PRISMA-7 and Risk for Short-Term Adverse Events in Older Patients Visiting the Emergency Department: Results of a Large Observational and Prospective Cohort Study.

BACKGROUND: The "Program of Research on the Integration of Services for the Maintenance of Autonomy" (PRISMA-7) is the reference tool for the assessment of older patients visiting the emergency departments (EDs) in the province of Quebec (Canada). This study aimed to examine 1) whether the PRISMA-7 high-risk level for disabilities was associated with the length of stay in ED and in hospital, and hospital admission; and 2) performance criteria (i.e., sensitivity, specificity, positive predictive value [PPV], negative predictive value [NPV], likelihood ratios [LR]) of the PRISMA-7 high-risk level for the length of stay in ED and hospital, and hospital admission in older ED users. METHODS: A total of 12,983 older ED users of the Jewish General Hospital (Montreal, Quebec, Canada) were recruited in this observational and prospective cohort study. All enrolled participants had a PRISMA-7 assessment upon their arrival at ED. The length of stay in ED and hospital, and hospital admission were used as outcomes. RESULTS: A PRISMA-7 high-risk level was associated with an increased length of stay in ED and hospital (ß ≥2.1 with P≤0.001 and Hazard ratio (HR)= ≥1.2 with P≤0.001) as well as in hospital (HR=1.27 with P≤0.001) in patients on a stretcher. All performance criteria were low (i.e., <0.78). Patients with a PRISMA-7 high-risk level were discharged significantly later from ED and hospital compared to those with low-risk level (P=0.001). INTERPRETATION: A PRISMA-7 high-risk level was associated with a long length of stay in ED and hospital, and hospital admission in patients on a stretcher but had poor performance criteria for these adverse events, suggesting that it cannot be used as a prognostic tool in older ED users.

Stressed neurons protect themselves by a tissue-type plasminogen activator-mediated EGFR-dependent mechanism.

In the central nervous system, tissue-type plasminogen activator (tPA) has been associated with both pro-death and prosurvival actions on neurons. In most cases, this has been related to exogenous tPA. In the present study, we addressed the influence of endogenous tPA. We first observed an increased transcription of tPA following either in vivo global brain ischemia in rats or in vitro oxygen glucose deprivation (OGD) on mice and rats hippocampal slices. Hippocampal slices from tPA-deficient mice were more sensitive to OGD than wild-type slices. Pharmacological approaches targeting the known receptors of tPA revealed that only the inhibition of phosphorylation of epidermal growth factor receptors (EGFRs) prevented the neuroprotective effect of endogenous tPA. This study shows that ischemic hippocampal neurons overproduce endogenous tPA as an intend to protect themselves from ischemic death, by a mechanism involving an activation of EGFRs. Thus, strategies contributing to promote either endogenous production of tPA or its associated EGFR-linked signaling pathway may have beneficial effects following brain injuries such as stroke.

NR2D-containing NMDA receptors mediate tissue plasminogen activator-promoted neuronal excitotoxicity.

Although the molecular bases of its actions remain debated, tissue-type plasminogen activator (tPA) is a paradoxical brain protease, as it favours some learning/memory processes, but increases excitotoxic neuronal death. Here, we show that, in cultured cortical neurons, tPA selectively promotes NR2D-containing N-methyl-D-aspartate receptor (NMDAR)-dependent activation. We show that tPA-mediated signalling and neurotoxicity through the NMDAR are blocked by co-application of an NR2D antagonist (phenanthrene derivative (2S(*), 3R(*))-1-(phenanthrene-2-carbonyl)piperazine-2,3-dicarboxylic acid, PPDA) or knockdown of neuronal NR2D expression. In sharp contrast with cortical neurons, hippocampal neurons do not exhibit NR2D both in vitro and in vivo and are consequently resistant to tPA-promoted NMDAR-mediated neurotoxicity. Moreover, we have shown that activation of synaptic NMDAR prevents further tPA-dependent NMDAR-mediated neurotoxicity and sensitivity to PPDA. This study shows that the earlier described pro-neurotoxic effect of tPA is mediated by NR2D-containing NMDAR-dependent extracellular signal-regulated kinase activation, a deleterious effect prevented by synaptic pre-activation.

