Biomedical subjects

A M Murray

Publications and source records attributed to A M Murray.

At least 37 records · Page 2Linked to original sources

PubMed1996

Distribution of dopamine D1-D4 receptor subtypes in human dorsal vagal complex.

The distribution of D1/D5, D2/D3, D2/D3/D4, and individually, putative D2-D4 receptors across the dorsal vagal complex of the human medulla was assessed with quantitative receptor autoradiography. D1/D5 receptors were found in very low levels. D2 receptors were concentrated in the intermediate and medial subnuclei of the nucleus of the solitary tract (NTS), and in the dorsal motor nucleus of the vagus (DMN), while D3 receptors were more homogeneous across the entire NTS, area postrema (AP), and DMN. In contrast, D4 receptors were found almost exclusively in the intermediate and medial subnuclei of the NTS, and in the DMN. These findings suggest that the "D2 family" of receptors is an important component of brain stem mechanisms regulating visceral function, including gastrointestinal systems, such as emesis, along with cardiovascular and pulmonary systems. Compounds with individual selectivity for D2, D3, or D4 receptors may be useful in the manipulation of neural networks regulating these visceral systems.

Adolescent↗

PubMed1995

Differences in intraepithelial lymphocyte T cell subsets isolated from murine small versus large intestine.

Intraepithelial lymphocytes (IELs) have been extensively studied in the murine small intestine. However, to date no studies have assessed IEL in the large intestine, despite the marked differences in function and lumenal environment. In the present study, we isolated IEL from both small and large intestine of three mouse strains (BALB/c, C3H/HeN, C57BL/6) and determined the frequency of CD2, CD4, and CD8 expression on CD3+ IEL, as well as the frequency of alpha beta and gamma delta TCR usage and V beta distribution. Higher numbers of IEL/unit length were always isolated from the small intestine (20-30 x 10(6)/5 mice) compared with large intestine (1.1-2.5 x 10(6)/5 mice). Interestingly, IEL from the large intestine of all strains were predominantly alpha beta TCR+ whereas gamma delta TCR+ IELs predominated in small intestine. Large intestinal IELs were mainly CD4+, in both BALB/c and C3H/HeN mouse strains. IELs from large intestine of C57BL/6 mice were mainly CD8+; however, the CD4+ subset was fourfold higher when compared with small intestine IEL. Potential functional differences between IEL subsets was assessed by determining the relative levels of mRNA for IL-1, 2, 4, 5, 10, IFN-gamma, TGF-beta, and TNF-gamma. Similar patterns of IL-1, IFN-gamma and TNF-alpha were seen while more IL-2, IL-4, IL-5, and IL-10 mRNA was noted in large intestinal IEL. Stimulation of C3H/HeJ IEL with anti-CD3 also resulted in higher levels of IL-3/GM-CSF, IL-4, and IL-6 by IEL from large intestine. These results show that marked differences occur among the T cell subsets present in IELs from mouse small and large intestine.

Animals↗

PubMed1995

Damage to dopamine systems differs between Parkinson's disease and Alzheimer's disease with parkinsonism.

Parkinsonism occurs in approximately 35 to 40% of patients with Alzheimer's disease (AD) even with little or no neuronal degeneration in the substantia nigra, which in idiopathic Parkinson's disease (PD) results in the severe loss of striatal dopamine transporter sites. It is not known if there is a loss of striatal dopamine transporter sites in AD with coexistent parkinsonism (AD/parkinsonism). We quantified the pattern of these sites in the striatum and midbrain of patients with the clinical diagnosis of PD, AD, and AD/parkinsonism in comparison with a group of age-matched control subjects. We also quantified the number of D2 receptors and the levels of tyrosine hydroxylase in the substantia nigra and ventral tegmental area of the same groups. The results showed that in AD the loss of dopamine transporter sites was restricted to the nucleus accumbens. The loss of these sites in the AD/parkinsonism group was more extensive than in the AD group, with the most severe losses in the rostral caudate and putamen and least in the caudal caudate and putamen. While the PD group showed an equally severe reduction in numbers of sites, the caudal to rostral gradient of loss differed from that in the AD/parkinsonism group. The PD group also showed a marked loss of dopamine transporter sites, tyrosine hydroxylase, and D2 autoreceptors (located on dopamine neurons) in the substantia nigra and ventral tegmental area. In contrast, no reductions in dopamine transporter sites, tyrosine hydroxylase, and D2 autoreceptors were observed in the substantia nigra and ventral tegmental area of the AD or AD/parkinsonism groups. Thus, the loss of striatal dopamine transporter sites in AD/parkinsonism may be related to the clinical parkinsonian symptoms. However, the loss is not simply the result of neuronal degeneration in the substantia nigra, but must derive from other processes.

