Low daily MEWS scores as predictors of low-risk hospitalized patients.

BACKGROUND: The Modified Early Warning System (MEWS) is a well-validated tool used by hospitals to identify patients at high risk for an adverse event to occur. However, there has been little evaluation into whether a low MEWS score can be predictive of patients with a low likelihood of an adverse event. AIM: The present study aims to evaluate the MEWS score as a method of identifying patients at low risk for adverse events. DESIGN: Retrospective cohort study of 5676 patient days and analysis of associated MEWS scores, medical comorbidities and adverse events. The primary outcome was the association of average daily MEWS scores in those who had an adverse event compared with those who did not. RESULTS: Those with an average MEWS score of >2 were over 9 times more likely to have an adverse event compared with those with an average MEWS score of 1-2, and over 15 times more likely to have an adverse event compared to those with an average MEWS score of <1. CONCLUSIONS: Our study shows that those with average daily MEWS scores <2 are at a significantly lower likelihood of having an adverse event compared with a score of >2, deeming them 'low-risk patients'. Formal recognition of such patients can have major implications in a hospital setting, including more efficient resource allocation in hospitals and better patient satisfaction and safety by adjusting patient monitoring according to their individual risk profile.

Elevated stress hormone levels and antidepressant treatment starting before pregnancy affect maternal care and litter characteristics in an animal model of depression.

Many women who take antidepressant medications become pregnant while taking their medication; however, the impact of depression and antidepressant medication on fetal development is not well understood. This study used a translational animal model of maternal depression to investigate the consequences of discontinuing antidepressant medication during pregnancy. First, rats received corticosterone (CORT; 40 mg/kg, s.c.) or vehicle to induce a depressive-like phenotype. After 16 days of treatment with CORT or vehicle, animals were treated with sertraline (a selective serotonin reuptake inhibitor, SSRI; 20 mg/kg) or vehicle via gavage. Following 21 days of CORT or oil treatment, rats were mated. One group receiving sertraline was discontinued from treatment on gestational day 16, and another group continued sertraline treatment throughout pregnancy to assess the effects of discontinuation. After weaning, dams were sacrificed via perfusion to investigate neurogenesis. As intended, CORT administration created a depressive-like phenotype with increased immobility in the Forced Swim Test and reduced body weight. Interestingly, sertraline treatment could not rescue these altered features. Pre-conceptional CORT exposure resulted in smaller litters and CORT dams that received sertraline until the end of gestation spent more time off of the nest compared to CORT dams that received vehicle or discontinued sertraline during gestation. There was no difference in hippocampal neurogenesis between any of the groups. Our results suggest that treatment with antidepressants may have different effects in healthy or depressed dams, however, we need more research to investigate the detailed and long-term effects of maternal depression and its treatment in translational animal models.

Effectiveness of different corticosterone administration methods to elevate corticosterone serum levels, induce depressive-like behavior, and affect neurogenesis levels in female rats.

High levels of chronic stress or stress hormones are associated with depressive-like behavior in animal models. However, slight elevations in corticosterone (CORT) - the major stress hormone in rodents - have also been associated with improved performances, albeit in a sex-dependent manner. Some of the discrepancies in the literature regarding the effects of high CORT levels may be due to different administrations methods. The current study aims to compare the effects of ∼40mg/kg given either via subcutaneous injection, through an implanted pellet, or in the drinking water, for ∼21days on CORT serum levels, depressive-like behavior in the forced swim test (FST), and neurogenesis levels in the dentate gyrus (DG) in adult female rats. We found that animals exposed to the daily injections showed elevated CORT levels throughout the administration period, while the pellet animals showed only a transient increase, and drinking water animals revealed no elevation in CORT in serum. In addition, only the injection group exhibited higher levels of immobility in the FST. Interestingly, animals receiving CORT via injection or drinking water had lower numbers of doublecortin-positive cells in the ventral DG one week after the last CORT administration compared to animals implanted with a CORT pellet. These results will contribute to the growing literature on the effects of chronic CORT exposure and may help to clarify some of the discrepancies among previous studies, particularly in females.

Changes in developmental body weight as a function of toluene exposure: A meta-analysis of animal studies.

