePhe-Gly-OH (DAMGO) is augmented in rats sustaining dopamine depletions. GABAergic projections from the nucleus accumbens to ventral pallidum and ventral tegmental area (VTA) are involved because stimulation of GABAB receptors in the VTA (by baclofen) or GABAA receptors in the ventral pallidum (by muscimol) inhibit the motor response induced by the microinjection of DAMGO into the nucleus accumbens. The present study was done to determine which of these projections is mediating the augmented DAMGO-induced motor activity that follows 6-hydroxydopamine lesions of the nucleus accumbens. The inhibition of DAMGO-induced activation by pallidal injections of muscimol was markedly attenuated in lesioned animals, whereas the inhibition by VTA injections with baclofen was greatly enhanced. A similar switch in emphasis from pallidal to mesencephalic efferents was not observed for dopamine-induced motor activity, because muscimol microinjections inhibited the response elicited by dopamine microinjection into the nucleus accumbens in all subjects. The stimulation of mu-opioid receptors in the ventral pallidum also elicits motor activation, and this is blocked by baclofen microinjection into the VTA. However, after dopamine depletion in the nucleus accumbens, baclofen in the VTA was ineffective in blocking the motor response by DAMGO in the ventral pallidum. These data reveal that dopamine depletion in the nucleus accumbens produces a lesion-induced plasticity that alters the effect of mu-opioid receptor stimulation on efferent projections from the nucleus accumbens and ventral pallidum.

Analgesics, Opioid↗
PubMed1997

Effect of structural modification of enol-carboxamide-type nonsteroidal antiinflammatory drugs on COX-2/COX-1 selectivity.

Meloxicam (5), an NSAID in the enol-carboxamide class, was developed on the basis of its antiinflammatory activity and relative safety in animal models. In subsequent screening in microsomal assays using human COX-1 and COX-2, we discovered that it possessed a selectivity profile for COX-2 superior to piroxicam and other marketed NSAIDs. We therefore embarked on a study of enol-carboxamide type compounds to determine if COX-2 selectivity and potency could be dramatically improved by structural modification. Substitution at the 6- and 7-positions of the 4-oxo-1,2-benzothiazine-3-carboxamide, alteration of the N-methyl substituent, and amide modification were all examined. In addition we explored several related systems including the isomeric 3-oxo-1,2-benzothiazine-4-carboxamides, thienothiazines, indolothizines, benzothienothiazines, naphthothiazines, and 1,3- and 1,4-dioxoisoquinolines. While a few examples were found with greater potency in the COX-2 assay, no compound tested had a better COX-2/COX-1 selectivity profile than that of 5.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1997

Expression of D1 receptor mRNA in projections from the forebrain to the ventral tegmental area.

In situ hybridization was combined with Fluoro-Gold retrograde labeling to determine if cells projecting from the forebrain to the ventral tegmental area (VTA) express D1 receptor mRNA. Cell counts were made in the prefrontal cortex, shell of the nucleus accumbens, and ventral pallidum to estimate the percentage of neurons projecting to the VTA that express D1 receptor mRNA. Retrogradely labeled cells were observed in the infralimbic and prelimbic regions of the prefrontal cortex, and up to 37% of the retrogradely labeled cells expressed D1 receptor mRNA. Double-labeled cells constituted up to 89% of retrogradely labeled neurons in the rostral shell and up to 68% in the caudal shell of the nucleus accumbens. The number of retrogradely labeled cells in the ventral pallidum that were double-labeled ranged from 13% in the rostral to less than 10% in the caudal portions. These data provide anatomical support for a role of D1 receptors in the reciprocal innervation between the forebrain and VTA.

Animals↗
PubMed1997

The ethics of providing intensive care in managed care organizations.