Aged↗

PubMed1995

Peritoneal cavity CD5 (Bla) B cells: cytokine induced IgA secretion and homing to intestinal lamina propria in SCID mice.

The mouse peritoneal cavity contains a unique population of B cells (Bla) with a high IgM/low IgD ratio, CD5+ (Ly1), MAC-1 + phenotype. These cells arise early in ontogeny, utilize a limited repertoire of immunoglobulin V genes, produce polyreactive IgM antibodies and have been implicated as the source of many auto-reactive immunoglobulins. Recent data from chimeric mice suggest that this B cell population also contains the precursors of many IgA plasma cells found in the lamina propria of the small intestine. In the present study we have investigated the potential of this cell population to secrete IgA (and IgG) in response to various cytokines. IL-5 alone, or in combination with IL-2, greatly enhanced secretion of both IgG and IgA. Cytokine-induced IgA secretion resulted from expansion of a subset of CD5 B cells co-expressing sIgA. Adoptive transfer of CD5 B cells while peripheral lymph nodes contained only IgM+ and some IgG+ B cells. Transfer of CD5+ B cells also reconstituted serum IgM, IgG and IgA and IgG, immunoglobulins characteristic of mucosal and anamnestic responses, when cultured in vitro with the appropriate cytokines. These cells also give rise to IgA plasma cells in the intestinal lamina propria following adoptive transfer to SCID mice, further supporting the hypothesis that cells of this lineage may be important in immune responses at mucosal surfaces.

Animals↗

PubMed1995

Distribution of putative D4 dopamine receptors in postmortem striatum from patients with schizophrenia.

The identification of five dopamine receptor subtypes has given the dopamine hypothesis of schizophrenia new life. The D4 receptor is particularly intriguing because it binds clozapine with high affinity. Putative D4 receptors were labeled in postmortem human brain by subtracting the binding of a saturating concentration of 3H-raclopride (6 nM, which labels D2 and D3 receptors) from that labeled by a saturating concentration of [3H]YM 09151-2 (1-1.3 nM, which labels D2, D3, and D4 receptors). In the control brain, putative D4 receptors show a homogenous distribution in striatum and nucleus accumbens. This is also true in schizophrenic brains, although the levels are significantly higher (twofold). These data are inconsistent with mRNA studies that have shown negligible amounts in striatum and accumbens, with modest amounts reported in most of cerebral cortex. These findings suggest that the putative D4 receptors are not synthesized in this region, but are presynaptically localized on striatal afferent terminals. Our findings confirm and extend the report of Seeman et al. (1993). Extension of these findings into the nucleus accumbens is important because of its extensive connections to the limbic system while the putamen is exclusively "motor" striatum.

Adult↗

PubMed1994

Localization of dopamine D3 receptors to mesolimbic and D2 receptors to mesostriatal regions of human forebrain.

We characterized the binding of [125I]epidepride to dopamine D2-like and D3-like receptors in tissue sections of human striatum. The competition for binding of [125I]epidepride by domperidone, quinpirole, and 7-hydroxy-N,N-di(1-propyl)-2-aminotetralin (7-OH-DPAT) was best fit by assuming one site in the caudate but two sites in nucleus accumbens. Guanosine 5'-[beta, gamma-imido]triphosphate showed a large modulatory influence in agonist inhibition of [125I]epidepride binding in caudate but not in nucleus accumbens. The binding of [125I]epidepride in the presence of 7-OH-DPAT (1000-fold selective for D3-like versus D2-like sites) and domperidone (20-fold selective for D2-like versus D3-like sites) was used to quantify the numbers of D2-like and D3-like receptors in areas of human brain. The distribution of D2-like and D3-like receptors was largely nonoverlapping. Binding of [125I]epidepride to D3-like receptors was negligible in the dorsal striatum but was concentrated in islands of dense binding in the nucleus accumbens and ventral putamen that aligned with acetylcholinesterase-poor striosomes. Binding to D3-like receptors was also enriched in the internal globus pallidus, ventral pallidum, septum, islands of Calleja, nucleus basalis, amygdalostriatal transition nucleus of the amygdala, central nucleus of the amygdala, and ventral tegmental area. Binding of [125I]epidepride to D2 but not D3 receptors was detected in cortex and hippocampus.