HtrA1-dependent proteolysis of TGF-beta controls both neuronal maturation and developmental survival.

Transforming growth factor-beta (TGF-beta) signalling controls a number of cerebral functions and dysfunctions including synaptogenesis, amyloid-beta accumulation, apoptosis and excitotoxicity. Using cultured cortical neurons prepared from either wild type or transgenic mice overexpressing a TGF-beta-responsive luciferase reporter gene (SBE-Luc), we demonstrated a progressive loss of TGF-beta signalling during neuronal maturation and survival. Moreover, we showed that neurons exhibit increasing amounts of the serine protease HtrA1 (high temperature responsive antigen 1) and corresponding cleavage products during both in vitro neuronal maturation and brain development. In parallel of its ability to promote degradation of TGF-beta1, we demonstrated that blockage of the proteolytic activity of HtrA1 leads to a restoration of TGF-beta signalling, subsequent overexpression of the serpin type -1 plasminogen activator inhibitor (PAI-1) and neuronal death. Altogether, we propose that the balance between HtrA1 and TGF-beta could be one of the critical events controlling both neuronal maturation and developmental survival.

NMDA-induced striatal brain damage and time-dependence reliability of thionin staining in rats.

Excitotoxic neuronal death induced by intracerebral injection of NMDA is a widely used model for investigating the potentially neuroprotective action of pharmacological agents against brain insults involving excitotoxic processes. Surprisingly, the time-course of NMDA-induced brain damage yet has not been investigated in the rat. Answering this question clearly needs to be assessed, given that the validity of preclinical neuroprotection studies requires to be insured that brain damage has reached a plateau that corresponds to the maximal extension of neuronal death at the time the brain is removed for histological analysis. Here, we investigated the time-course of neuronal death and the time-dependence validity of thionin coloration in rats that were given an intrastriatal injection of NMDA of 50 nmol or 70 nmol. Our results show that, whatever the dose used, NMDA-induced brain damage reaches its maximal value 24-48 h after the insult. They further indicate that the volume values of brain damage as estimated by thionin coloration constitute reliable data when the brain is removed up to 48 h after injection of NMDA. However, if the brain is removed more than 48 h after the excitotoxic insult onset, there is no alternative of using other techniques, such as immunochemical or neuroimaging techniques.

Regulation of neuropeptide Y and its mRNA by glucocorticoids in the rat adrenal gland.

The effects of glucocorticoids on adrenal neuropeptide Y (NPY) and NPY mRNA levels have been investigated on adult male rats of the Wistar strain subcutaneously injected twice a day with dexamethasone (5 mg/day), metyrapone (66 mg/day) or solvent (NaCl 0.9%) for 2.5 days and sacrificed 2 h after the last injection. Dexamethasone induced a significant decrease in both the adrenal weight (30%) and the plasma corticosterone concentration (85%) but a significant increase of the adrenal NPY content (about 25%) as well as of its mRNA (0.8 kb) (> 100%), revealed by Northern blot analysis and by in situ hybridization. Dexamethasone was unable to affect significantly dopamine (DA), norepinephrine (NE) and epinephrine (E) content of the adrenals; in contrast, it induced a significant decrease (30%) of the plasma NE level. Metyrapone elicited a drop of the plasma corticosterone level (80%), but a rise (near 150%) of the plasma ACTH concentration associated with an increase (19%) of the adrenal weight, a significant increase (30%) in the amount of adrenal NPY as well as a rise (> 200%) of NPY mRNA content of the adrenal. Such treatment increased DA and NE (40%), and decreased E (> 30%) content of the adrenals. Metyrapone-induced changes of catecholamine concentrations in the plasma were similar to that observed in the adrenal gland. Data suggest that the increase in adrenal NPY mRNA content induced by dexamethasone is more likely due to humoral effect rather than nervous effect of this synthetic glucocorticoid on the adrenal medulla. A neural mechanism as splanchnic nerve activation in response to severe corticosterone deficiency is a reasonable hypothesis to explain the increase in adrenal NPY mRNA induced by metyrapone, although there are probably other, nonneural mechanisms by which metyrapone could stimulate adrenal NPY. Present data are consistent with glucocorticoid regulation of NPY gene expression and/or steady-state level of NPY mRNA in the adrenal gland.