To provide adequate and equitable care of critically ill patients, managed care organizations need to dedicate a reasoned proportion of organizational resources to the provision of critical care, distribute these resources fairly, establish appeal mechanisms, and monitor the outcomes of critical care. As in any healthcare delivery system with limited resources, it is inevitable that there will be limits to highly technological and costly life-sustaining care. Patients, physicians, and plan administrators will need to collaborate to decide priorities for care, since difficult trade-offs will need to be made between types of care and between quality and cost of care. The use of life-sustaining treatments should be informed by patient preferences and guided by many of the established guidelines for the provision of critical care. Physicians who provide critical care in a managed care organization should provide the most skilled and compassionate care to critically ill patients within the constraints of the ethically acceptable guidelines.

Advance Directives↗
PubMed1996

The mediodorsal nucleus of the thalamus in rats--I. forebrain gabaergic innervation.

The aim of this study was to determine whether forebrain neurons projecting to the mediodorsal nucleus of the thalamus in rats express glutamate decarboxylase messenger RNA as a marker for GABAergic neurons. Forebrain glutamate decarboxylase messenger RNA-containing neurons that project to the mediodorsal nucleus were identified using a combination of retrograde tracing with Fluoro-Gold and in situ hybridization for the messenger RNA encoding the 67,000 molecular weight synthetic enzyme for GABA. Glutamate decarboxylase messenger RNA-containing afferents to the mediodorsal nucleus were observed in the olfactory tubercle, vertical limb of the diagonal band of Broca, ventral pallidum, sublenticular substantia innominata, globus pallidus, lateral preoptic area, bed nucleus of the stria terminalis and reticular nucleus of the thalamus. The largest proportions of glutamate decarboxylase messenger RNA-containing afferents to the mediodorsal nucleus were observed in the vertical limb of the diagonal band, ventral pallidal parts of the olfactory tubercle and the reticular nucleus of the thalamus. Somewhat fewer glutamate decarboxylase messenger RNA-containing, retrogradely labeled neurons were observed in the subcommissural ventral pallidum and sublenticular substantia innominata. These data suggest that a GABAergic projection from the basal forebrain to the mediodorsal nucleus of the thalamus can influence the function of this nucleus.

Animals↗
PubMed1996

The mediodorsal nucleus of the thalamus in rats--II. Behavioral and neurochemical effects of GABA agonists.

The aim of this study was to determine how GABA receptors in the mediodorsal nucleus of the thalamus in rats might contribute to the regulation of locomotor behavior. Microinjections of the GABAB and GABAA agonists, baclofen and muscimol, into the mediodorsal nucleus produced dose-dependent increases in locomotion that were blocked by co-administration of the GABAB antagonist, 2-hydroxysaclofen. Microinjection of baclofen along the midline, lateral into the ventrolateral thalamus or into the lateral ventricles produced significantly smaller dose-dependent increases in locomotion, indicating that the anatomical locus for baclofen-induced locomotion resides in the mediodorsal nucleus. The motor response elicited by microinjected baclofen was associated with a reduction in dopamine metabolism in the prefrontal cortex and an increase in metabolism in the core of the nucleus accumbens, but not in the accumbal shell or the dorsolateral striatum. These results suggest that GABAergic afferents to the mediodorsal nucleus may oppose a tonic inhibitory tone on locomotor activity. The data also suggest that the motor response produced by baclofen in the mediodorsal thalamus may arise by inhibiting the projections to the prefrontal cortex which modulate mesocorticolimbic dopamine transmission.

Animals↗
PubMed1996

p53 immunoreactivity in non-melanoma skin cancer from immunosuppressed and immunocompetent individuals: a comparative study of 246 tumours.

p53 immunoreactivity was examined in 132 cutaneous non-melanoma tumours from renal transplant recipients and in 114 histologically matched specimens from immunocompetent individuals. Skin lesions examined included 52 viral warts, 50 dysplastic keratoses, 51 intraepidermal carcinomas (IEC), 50 invasive squamous cell carcinomas (SCC) and 43 basal cell carcinomas (BCC). Overall, 51% (51/101) pre-malignant skin lesions and 45% (42/93) non-melanoma skin cancers (NMSC) showed p53 immunoreactivity, with extensive (> 50% cells positive) p53 staining in 27% (27/101) of pre-malignant and 20% (19/93) of malignant lesions. 17% (9/52) viral warts showed p53 immunoreactivity, but this was limited to focal or basal p53 staining. p53 immunoreactivity in all tumours was less in transplant than in non-transplant patients and this reached statistical significance for SCCs (p = 0.03).

