A Novel Tool for the Early Identification of Frailty in Elderly People: The Application in Primary Care Settings.

BACKGROUND: Frailty is a pre-disability condition in older persons providing a challenge to Health-Care Systems. Systematic reviews highlight the absence of a gold-standard for its identification. However, an approach based on initial screening by the General Practitioner (GP) seems particularly useful. On these premises, a 9-item Sunfrail Checklist (SC), was developed by a multidisciplinary group, in the context of European Sunfrail Project, and tested in the Community. OBJECTIVES: - to measure the concordance between the judgments of frailty (criterion-validity): the one formulated by the GP, using the SC, and the one subsequently expressed by a Comprehensive Geriatric Assessment Team (CGA-Team); - to determine the construct-validity through the correspondence between some checklist items related to the 3 domains (physical, cognitive and social) and the three tools used by the CGA-Team; - to measure the instrument's performance in terms of positive predictive value (PPV) and negative predictive value (NPV). DESIGN: Cross-sectional study, with a final sample-size of 95 subjects. SETTING: Two Community-Health Centers of Parma, Italy. PARTICIPANTS: Subjects aged 75 years old or more, with no disability and living in the community. MEASUREMENTS: We compared the screening capacity of the GP using the SC to that one of CGA-Team based on three tests: 4-meter Gait-Speed, Mini-Mental State Examination and Loneliness Scale. RESULTS: 95 subjects (51 women), with a mean age of 81±4 years were enrolled. According to GPs 34 subjects were frail; the CGA-Team expressed a frailty judgment on 26 subjects. The criterion-validity presented a Cohen's k of 0.353. Construct-validity was also low, with a maximum contingency-coefficient of 0.19. The analysis showed a PPV of 58.1% and a NPV equal to 84.6%. CONCLUSIONS: Our data showed a low agreement between the judgements of GP performed by SC and CGA-Team. However, the good NPV suggests the applicability of SC for screening activities in primary-care.

Methamphetamine alters prodynorphin gene expression and dynorphin A levels in rat hypothalamus.

Chronic administration of morphine or cocaine affects opioid gene expression. To better understand the possible existence of common neuronal pathways shared by different classes of drugs of abuse, we studied the effects of methamphetamine on the gene expression of the opioid precursor prodynorphin and on the levels of peptide dynorphin A in the rat brain. Acute (6 mg/kg, intraperitoneally, i.p.) and chronic (6 mg/kg, i.p. for 15 days) methamphetamine markedly raised prodynorphin mRNA levels in the hypothalamus, whereas no effect was observed in the hippocampus. Dynorphin A levels increased after chronic treatment in the hypothalamus and in the striatum, whereas no significant changes were detected after acute treatment. These results indicate that methamphetamine affects prodynorphin gene expression in the hypothalamus, which may be an important site (also for its relevant neuroendocrine correlates) for opioidergic mechanisms activated by addictive drugs.

Region-specific changes in prodynorphin mRNA and ir-dynorphin A levels after kindled seizures.

The opioid peptide dynorphin is thought to be implicated in specific types of seizures. In particular, complex partial seizures have been shown to cause release of dynorphin, activation of prodynorphin gene expression, and new peptide synthesis in the hippocampus. In this study, the kinetics of the seizure-induced changes in prodynorphin mRNA and ir-dynorphin A levels in the hippocampus have been compared with those induced in the temporal and frontal cortex, i.e., in other regions involved in the pathophysiology of complex partial seizures. Experiments have been run using kindling, one of the most valuable models of partial epilepsy. In the hippocampus (1) prodynorphin mRNA levels transiently increase (threefold) 1 h after kindled seizures, and return to baseline by 2 h, and (2) dynorphin A levels are slightly decreased at 1 h, but increase (twofold) at 2 h and return to baseline by 6 h. In the temporal and in the frontal cortex, a late (beginning at 2 h) and prolonged (up to 24 h) decrease in both prodynorphin mRNA and ir-dynorphin A levels have been observed. These data suggest that differential changes in dynorphin metabolism occur in different brain areas after seizures. The mechanisms and functional implications of this observation remain to be investigated.

Dopamine-2 receptor blockade potentiates the renal effects of nitric oxide inhibition in humans.