Molecular pharmacology of somatostatin receptors.

Somatostatin was discovered for its ability to inhibit growth hormone (GH) secretion. Later, it was found to be widely distributed in other brain regions, in which it fulfills a neuromodulatory role, and in several organs of the gastrointestinal tract where it can act as a paracrine factor or as a true circulating factor. In mammals, two molecules of 14 (somatostatin 14) and 28 (somatostatin 28) amino acids are the only biologically active members of the family. They originate from a single gene which gives rise to a single propeptide alternately cleaved in different tissues. In 1992, a major breakthrough in our understanding of somatostatin functions was made with the cloning of five different receptor genes (sstr1 to sstr5) which belong to the seven transmembrane domain receptor family. Their closer relatives are opioid receptors. In first approximation, the tissular expression of the sstrs matches quite well with the distribution of somatostatin binding sites in the "classical" targets of the peptide ie brain, pituitary pancreatic islets and adrenals. The pharmacology of GH inhibition is very close to sstr2 binding but other actions of somatostatins have not yet been attributed clearly to a single receptor subtype. All clinically relevant agonists tested so far (octreotide, lanreotide and vapreotide) are selective of sstr2 being less potent on sstr3 and inactive for sstr1 and sstr4. Surprisingly, rat sstr5 displays nanomolar affinities for octreotide and vapreotide while these agonists are only active at much higher concentrations on human sstr5. All five receptors can be more or less efficiently coupled to inhibition of adenylate cyclase activity in transfected cell systems.(ABSTRACT TRUNCATED AT 250 WORDS)

Developmental patterns of somatostatin-receptors and somatostatin-immunoreactivity during early neurogenesis in the rat.

The temporal pattern of distribution of somatostatin receptor was investigated using the somatostatin analogue [125I]Tyr0-DTrp8-somatostatin14 as a ligand and compared with that of somatostatin immunoreactivity during early developmental stages in the spinal cord and the sensory derivatives in rat fetuses. Qualitative and quantitative analysis showed that somatostatin receptors were detected in a transient manner. In the neural tube, they were clearly associated with immature premigratory cells and with the developing white matter. During the time-period examined (from day 10.5 to 16.5), the disappearance of somatostatin receptors followed a ventro to dorsal gradient probably linked to the regression of the ventricular zone. In sensory derivatives, they were expressed in the forming ganglia and their central and peripheral nerves from embryonic day 12.5 to 16.5 inclusive, with a peak around day 14.5 and low levels observed at day 16.5. Competition experiments performed at embryonic day 14.5 demonstrated that somatostatin1-14, somatostatin1-28, and Octreotide displaced specific binding with nanomolar affinities while CGP 23996 was only active at micromalar doses. Such displacements are compatible with the SSTR2 and/or SSTR4 pharmacology. During the time period examined, some transient somatostatin immunoreactive cell bodies and fibers were detected in the neural tube and in the sensory derivatives. These results demonstrate the existence, in neuronal derivatives, of a complex temporal and anatomical pattern of expression of somatostatin receptors, from the SSTR2/SSTR4 subtype(s), and somatostatin immunoreactivity. It appears that the transient expression of somatostatin receptors and/or somatostatin immunoreactivity characterizes critical episodes in the development of a cohort of neurons; a fact that unequivocally reinforces the notion that somatostatin plays a fundamental role during neurogenesis in vertebrates.

In vitro steroidogenic effects of neuropeptide Y (NPY1-36), Y1 and Y2 receptor agonists (Leu31-Pro34 NPY, NPY18-36) and peptide YY (PYY) on rat adrenal capsule/zona glomerulosa.

