Multimorbidity among persons aged 25-64 years: a population-based study of social determinants and all-cause mortality.

BACKGROUND: Despite increasing multimorbidity across the lifespan, little is known about the co-occurrence of conditions and risk factors among younger adults. This population-based study examines multimorbidity, social determinants and associated mortality among younger and middle-age adults. METHOD: Analysis was based on the Northern Ireland population aged 25-64 years enumerated in the 2011 Census (n = 878 345), with all-cause mortality follow-up to 2014 (8659 deaths). Logistic regression was used to examine social determinants and Cox proportional hazards models in the analysis of associated mortality. RESULTS: Prevalence of multimorbidity was 13.7% in females and 12.7% in males. There was a strong association between multimorbidity that included mental/cognitive illness and deprivation. Among those never married, multimorbid physical conditions were less likely [relative risk ratios (RRR) = 0.92: 95% confidence interval (CI) = 0.88, 0.95 for males; and RRR = 0.90: 0.87, 0.94 for females]. Rurality was associated with lower physical multimorbidity (RRR = 0.92: 0.89, 0.95) but higher mental/cognitive multimorbidity (RRR = 1.35: 1.12, 1.64) among females. All multimorbid categories were associated with elevated risk of mortality. CONCLUSION: The health and economic challenges created by multimorbidity should be addressed further 'upstream'. Future multimorbidity research should include younger adults to inform the development of preventative interventions and align health and social care services more closely with patients' needs.

Distinct neurochemical populations in the rat central nucleus of the amygdala and bed nucleus of the stria terminalis: evidence for their selective activation by interleukin-1beta.

The lateral division of the central nucleus of the amygdala (CEAl) and the oval nucleus of the bed nucleus of the stria terminalis (BSTov) have been linked closely anatomically and functionally. To determine whether these regions may be subdivided further on a neurochemical basis, dual in situ hybridization was used to determine the colocalization of corticotropin-releasing hormone (CRH), enkephalin (ENK), or neurotensin (NT) with glutamic acid decarboxylase isoforms 65 and 67 [used concurrently as a marker for gamma-aminobutyric acid GABA] in these nuclei. It was found that, for both regions, each peptide invariably was localized in a GABAergic cell. Although there was a similar overlap in the distribution of NT with ENK in the BSTov and CEAl, it was observed that CRH and ENK rarely were colocalized in either nucleus. To determine whether these distinct neuronal populations could be activated differentially, male rats were given a systemic injection of interleukin-1beta (IL-1beta; 5 microg/kg, i.p.), a stimulus that results in a robust increase in c-fos mRNA expression in the BSTov and CEAl. The neurochemical identity of these activated neurons showed striking similarities between the BSTov and the CEAl; All IL-1beta-responsive cells were GABAergic, the majority of c-fos- positive cells expressed ENK mRNA (BSTov, 81%; CEAl, 94%), and some expressed NT mRNA (BSTov, 23%; CEAl, 22%), whereas very few expressed CRH mRNA (BSTov, 4%; CEAl, 1%). These data provide evidence for the existence of discrete neural circuits within the BSTov and CEAl, and the similarities in the patterns of neurochemical colocalization in these nuclei are consistent with the concept of an extended amygdala. Furthermore, these data indicate that intraperitoneal IL-1beta recruits neurochemically distinct pathways within the BSTov and CEAl, and it is suggested that this differential activation may mediate specific aspects of immune, limbic, and/or autonomic processes.

Psychomotor stimulant- and opiate-induced c-fos mRNA expression patterns in the rat forebrain: comparisons between acute drug treatment and a drug challenge in sensitized animals.

Amphetamine-, cocaine-, and morphine-induced c-fos expression patterns were examined following an injection protocol that has previously been shown to produce behavioral sensitization and enhanced dopamine release in the striatal complex. Drug-specific c-fos patterns were observed in both acute and sensitization injection paradigms. A sensitization pretreatment schedule did, however, alter the c-fos expression patterns induced by all the drugs in the caudate putamen, nucleus accumbens, and the cerebral cortex. In some striatal and cortical regions, there was an increase or recruitment of cells expressing c-fos whereas in others there was an apparent decrease or inhibition. The somatosensory cortex was one area where pretreatment with all three drugs increased c-fos expression. The results suggest that the neuronal networks that are modulated by systemic drug injections in the sensitized animal differ from those affected by the initial drug exposure; areas of overlap may indicate common "sensitization' circuits.

Dopamine receptor mRNA expression patterns by opioid peptide cells in the nucleus accumbens of the rat: a double in situ hybridization study.

Colocalization of proenkephalin and prodynorphin mRNAs with each other as well as with D1, D2, and D3 dopamine receptor mRNAs was analyzed in the nucleus accumbens of the rat. Distinct combinations were detected in the rostral pole, core, and shell subdivisions of the nucleus accumbens. Proenkephalin and prodynorphin mRNAs were principally localized in separate cells in the core. All detectable prodynorphin cells in the core expressed D1 mRNA but not D2 mRNA. Conversely, approximately 95% of the proenkephalin-positive cells in this region expressed D2 mRNA but not D1 mRNA. This pattern was identical to that observed in the caudate putamen. In the rostral pole and the shell, embedded in a background of this "typical" colocalization pattern, clusters of cells expressing a distinct configuration were found. In these clusters, proenkephalin-positive cells expressed both prodynorphin and D1 mRNAs, but they did not express D2 mRNA. D3 and prodynorphin mRNAs were colocalized in "limbic" striatal areas, including the ventromedial caudate putamen, the rostral pole, and the medial shell. In contrast, D3 mRNA was not detected in any proenkephalin-positive cells. Together with the prodynorphin/D1 data, this suggests that a subset of prodynorphin cells expresses both D1 and D3 mRNAs. It is concluded that 1) clusters of cells that coexpress proenkephalin, prodynorphin, and D1 mRNAs overlap extensively with previously defined cytoarchitectural cell clusters in the nucleus accumbens and 2) a subset of the prodynorphin cells in the ventromedial caudate putamen and the nucleus accumbens contains both D1 and D3 mRNAs.