Autoradiography↗

PubMed1993

Acute delirium and functional decline in the hospitalized elderly patient.

BACKGROUND: Delirium is often considered a transient cognitive syndrome. Its effect on long-term physical function, however, has not been well defined. METHODS: In a prospective study of 325 hospitalized community and nursing home elderly, we analyzed the effect of in-hospital delirium on subsequent physical function. ADL performance was assessed prior to admission, and at 3 and 6 months after hospital discharge. RESULTS: There was a strong univariate (unadjusted) association between incident delirium and functional decline (p < .02). Delirious subjects lost a mean of almost one ADL, as measured 3 months after hospital discharge. Using multivariate linear regression analysis, with adjusted change in function as the dependent variable, delirium persisted as the sole predictor of loss of function (p = .009) at 3 months after discharge. The functional decline persisted at 6 months after hospital discharge. CONCLUSION: This finding of a nontransient, perhaps permanent consequence of delirium invites reexamination of the definition of delirium from that of an acute, reversible syndrome to one of acute onset with long-term sequelae.

Activities of Daily Living↗

PubMed1993

Induction of phenotypic changes in SCLC cell lines in vitro by hexamethylene bisacetamide, sodium butyrate, and cyclic AMP.

BACKGROUND: Hexamethylene bisacetamide (HMBA), sodium butyrate (NaBt), and cyclic AMP (cAMP) have been shown to induce differentiation, which may regulate tumour growth differently from conventional cytotoxic drugs. It was the intention in the present study to determine whether alterations could be induced in the phenotype of small cell lung cancer (SCLC) cell lines with HMBA, NaBt and cAMP, and whether these alterations would correlate with reduced growth in vivo, implying a phenotypic shift from malignancy towards differentiation. MATERIALS AND METHODS: The cell lines were NCI-H69, H187 and H128. The activity of dopa decarboxylase (DDC), the BB isozyme of creatine kinase (CK-BB), the synthesis of bombesin-like peptide (BLI), and the presence of neurone specific enolase (NSE) and chromogranin were used as markers of the small cell phenotype. Clonogenicity in suspension in agar, and growth as xenografts in nude mice, were used as malignancy-associated properties. Cell proliferation in vitro was determined by cell counting and growth curve analysis. RESULTS: HMBA, NaBt and cAMP were found to be reversibly cytostatic in liquid culture and pre-exposure reduced the cloning efficiency in agar by 60%-80%. Growth as xenografts was inhibited (three- to five-fold increase in the tumour doubling time), most significantly by NaBt. Effects of phenotypic markers were more complex. The most significant were a two-fold reduction in DDC with NaBt and HMBA, a 50% increase in CK-BB with cAMP, and a 70%-100% increase in secreted BLI with HMBA and cAMP, in NCI-H69 cells. No significant effects were seen on NSE and chromogranin. There was little sign of an interaction with adriamycin and vincristine, although a slight increase was observed in the ID50 of VP-16 following treatment with cAMP. CONCLUSIONS: NaBt, HMBA and cAMP were cytostatic and inhibited tumour growth, but there was no coordinated response in marker expression that would confirm phenotypic alteration indicative of differentiation. The problem of defining differentiation in SCLC further complicated the analysis. The possibility remains of combining these agents with conventional cytotoxics as there appears to be little antagonistic effect, and other studies have suggested synergism may be possible with correct scheduling.

Acetamides↗

PubMed1992

Visualization of dopamine D3-like receptors in human brain with [125I]epidepride.

In sections of human brain containing the striatum (caudate, nucleus, putamen, nucleus accumbens) the competition for binding of [125I]epidepride by compounds with differing selectivity for dopamine D2 and D3 receptors was examined. Domperidone showed higher affinity for D2-like than D3-like sites whereas 7-OH-DPAT (7-hydroxy-2-(N,N-di-n-propylamino)tetralin) and quinpirole demonstrated the reverse selectivity. The pattern of [125I]epidepride binding in the presence of a high concentration of domperidone was negligible in the dorsal striatum but indicated islands of dense binding to D3-like receptors in the nucleus accumbens and ventral putamen.

Autoradiography↗

PubMed1990

The interaction of clozapine with dopamine D1 versus dopamine D2 receptor-mediated function: behavioural indices.