In eight young healthy subjects on a 240 mM Na diet mean arterial pressure (MAP), renal hemodynamics and renal handling of Na and exogenous Li were measured at baseline and during acute nitric oxide (NO) inhibition with 90-minute infusion of 3.0 microg/kg x min(-1) of N(G)-L-arginine methyl ester (L-NAME). The same experiment was repeated with infusion of 50 microg/kg x min(-1) of DA2 receptor blocker L-Sulpiride (L-SULP) alone and, finally, with simultaneous infusion of both L-NAME and L-SULP. L-SULP alone did not elicit any effect. L-NAME alone produced no changes in MAP from 0 to 45 minutes (P1) and a 6.6% increase at 45 to 90 minutes (P2) of infusion. Effective renal plasma flow (ERPF, PAH clearance) and glomerular filtration rate (GFR, inulin clearance) declined by 10.2% and 7.6%, respectively, in P1 and by 15.3% and 11.5% in P2. Filtration Fraction (FF) rose by 4.2% in P2. Calculated renal vascular resistance (RVR) increased by 13.0% to 25.6%. Fractional excretion of Na (FENa) and Li (FELi) fell by 20.0% and by 16.0%, respectively, in P1 and by 40.0% and 25.1% in P2. All these variations, except for MAP and GFR, were significantly greater during coinfusion of L-NAME and L-SULP. ERPF declined by 17.8% to 33.7%, FENa by 26.7% to 53.3%, FELi by 13.8% to 34.8%, while RVR rose by 22.5% to 59.1% and FF by 10.1% to 29.3%. The present data confirm that NO blockade with low-dose systemic infusion of L-NAME produces renal vasoconstriction, reduced GFR with slight increase in FF, and enhanced tubular Li, and Na reabsorption. Since increase in RVR and FF and decrease in FENa and FELi are markedly potentiated by the simultaneous infusion of DA2 blocker L-SULP, which exerts no effects by itself, we suggest that DA interactions between DA system at the level of DA2 receptors and basal NO production play a physiological role in the regulation of renal function in humans.

Kindled seizure-induced c-fos and prodynorphin mRNA expressions are unrelated in the rat brain.

Levels of mRNA for c-fos and prodynorphin were studied by in situ hybridization in adjacent coronal sections taken from kindled rats 30-60 min after the last seizure. Within this time frame, expression of both genes was induced in multiple brain areas. Anatomical colocalization of the induced gene expressions was found in the hippocampus. Induction of c-fos in the dentate gyrus was bilateral and symmetrical in a subgroup of rats, ipsilateral in another subgroup and absent in a third subgroup. However, no relative increase was observed in the ipsilateral compared with the contralateral prodynorphin expression in the dentate gyrus when c-fos expression was induced ipsilaterally only. These observations suggest that, at variance with other experimental situations, Fos is not involved in the mechanisms of kindled seizure-induced activation of prodynorphin transcription in the rat forebrain.

Chronic intracerebroventricular cocaine differentially affects prodynorphin gene expression in rat hypothalamus and caudate-putamen.

We investigated the effects of sustained administration of cocaine on the regulation of prodynorphin gene expression in rat brain. Intracerebroventricular (i.c.v.) infusion of cocaine hydrochloride (30 micrograms/day) for 7 days, by means of osmotic minipumps, elicited a significant 35% decrease of prodynorphin mRNA levels in rat hypothalamus and increase (22%) in caudate-putamen. At the same time and in the same animals, no significant changes were detected in the hippocampus or in the nucleus accumbens. These results indicate that continuously infused cocaine is able to modulate expression of the prodynorphin gene in opposite directions or has no effect on prodynorphin expression, depending on the brain region analysed. Cocaine, as well as opiates, might activate specific neuronal pathways, shared by different classes of drugs of abuse, involving, at least in part, the endogenous opioid system.

Early changes in prodynorphin mRNA and ir-dynorphin A levels after kindled seizures in the rat.

Prodynorphin mRNA and immunoreactive dynorphin A (ir-dynorphin A) levels were measured in different brain areas at various time points after amygdala kindled seizures. In the hippocampus, striatum and hypothalamus, prodynorphin mRNA levels were not significantly changed in kindled rats (killed 1 week after the last stimulus-evoked seizure), but they were significantly increased 1 h after seizures. The relative increase was the highest in the hippocampus (approximately 3-fold). In the brainstem, midbrain and cerebral cortex no changes in prodynorphin mRNA were detected in kindled rats, 1 h or 1 week after a kindled seizure. ir-Dynorphin A levels were significantly reduced in the hippocampus and in the striatum of kindled rats, as well as 5 and 60 min after kindled seizures, but they were increased back to control levels after 120 min. In the hypothalamus, ir-dynorphin A levels were significantly increased 120 min after a kindled seizure. ir-Dynorphin A levels were also significantly reduced in the brainstem and in the frontal, parietal and temporal cortex 120 min, but not 5 or 60 min, after a kindled seizure. Taken together, these data support the hypothesis that the dynorphinergic system is activated after amygdala kindled seizures, with different kinetics in different brain areas.

Long-term exposure to opioid antagonists up-regulates prodynorphin gene expression in rat brain.