Inhalant abuse is a globally prevalent health issue with particular concerns about substance-abusing pregnant women. In both animal models and clinical case reports of toluene exposure, the primary physiological outcome measure of prenatal inhalant exposure is low birth weight (BW). However, the effect of prenatal toluene exposure on animal BW varies widely in the literature. To clarify this effect and investigate possible design moderators of pup BW, a systematic review and meta-analytic techniques were applied to the existing peer-reviewed animal literature of prenatal and postnatal exposure models to the inhaled solvent toluene. Of 288 studies screened, 24 studies satisfied the inclusion criteria. Evaluation of these studies indicated that toluene exposure was negatively associated with pup BW (d = -0.39), with external inhaled concentration, route of administration, day of weighing, and toluene exposure magnitude moderating this association. Investigators doing animal studies should be cognizant of these factors before investigating the reproductive and developmental outcomes associated with prenatal and postnatal toluene exposure.

Host primary olfactory axons make synaptic contacts in a transplanted olfactory bulb.

Previous light microscopic studies have shown that host olfactory neurons are able to grow into a transplanted fetal olfactory bulb, and behavioral studies have shown that animals with transplanted olfactory bulbs recover functional olfactory abilities. We examined the olfactory bulb transplant at the ultrastructural level to determine whether synaptic contacts are reestablished between host olfactory neurons and donor olfactory bulb. Mature rats that, as neonates, had received embryonic olfactory bulb transplants following olfactory bulb removal were studied. An antibody specific for olfactory marker protein was used to identify the primary olfactory neurons; it was bound by a gold-conjugated secondary antibody for visualization. To preserve the antigenicity of the olfactory marker protein for immunolabeling, Lowicryl K4M hydrophilic resin was used. Synaptic contacts were unmistakable between labeled axons of host olfactory neurons and unlabeled processes within glomerulus-like areas of the transplanted olfactory bulb. The surrounding neuropil contained other elements similar to those found in normal tissue, including synaptic contacts between unlabeled profiles. We clearly show that the transplanted olfactory bulb exhibits sufficient plasticity to form an array of normal synaptic contacts, including the contacts from host primary olfactory neurons.

The development of glial fibrillary acidic protein-positive cells and the appearance of laminin-like immunoreactivity in fetal olfactory bulb transplants.

Embryonic rat olfactory bulbs were transplanted into the site vacated by aspiration of an olfactory bulb from a neonatal rat. This paper presents our findings related to the development of glial fibrillary acidic protein (GFAP) positive (+ve) glial cells and the appearance of laminin-like immunoreactivity in these transplants. The GFAP+ve glial cells formed perivascular end-feet on the invading vasculature and formed a glia limitans along the pial surface of the transplant. This reconstituted glia limitans was continuous with that of the host brain, there being no glia limitans at the donor-host interface. Thus, the donor tissue was well-integrated with that of the host brain.

Nerve growth factor receptor expression in the young and adult rat olfactory system.

Nerve growth factor (NGF) and its receptor (NGFR) are proteins that have a role in the normal development and survival of neurons in the peripheral and central nervous systems. During development, NGF is necessary for outgrowth of axons and establishment of synapses, and NGFR is the transmembrane protein that binds NGF and brings it into the cell. NGF and NGFR expression in the rat olfactory system have been studied previously, and age differences in NGFR are explored further in this study, using immunocytochemistry and immunoelectron microscopy to determine the changes in two different ages: postnatal day 5 and the adult. Dramatic differences were found in the distribution of NGFR immunoreactivity in the olfactory system of each of the two ages studied. Electron microscopy revealed that glial cells were responsible for this immunoreactivity.

Recovery of olfactory function in thirteen-day-old rats after olfactory bulb transplantation but not after olfactory bulb ablation.

Previous studies have shown recovery of olfactory ability along with reconnectivity of olfactory nerve (ON) following both olfactory bulb (OB) lesions and OB transplants (TX) when performed in newborn rats. The purpose of the present study is to correlate functional recovery with patterns of anatomical reconnectivity in older, postnatal (PN) 13-day-old rats (a possible critical period for plasticity in the system). Reinnervation of olfactory areas was seen in all OB TX animals regardless of the extent of functional recovery. Eight of nineteen animals with OB TXs demonstrated some degree of behavioral recovery. No reinnervation or behavioral recovery of OB lesion animals was observed. At this age, behavioral recovery is dependent upon reconnectivity within the system and transplantation may be required to facilitate this process.