The effects of neuropeptide Y (NPY1-36), of two analogs (Leu31-Pro34 NPY and NPY18-36) and of Peptide YY (PYY) on aldosterone and corticosterone secretions by freshly isolated rat adrenal capsule/zona glomerulosa preparations were investigated in vitro. NPY-related peptides (NPY1-36, Leu31-Pro34 NPY, NPY18-36), but not PYY, induced a dose-dependent release of aldosterone at concentrations ranging from 10(-8) to 10(-6) M. All the investigated peptides failed to significantly affect corticosterone secretion in concentrations ranging from 10(-10) to 10(-6) M (NPY1-36, NPY18-36), 10(-11) to 10(-6) M (Leu31-Pro34 NPY) or 10(-9) to 10(-6) M (PYY). Aldosterone secretion by this preparation of isolated adrenal capsule/zona glomerulosa was also significantly stimulated by high potassium levels (55 mEq) or by angiotensin II (AII) in concentrations ranging from 10(-8) to 10(-6) M. Moreover, NPY and Y1 or Y2 receptor agonists were positive aldosterone releasing agents as potent as AII. The present data support the existence of: (1) NPY binding sites of the Y3-like subtype, on rat adrenal capsule/zona glomerulosa. (2) A stimulatory effect of NPY on aldosterone production. So that the NPYergic innervation of the rat adrenal capsule/zona glomerulosa could be implicated in the multifactorial control of aldosterone production.

Neuropeptide Y (NPY)- and vasoactive intestinal peptide (VIP)-induced aldosterone secretion by rat capsule/glomerular zone could be mediated by catecholamines via beta 1 adrenergic receptors.

The effects of two Neuropeptide Y (NPY) analogs (Y1- and Y2-type) and vasoactive intestinal peptide (VIP) on both catecholamine (adrenaline and noradrenaline) release and aldosterone production by rat adrenal capsule/glomerular zone, have been investigated in vitro. The adrenal capsule/glomerular zones, collected from adult male rats, were incubated in a medium (Krebs-Ringer bicarbonate buffer supplemented with glucose and bovine serum albumin) containing or not one of the following synthetic peptides: human Leu31,Pro34-NPY (an agonist of the Y1-type receptors), human/porcine NPY18-36 (an agonist of the Y2-type receptors) and VIP at the concentration of 10(-7) M, associated or not with 10(-7) M atenolol (a beta 1 adrenergic antagonist) or ICI-118,551 hydrochloride (a beta 2 adrenergic antagonist). The two NPY analogs as well as the VIP stimulated the release of catecholamines and of aldosterone. The beta 1 adrenergic antagonist, but not the beta 2 one, which failed to affect basal aldosterone production when given alone, prevented NPY18-36-, Leu31,Pro34-NPY- or VlP-induced aldosterone secretion. Present data support the hypothesis that adrenaline and/or noradrenaline could mediate the effects of both NPY and VIP on aldosterone secretion via beta 1 adrenergic receptors; alternatively, the steroidogenic effect of NPY or VIP could be related to direct interaction between NPY- or VIP-specific binding sites, present on the capsule/glomerular zone of the rat adrenal cortex, and beta 1 adrenergic receptors. Then the NPYergic, VIPergic and catecholaminergic innervation of the adrenal cortex, previously characterized by immunohistochemistry, may be a potent stimulatory element in the nervous control of the aldosterone secretion.

Effect of adrenal demedullation on neuropeptide Y content of the capsule/glomerulosa zone of the rat adrenal gland.

The capsule/glomerulosa zone of the adrenal gland is richly innervated by neuropeptide Y (NPY)-containing nerve fibers. The content and concentration of NPY in the capsule/glomerulosa zone of the female rat adrenal were determined by radioimmunoassay both in unoperated females (controls) and in operated ones, a week after in situ unilateral demedullation which excludes both the medulla and the fasciculata/reticularis zones. Demedullation induced a significant weight increase of the capsule/glomerulosa zone of the operated gland (compared to contralateral intact one) as well as of the medulla/fasciculata-reticularis zone of the contralateral intact one (compared to the corresponding part of the gland of controls). Both NPY content and concentration in the capsule/glomerulosa zone of the demedullated adrenal were significantly reduced in comparison with those in the corresponding part of the contralateral intact gland. NPY immunoreactive fibers, revealed by immunofluorescence, were present in the capsule/glomerular zone of both intact and contralateral demedullated adrenal gland. In the former, NPY fibers were regularly distributed in this part of the gland, while in the latter, some areas were devoid of immunoreactive fibers. NPY content, but not concentration, was increased in the medulla/fasciculata-reticularis zone of the contralateral intact gland. Present data support a dual origin for the NPY nerves present in the capsule/glomerulosa zone of the adrenal cortex: one part could arise from extra-adrenal site possibly the suprarenal ganglia while the other part could arise from intra adrenal ganglia cells which also contain NPY.