We investigated the effect of long-term administration of opioid antagonists on the regulation of prodynorphin gene expression in rat brain. Intracerebroventricular (i.c.v.) injections for seven days of nor-binaltorphimine (nor-BNI), the highly selective kappa opioid antagonist, naloxone and its longer acting analog naltrexone, both relatively selective antagonists for the mu opioid receptor, markedly raised prodynorphin mRNA levels in rat hypothalamus, hippocampus and striatum. Peptides, namely immunoreactive-dynorphin A (ir-dyn A), were unaffected after chronic treatment with all antagonists, in the same tissues. These results, taken together with our previous observations, suggest that chronic opioid antagonists, acting on kappa and mu opioid receptors, clearly up-regulate prodynorphin gene expression in discrete rat brain regions, activating its biosynthesis. Moreover, our data support the hypothesis that the endogenous opioid system plays a role in the mechanisms underlying the development of opiate tolerance.

Binding profile of benextramine at neuropeptide Y receptor subtypes in rat brain areas.

Binding studies in rat whole brain, frontoparietal cortex and brainstem membrane preparations revealed that benextramine displaced [3H]neuropeptide Y specific binding from a low and a high affinity site with IC50 values in the microM (36 +/- 2, 4.4 +/- 1.4 and 300 +/- 120 microM, respectively) and the pM (29.3 +/- 12.1, 0.35 +/- 0.11 and 0.42 +/- 0.03 pM, respectively) range, whereas in rat hippocampus benextramine displaced [3H]neuropeptide Y specific binding from one site only with an IC50 value of 22.8 +/- 5.7 microM. With the exception of frontoparietal cortex binding assay, benextramine was not able to completely inhibit [3H]neuropeptide Y specific binding revealing the presence of a benextramine nonsensitive third binding site. Benextramine pretreatment followed by membrane washing demonstrated that benextramine inhibited irreversibly both high and low affinity sites.

Studies on the anti-phospholipase A2 and anti-inflammatory activities of a uteroglobin fragment and related peptides.

The nonapeptide antiflammin P1 (H-Met-Gln-Met-Lys-Lys-Val-Leu-Asp-Ser-OH), its isoAsp8 analogue and the corresponding aminosuccinyl peptide were prepared, characterized and tested for inhibition of phospholipase A2 (PLA2) in vitro and for anti-inflammatory activity in vivo under assay conditions recently recommended. All peptides are devoid of PLA2 inhibitory and anti-inflammatory activity.

Phagocytosis reduces HIV-1 production in human monocytes/macrophages infected in vitro.

The addition of ingestable particles (opsonized erythrocytes or latex beads) or a phorbol ester activates monocytes--derived human macrophages (MDHM) cultured in vitro, and markedly reduces virion release from HIV-infected MDHM as well as their ability to transmit the infection to cocultured lymphoid CD4-positive CEM cells.

Alterations in vasoactive intestinal polypeptide-related peptides after pentylenetetrazole-induced seizures in rat brain.

The possible involvement of vasoactive intestinal polypeptide-related peptides in pentylenetetrazol (PTZ)-induced seizures in rats was investigated. The chemoconvulsant PTZ was administered (45 mg/kg i.p.) either acutely or chronically for three days. The detailed time course of changes in VIP-(1-28) and VIP-(22-28) was examined in several rat brain areas 5 and 20 min and 24 h after acute treatment and after three days chronic treatment. Ir-VIP levels dramatically decreased in all areas 5 min after PTZ injection, remained low after 20 min and progressively increased back to control values after 24 h and after three days of repeated treatment (except for the cortex). Chromatographic analysis of extracts prepared from PTZ-treated rats revealed a concomitant decrease in VIP-(1-28) and increase in VIP-(22-28). Thus VIP-(22-28) might be a product of the internal cleavage of the precursor VIP-(1-28) after its neuronal release; alternatively, VIP-(22-28) might be generated by post-transcriptional processing of VIP-(1-28), and thus be an 'independent' neuropeptide. The results suggest that VIP-(1-28)/VIP-(22-28)-containing neurons might be involved in PTZ-induced seizures in rat brain, and that VIP-(22-28) might play a role in these experimental seizures.

Substance P levels are decreased in lesional skin of atopic dermatitis.

There is increasing evidence that neuropeptides (NP) such as substance P (SP) and vasoactive intestinal polypeptide (VIP) are involved in the pathogenesis of atopic dermatitis (AD). Vasoactive intestinal polypeptide levels were found to be significantly elevated in lesional skin of AD as compared to controls. We evaluated by radioimmunoassay the SP content in whole skin homogenates from chronic lichenified lesions of patients with AD. The levels of SP were significantly decreased in lesional skin from AD patients as compared to control skin (0.25 +/- 0.03 vs. 0.97 +/- 0.24 pmol/g tissue, p < 0.01). The diminished SP levels as opposed to increased VIP concentrations could be consistent with different roles of these NP as modulatory agents in the mechanisms associated with AD.