Optimising the ISAR-HP to screen efficiently for functional decline in older patients.

INTRODUCTION: The Identification of Seniors At Risk-Hospitalised Patients (ISAR-HP) has recently been included in guidelines as a frailty indicator to identify patients for comprehensive geriatric assessment. Previous studies showed that the conventional cut-off score incorrectly classifies a high percentage of patients as high risk. We aimed to optimise the predictive value of ISAR-HP by using different cut-offs in older acutely hospitalised patients. METHODS: A prospective follow-up study was performed in two Dutch hospitals. Acutely hospitalised patients aged ≥ 70 years were included. Demographics, illness severity parameters, geriatric measurements and the ISAR-HP scores were obtained at baseline. The primary outcome was a combined end point of functional decline or mortality during 90-day follow-up. RESULTS: In total 765 acutely hospitalised older patients were included, with a median age of 79 years, of whom 276 (36.1%) experienced functional decline or mortality. The conventional ISAR-HP cut-off of ≥ 2 assigned 432/765 patients (56.5%) as high risk, with a positive predictive value (PPV) of 0.49 (95%CI 0.45-0.54) and a negative predictive value of 0.81 (95%CI 0.76-0.85). Thus, 51% of those whom the ISAR-HP denoted as high risk did not experience the outcome of interest. Raising the cut-off to ≥ 4 assigned 205/765 patients (26.8%) as high risk, with a marginally increased PPV to 0.55 (95%CI 0.48-0.62). CONCLUSION: The ISAR-HP with the conventional cut-off of ≥ 2 incorrectly identifies a large group of patients at high risk for functional decline or mortality and raising the cut-off to 4 only marginally improved performance. Caution is warranted to ensure efficient screening and follow-up interventions.

Regional and cellular distribution of serotonin 5-hydroxytryptamine2a receptor mRNA in the nucleus accumbens, olfactory tubercle, and caudate putamen of the rat.

This paper describes the regional and cellular distribution of serotonin 5-hydroxytryptamine2a (5-HT2a) receptor mRNA in (sub)regions of the rat striatum by using in situ hybridization. Our results indicate that 5-HT2a mRNA is distributed heterogeneously in this brain region. Regional densitometry of autoradiograms from striatal sections hybridized with isotope-labeled cRNA probes showed that mRNA levels were highest in the olfactory tubercle, lower in the nucleus accumbens, and lowest in the caudate-putamen. In the nucleus accumbens, the average mRNA levels in the shell were higher than those in the core. These data suggest a particular relevance for the 5-HT2a receptor for olfactory tubercle- and shell-related functions. Therefore, in the nucleus accumbens and the olfactory tubercle, the cellular localization of 5-HT2a mRNA was investigated by determining the colocalization of 5-HT2a mRNA with enkephalin mRNA or dynorphin mRNA. 5-HT2a mRNA was found in enkephalinergic as well as dynorphinergic neurons. Thus, there does not seem to be a differential distribution of this receptor in the output routes of the ventral striatum. In all of the subregions investigated (core, medial shell, and lateral shell of the nucleus accumbens and the olfactory tubercle), only subpopulations of the total enkephalinergic and dynorphinergic populations were found to contain 5-HT2a mRNA. For enkephalin, the percentage colocalization was higher in the lateral shell (61%) compared with the other subregions (38-45%). For dynorphin, the percentage colocalization was higher in the olfactory tubercle (68%) than in the other subregions (34-43%). The differences in (sub)regional mRNA levels and in colocalization with opioids suggest a considerable regional differentiation in the effects of 5-HT2a-mediated neurotransmission in the striatum.

Delayed occurrence of enhanced striatal preprodynorphin gene expression in behaviorally sensitized rats: differential long-term effects of intermittent and chronic morphine administration.

Protracted changes in basal "steady-state" opioid peptide gene expression in the brain may represent adaptations underlying the behavioral effects of drugs of abuse, observed long after drug exposure. Here, we have studied the long-term effects of two distinct regimens of morphine administration ("intermittent" vs "chronic" morphine treatment) on behavioral sensitization and "steady-state" striatal preprodynorphin and preproenkephalin gene expression in rats. Opioid peptide gene expression was investigated using in situ hybridization at three rostrocaudal levels (rostral, intermediate and caudal) of the caudate-putamen and the nucleus accumbens. Behavioral studies showed that the intermittent morphine treatment resulted in a significantly greater enhancement of morphine-induced locomotion than the chronic morphine treatment three weeks after cessation of opiate exposure. The intermittent morphine treatment resulted in an initial decrease of preprodynorphin gene expression of about 5-10% in the caudate-putamen and the nucleus accumbens at the rostral and intermediate levels one day after the last morphine administration. In contrast, a protracted increase of preprodynorphin gene expression of about 20% throughout the caudate-putamen and of about 6% in intermediate sections of the nucleus accumbens was observed 21 days after cessation of intermittent morphine treatment. Although the chronic morphine treatment induced a decrease of preprodynorphin messenger RNA levels one day after the last administration, no significant changes were observed three weeks after cessation of chronic morphine treatment. No long-term changes were observed in preproenkephalin gene expression after either morphine treatment. Since the intermittent morphine administration induced long-term behavioral sensitization much more effectively than the chronic morphine treatment, we tentatively suggest that the protracted increase of preprodynorphin gene expression may play a facilitative role in the long-term character of opiate-induced behavioral sensitization.

Co-localization of mu opioid receptor is greater with dynorphin than enkephalin in rat striatum.

Using a combination of radioactive and non-radioactive in situ hybridization, the mu opioid receptor mRNA was localized in enkephalin as well as dynorphin neurones of the rat striatum. The proportion of enkephalin neurones showing co-localized mu opioid receptor mRNA was dependent on the rostrocaudal level (17-39% in rostral/intermediate levels vs 0.4-5% caudally) but did not differ between striatal subregions. For dynorphin neurones the reverse was true, with consistently higher levels of co-localization in the caudate-putamen (56-77%) than the nucleus accumbens (15-43%), but no differences along the rostrocaudal axis. Furthermore, the degree of enkephalin/mu co-localization was significantly lower than that of dynorphin/mu. These results suggest a fine-grained topological differentiation of mu receptor modulation of striatal opioid systems.