Early transient expression of somatostatin (SRIF) immunoreactivity in dorsal root ganglia during ontogenesis in the rat.

Immunofluorescence was used in the rat to study the early ontogenetic expression of somatostatin (SRIF) in the dorsal root ganglia (DRGs) from gestational day 10.5 to day 15.5. SRIF-immunoreactivity (IR) was not detectable in day-10.5 embryos, was first observed in DRGs at day 11.5, reached a peak in intensity and distribution at around day 13.5 and thereafter decreased to become undetectable by day 15.5 in the DRGs of the trunk region. The dynamic expression of SRIF-IR in DRG perikarya could be correlated with its expression in nerve fibers located in the limbs and the abdominal mesenchyme. Thus, SRIF-IR is expressed at a time when sensory fibers could have established connections with their embryonic targets and when DRG neurons could have undergone their final mitotic phase. These data showing the earliest and transient expression of a neuropeptide in developing DRGs confirm and extend the notion that SRIF plays an important role in developmental processes.

Effects of Estrous Cycle and of in vivo Unilateral or Bilateral Adrenal Demedullation on the Distribution of Norepinephrine and Epinephrine Between Different Zones of the Adrenal.

Abstract The distribution of norepinephrine (NE) and epinephrine (E) between the capsule/glomerular zone and the remainder of the adrenal was studied in the adult female rat. Both catecholamines were present in these two parts of the gland. The concentration of E was higher than that of NE. In the capsule/glomerular zone the catecholamine concentrations were more than twenty to thirty times lower than in the inner part of the gland. The circulating levels of catecholamines were always very low. The present data also support very weak or no changes in catecholamine concentrations in both parts of the adrenal during the different stages of the estrous cycle. The plasma levels of both aldosterone and corticosterone, like those of catecholamines, did not vary significantly throughout the estrous cycle. One week after unilateral or bilateral demedullation, both E content and concentration were reduced in the whole capsule/glomerular zone of the adrenal although the NE content did not change. The reduction of NE concentration could be related to the drastic weight increase of this part of the gland on the operated side. Moreover, unilateral demedullation was unable to significantly modify the plasma levels of both E and NE. In contrast bilateral demedullation suppressed circulating E and induced a significant reduction (about 50%) of NE plasma level. The present data suggest: 1) an extra-adrenal origin for the NE innervation of the capsule/glomerular zone of the adrenal cortex, and 2) a dual origin for E in the capsule/glomerular zone; part of E could arise from the adrenal medulla and part from an extra-adrenal site.

Co-localization of vasoactive intestinal polypeptide and neuropeptide Y immunoreactivities in the nerve fibers of the rat adrenal gland.

The co-localization of Vasoactive Intestinal Polypeptide (VIP) with Neuropeptide Y (NPY) or its C-flanking peptide (C-PON) was investigated with immunocytochemistry methods in the adrenal gland of the rat. Most of the VIP immunoreactive (+) nerve fibers found in the capsule/glomerular zone also exhibited NPY or C-PON immunoreactivity (IR). We found that at least two populations of VIP varicose nerve fibers can be observed, the most prevalent exhibited both VIP/NPY or VIP/C-PON IR and the other which was rather scarce lacked NPY or C-PON IR. In the superficial cortex VIP/NPY or VIP/C-PON IR nerve fibers were often associated with capsular or subcapsular vascularization and extended into the zona glomerulosa. In the deeper layers of the adrenal cortex radial fibers were closely associated with the inner vascularization of the zona fasciculata and reticularis. In the adrenal medulla NPY or C-PON immunoreactivity was associated with ganglion neurons as well as chromaffin cells; these last cells were always VIP (-). VIP and NPY/C-PON IR could be co-localized in catecholaminergic nerve terminals of the adrenal cortex but not in the adrenal medulla.