Adrenal medulla grafts in the hemiparkinsonian rat: profile of behavioral recovery predicts restoration of the symmetry between the two striata in measures of pre- and postsynaptic dopamine function.

Following unilateral striatal dopamine depletion, the hemiparkinsonian rat exhibits rotational behavior in response to amphetamine and apomorphine. The rotational behaviors induced by these drugs are thought to reflect an asymmetry in presynaptic striatal dopamine release and an asymmetry in postsynaptic striatal dopamine receptor function, respectively. Grafts of adrenal medulla cells in the lateral ventricle of hemiparkinsonian rats have been reported to reduce behavioral asymmetry. More than one profile of behavioral recovery, however, is observed. Some animals show a graft-induced decrease only in the response to apomorphine, but others show a decrease in the response to amphetamine, and still others show a decrease in the behavioral responses to amphetamine and apomorphine. In this report, amphetamine- and apomorphine-induced turning behaviors were determined in hemiparkinsonian rats prior to and following intraventricular grafts of adrenal medulla or control tissue. Both bilateral intrastriatal microdialysis in freely moving animals and quantitative dopamine receptor autoradiography procedures were conducted in each animal so as to determine the relations between pre- and postsynaptic dopaminergic measures as well as the association between these measures and the different profiles of behavioral recovery after adrenal medulla grafts. We report here that in animals with an adrenal medulla graft-induced decrease in the behavioral response to amphetamine, the balance between the two striata in extracellular striatal dopamine concentrations and D2 dopamine receptor binding was restored. Furthermore, enhanced extracellular striatal dopamine concentrations were highly correlated with the graft-induced symmetry in striatal D2 dopamine receptor binding. In contrast to animals with decreased amphetamine-induced turning, in animals with a graft-induced decrease exclusively in response to apomorphine, the presynaptic symmetry was not restored and there was a significantly smaller effect on D2 receptor binding. We conclude that those animals that show decreased amphetamine-induced turning after adrenal medulla grafts had the most effective grafts, and suggest that methods designed to optimize this behavioral profile are most likely to lead to enhanced clinical efficacy with this procedure.

Changes in blood-brain barrier permeability are associated with behavioral and neurochemical indices of recovery following intraventricular adrenal medulla grafts in an animal model of Parkinson's disease.

Intraventricular adrenal medulla grafts were found to produce dissociable effects on rotational behavior induced by amphetamine and apomorphine in rats with unilateral striatal dopamine depletions. Some animals showed a decrease in the behavioral response to apomorphine, some showed a decrease to amphetamine, and some showed a decrease to both amphetamine and apomorphine. Using in vivo microdialysis, the experiments reported demonstrate that in animals with decreased rotational behavior, assessed with either amphetamine or apomorphine, there was an increase in the permeability of the blood-brain barrier to dopamine. The increased blood-brain barrier permeability was visually confirmed with horseradish peroxidase. The extent of the blood-brain barrier disruption, however, was greater in animals with a decreased response to amphetamine. Animals that exhibited decreased amphetamine-induced turning after adrenal medulla grafts also had a greater amphetamine-stimulated increase in striatal dopamine and greater extracellular striatal dihydroxyphenylacetic acid concentrations compared to controls and animals with a graft-induced decrease in the response to apomorphine. We conclude that more than one mechanism is involved in mediating the behavioral effects of adrenal medulla grafts.

Adrenal medulla graft induced recovery of function in an animal model of Parkinson's disease: possible mechanisms of action.

Following unilateral dopamine (DA) denervation of the striatum in animals, there is an asymmetry in the striatal DA system. Animals with such denervations will rotate vigorously when given dopaminergic drugs. Adrenal medulla grafts placed in the lateral ventricle adjacent to a DA-denervated striatum decrease rotational behaviour induced by DA receptor agonists or DA-releasing agents. This discussion reviews research on the use of adrenal medulla grafts to reverse behavioural deficits following DA-denervation of the striatum. Results from basic animal research and from the application of the procedure to patients with Parkinson's disease suggests that at least three different fundamental processes may mediate the functional effects of adrenal medulla grafts: (a) Adrenal medulla grafts may induce changes in the blood-brain barrier; (b) adrenal medulla grafts may induce an increase in serum DA; and (c) adrenal medulla grafts may have a trophic effect on the host brain. Hypotheses are proposed to explain the behavioural effects of adrenal medulla grafts in light of the processes that are thought to mediate their effects.

Factors affecting time allocations of teaching physicians.

Regression analysis was used to determine the relative influence of amounts of compensation from patient care and research, as well as teaching hospital characteristics, specialty, and compensation arrangements (strict full time versus geographic full time), on teaching physicians' time allocation between patient care and teaching/research activities. The results show that the amounts of compensation and the compensation arrangements have some effects, but physician specialty, hospital size and ownership, and whether the hospital's patients are private or non-private are more important determinants of their time allocations.