Studies were undertaken to clarify further the mechanism(s) of action of the atypical neuroleptic clozapine, using a behavioural model with the ability to distinguish between relative antagonism of D1 vs. D2 dopamine receptor-mediated function. Pretreatment with low doses of clozapine (2.5-25.0 mg/kg) readily antagonised intense grooming induced by the selective D1 agonist SK&F 77434 (0.75 mg/kg), and in a less consistent manner antagonised hyperactivities induced by the selective D2 agonist LY 163502 (0.05 mg/kg). In animals whose typical responses to SK&F 77434 were antagonised by clozapine, no atypical behaviours such as vacuous chewing emerged. However, in animals whose typical responses to LY 163502 were antagonised by clozapine, a syndrome of atypical limb/body jerking was released. Despite clozapine showing comparable affinities for D1 and D2 receptors in vitro, this behavioural profile shows similarities to that seen when these agonists are given after pretreatment with a selective D1 antagonist, rather than with a selective D2 antagonist or with non-selective neuroleptics. These results suggest that clozapine has some preferential though not selective action in vivo to antagonise D1 dopamine receptor-mediated function.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

PubMed1990

New putative selective agonists at the D-1 dopamine receptor: behavioural and neurochemical comparison of CY 208-243 with SK&F 101384 and SK&F 103243.

Three putative D-1 agonists with nonbenzazepine structures were compared with the prototype benzazepine D-1 partial agonist SK&F 38393 for their behavioural effects in the intact adult rat, and for their relative affinities for D-1 and D-2 dopamine receptors in vitro. SK&F 103243, a restricted conformation analogue of SK&F 38393, and SK&F 101384 (8-Cl-ADTN) showed low affinity for D-1 and D-2 receptors in in vitro binding studies, and failed to induce any behavioural effects on peripheral administration. CY 208-243, an indolophenanthridine derivative, showed appreciable affinity not only for D-1 receptors but also for D-2 receptors, while in behavioural studies it showed some of the characteristics of a partial D-1 dopamine receptor agonist; thus, it failed to promote stereotyped behaviour, but induced episodes of intense grooming which were sensitive to blockade by the D-1 antagonist SCH 23390. No such effect was induced by the selective D-2 agonist RU 24213. CY 208-243 is the first nonbenzazepine which shows some of the properties of a D-1 agonist in the intact adult animal. However, the differences between its in vitro binding characteristics and its functional properties remain enigmatic.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

PubMed1990

Propofol for long-term sedation in the intensive care unit. A comparison with papaveretum and midazolam.

Thirty-seven patients with a wide range of illnesses were studied during mechanical ventilation of the lungs in an intensive care unit. Fifteen were sedated with a continuous propofol infusion, with analgesia provided by bolus doses of papaveretum. Twelve received a continuous infusion of papaveretum, supplemented by bolus doses of midazolam. The level of sedation was assessed every four hours and measurements were made of haemodynamic and respiratory variables. Levels of sedation were generally satisfactory in both groups. Six patients who received propofol required the use of muscle relaxants, because of their strong respiratory drives, to achieve synchronisation with the ventilator. There was no significant difference in respiratory or haemodynamic variables between the groups, but several patients required inotropic support because of their disease. There was no evidence of inhibition of adrenal steroidogenesis in the propofol group. Propofol can be a useful sedative agent in the intensive care unit, but sedative regimens should be tailored to individual patient requirements.

Adolescent↗

PubMed1989

Outcomes of cardiopulmonary resuscitation in the elderly.

STUDY OBJECTIVE: To determine the success rate of cardiopulmonary resuscitation in the elderly and to define characteristics of elderly patients for whom cardiopulmonary resuscitation is effective. DESIGN: Retrospective chart review. SETTING: Five Boston health-care institutions: two acute-care hospitals; two chronic-care hospitals; and one long-term-care institution. PATIENTS: Five hundred and three consecutive patients aged 70 and over who received cardiopulmonary resuscitation. MEASUREMENTS AND MAIN RESULTS: Of 503 patients, 112 (22%) survived initially but only 19 (3.8%) survived to hospital discharge. The poorest outcomes were for patients with unwitnessed arrests (1 of 116 survived), terminal arrhythmias such as asystole and electromechanical dissociation (1 of 237 survived), and patients with cardiopulmonary resuscitation lasting more than 15 minutes (1 of 360 survived). Only 2 (0.8%; CI, 0.0% to 2.0%) of 244 patients with out-of-hospital cardiopulmonary arrests left the hospital alive. Of 259 patients with in-hospital arrests, 17 (6.5%; CI, 3.4% to 9.6%) survived to discharge. Most survivors had ventricular arrhythmias and were resuscitated within minutes. Initial survivors with either impaired consciousness or functional impairment after the arrest had significantly worse chances of survival than patients without these impairments. CONCLUSION: Cardiopulmonary resuscitation is rarely effective for elderly patients with cardiopulmonary arrests that are either out-of-hospital, unwitnessed, or associated with asystole or electromechanical dissociation.