Carcinoma↗
PubMed1996

Involvement of the ventral tegmental area in locomotion elicited from the nucleus accumbens or ventral pallidum.

This study was designed to evaluate the role of the circuit containing the nucleus accumbens, ventral pallidum (VP) and ventral tegmental area (VTA) in the motor stimulation produced by the microinjection of dopamine, alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) or [D-Ala2, MePhe4,Gly-ol5]enkephalin (DAMGO) into VP or the shell and core compartments of the nucleus accumbens. Initial dose-response curves revealed that dopamine was approximately equipotent at producing motor activity after microinjection into the core and shell, AMPA was more effective in the core, whereas DAMGO was more potent in the shell. A role for the VTA in the motor responses elicited by dopamine, AMPA or DAMGO microinjection into the shell, core or VP was evaluated by microinjecting the tau-aminobutyric acidB agonist baclofen into the VTA to inhibit neuronal activity. Baclofen treatment abolished the motor responses elicited by AMPA from the shell, core and VP. The motor effect of DAMGO in the VP was abolished by baclofen, whereas the response in the shell was attenuated. The motor response to dopamine was unaltered by baclofen, regardless of the injection site. These data indicate that there exist differences between the core and shell of the nucleus accumbens in the capacity of neurotransmitter analogs to elicit motor activity, and that although AMPA-induced motor activity is dependent upon neurotransmission in the VTA after microinjection into the core, shell and VP, DAMGO-induced locomotion only requires such tone after microinjection into the VP and shell.

Animals↗
PubMed1995

GABAergic projection from the ventral pallidum and globus pallidus to the subthalamic nucleus.

There exists a topographically organized projection from the globus pallidus and ventral pallidum to the subthalamic nucleus and adjacent lateral hypothalamus. The participation of GABA as a neurotransmitter in this projection was evaluated by retrograde labeling of cells in the pallidal area from an iontophoretic deposit of Fluor-Gold in the subthalamus combined with in situ hybridization for mRNA of the GABA synthetic enzyme, glutamate decarboxylase (GAD). A rostrocaudal gradient in the contribution of GABA to the projection was demonstrated with a relatively small percentage of retrogradely labeled cells in the rostral ventral pallidum containing GAD mRNA (7%) compared to the caudal globus pallidus which had over 70% of the Fluoro-Gold containing cells double-labeled for GAD mRNA. Overall the ventral pallidum contribution to the subthalamic nucleus was less GABAergic than the portion arising from the globus pallidus (35% vs. 61%, respectively).

Animals↗
PubMed1995

Dopamine depletion augments endogenous opioid-induced locomotion in the nucleus accumbens using both mu 1 and delta opioid receptors.

The aim of this study is to analyze further the opioid receptor subtypes involved in the augmentation of behavioral activity after dopamine depletion in the nucleus accumbens of rats. Initially, the opioid receptors involved in the augmentation of locomotion produced by endogenous opioids were evaluated by microinjection of kelatorphan, an inhibitor of proteolytic enzymes that inactivates enkephalin, with or without specific antagonists for mu 1 or delta-opioid receptors, naloxonazine or naltrindole, respectively. Kelatorphan produced a dose-dependent increase in horizontal photocell counts and vertical movements. At all doses examined the behavioral response was augmented in rats sustaining accumbal dopamine lesions. The augmentation in dopamine-depleted rats was partially blocked by naloxonazine or naltrindole. Since the motor stimulant response to intra-accumbens microinjection of the delta-opioid agonist, [D-penicillamine2,5]-enkephalin, was not augmented in a previous study, we tested the behavioral response to a new endogenous delta-opioid agonist, [D-Ala2] deltorphin I. The locomotor response to deltorphin was slightly augmented in dopamine-depleted rats. These data suggest that the augmentation in the motor response elicited by endogenous opioids after dopamine lesions in the nucleus accumbens involves both mu 1, and delta-opioid receptors.

Analgesics↗