Age Factors↗

PubMed1989

The induction of grooming and vacuous chewing by a series of selective D-1 dopamine receptor agonists: two directions of D-1:D-2 interaction.

A range of 3- and 6-substituted 1-phenyl-1H-3-benzazepine analogues of SK&F 38393 with D-1 agonist activity were compared for their behavioural effects in the intact adult rat and for their relative affinities for D-1 and D-2 dopamine receptors in vitro. All compounds showed selective affinity for D-1 receptors and induced prominent grooming behaviour, but those with the lower D-1:D-2 selectivity ratios also induced additional episodes of non-stereotyped sniffing, locomotion and rearing. No vacuous chewing was noted. There were marked differences in in vivo potency, extending over a 100-fold range. These responses to the most potent agonist, SK&F 77434 (3N-allyl-SK&F 38393) were reduced enantioselectively by the D-1 antagonist R-SK&F 83566. They were also reduced enantioselectively by the D-2 antagonist R-piquindone, but this pretreatment additionally released a marked vacuous chewing response to SK&F 77434. Prominent grooming may be a characteristic behavioural response to a range of D-1 agonists. It is suggested that there may be at least two forms of functional interaction between D-1 and D-2 systems, manifested concurrently in distinct elements of behaviour: one co-operative, as in the regulation of grooming, and with correlates in the regulation of pallidal neural activity; the other oppositional, as in the regulation of vacuous chewing, and with correlates in the regulation of striatal adenylate cyclase activity.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

PubMed1989

Further evidence for two directions of D-1:D-2 dopamine receptor interaction revealed concurrently in distinct elements of typical and atypical behaviour: studies with the new enantioselective D-2 agonist LY 163502.

The new, extremely potent and enantioselective D-2 agonist LY 163502 failed to induce compulsive stereotyped behaviour. Very low doses (3-6 micrograms/kg) inhibited spontaneous sniffing and locomotion, while higher doses (12-50 micrograms/kg) induced episodes of non-stereotyped sniffing and chewing; these actions showed complete enantioselectivity. Up to 200-fold higher doses modestly induced only locomotion. Responsivity to LY 163502 was enantioselectively blocked by the selective D-2 antagonist R-piquindone. This responsivity was also enantioselectively blocked by the selective D-1 antagonist R-SK&F 83566 but, additionally, episodes of atypical limb/body jerking behaviour were released; thus, LY 163502 induced such jerking only when tonic D-1 activity was suppressed. These data extend our notion that there may be at least two forms of functional interaction between D-1 and D-2 receptor systems: one cooperative, as in the regulation of typical sniffing, and another oppositional, as in the regulation of atypical jerking.

Animals↗

PubMed1989

Crystalloid versus colloid for circulatory preload for epidural caesarean section.

Sixty mothers were randomly allocated to receive either 2 litres of crystalloid or 1 litre of colloid solution (hydroxyethyl starch) in order to preload the circulation prior to elective Caesarean section under epidural anaesthesia. There were no differences in the incidence of hypotension, degree of haemodilution, umbilical cord blood gas tensions or umbilical blood osmolalities between the two groups.

Adult↗

PubMed1989

Discontinuation of orthodontic treatment: a study of the contributing factors.

The article reports on a project to determine the percentage of orthodontic patients who failed to complete orthodontic treatment at the Eastman Dental Hospital, London, and to identify factors that appeared to influence this. Records of patients who had undergone active orthodontic treatment which concluded either with successful completion, or early termination due to poor attendance, inadequate oral hygiene, or appliance maintenance, were studied and analysed statistically.

Adolescent↗

PubMed1989

Magnets and orthodontics.

The first part of this paper is a literature review of magnets and their uses in orthodontics. The biological safety of magnets is considered and a report is given of experiments carried out on rat osteosarcoma cell line UMR-106. The second part of the paper describes a case where neodynium-iron-boron magnets were used to assist eruption of an unerupted, vertically impacted upper right canine. Previously, space was available for this tooth, but it failed to show signs of eruption. Following surgical attachment of a magnet, and the use of a second magnet attached to an upper removable appliance, rapid eruption occurred producing a favourable position for bonding.

Animals↗