Recovery of olfactory behavior. I. Recovery after a complete olfactory bulb lesion correlates with patterns of olfactory nerve penetration.

The olfactory system is an excellent system in which to study issues related to potential functional recovery after a debilitating brain injury. The olfactory system is well-characterized, easily accessible and there are a vast number of studies available from a variety of perspectives. The experimental aim of this research is to examine the anatomical correlates associated with potential behavioral recovery in rats that receive complete olfactory bulb lesions as neonates or as adults. The results show that behavioral recovery occurs only when olfactory nerve penetration of the central nervous system is observed. Further, both olfactory nerve penetration and behavioral recovery are age-dependent phenomena. The olfactory nerve penetration only occurs when the olfactory bulb lesion is performed in neonates. Behavioral recovery of olfactory ability follows a linear trend and reaches near normal levels during the six weeks behavioral testing period. Histological analysis using an antibody for olfactory marker protein (an olfactory nerve-specific marker) reveals two potential candidates for the anatomical pathway responsible for behavioral recovery: olfactory nerve to orbital frontal cortex and olfactory nerve to olfactory peduncle. This report presents evidence that recovery of olfactory ability can occur in the absence of the olfactory bulb if the lesion is performed when the rat is still a neonate.

Recovery of olfactory behavior. II. Neonatal olfactory bulb transplants enhance the rate of behavioral recovery.

Previous experiments in this laboratory have shown that transplants of a fetal olfactory bulb into a neonatal rat are viable and that they establish connections with the olfactory peduncle and olfactory cortex. The focus of this experiment was to investigate the anatomical correlates of any behavioral recovery seen in rats that had one olfactory bulb removed along with an immediate transplant of a fetal olfactory bulb. Anatomical details, such as transplant organization and olfactory nerve repenetration patterns were analyzed using a variety of histological and immunohistochemical techniques. The rats in this experiment showed behavioral recovery of olfactory ability. The recovery rates observed in these animals were compared to two other groups of rats that this laboratory has shown to be behaviorally competent: normal rats and rats with neonatal ablations of the olfactory bulb but no transplant. Although the animals with transplants did not recover to completely normal levels of olfactory ability, they did start behavioral testing in a more behaviorally competent condition than rats with simple neonatal lesions. Anatomical analysis revealed that the transplanted olfactory bulb was heavily penetrated by incoming olfactory nerve fibers but olfactory nerve penetration was not limited to the transplanted olfactory bulb. The extra-bulbar host regions that were penetrated included the orbital frontal cortex and three olfaction-related areas; olfactory cortex, olfactory peduncle and the subependymal cell layer. The olfactory nerve penetration patterns observed beyond the transplant were essentially the same as those observed in rats with only neonatal lesions of the olfactory bulb. Thus, multiple pathways may have contributed to the recovery observed in the rats with olfactory bulb transplants.

Developmental localization of GAP-43 and olfactory marker protein in rat olfactory bulb transplants.

In an effort to identify and understand the laminar disorganization that occurs in the transplanted (TX) rat olfactory bulb (OB), we examined the development of fiber systems within these TX OBs. One antibody for olfactory marker protein (OMP) was used to identify axons of mature olfactory receptor neurons (ONs) and a second antibody, for a growth-associated protein (GAP-43), provided a marker for all extending or immature fibers. Donor OBs were taken from fetuses on embryonic days 14 or 15 (sperm-positive day is zero) and TX directly into the cavity produced by removal of an OB in 1-day-old hosts of the same strain. After survival times of 1 and 2 weeks and at maturity, adjacent 8 microns paraffin sections from the TX material were examined for OMP and GAP-43 reactivity. Fiber bundles, reactive for OMP, were found within the TX by 1 week post-TX, indicating rapid re-innervation of the donor OB by ONs. The appearance of OMP reactivity gradually shifted from tightly packed, well-defined fiber bundles at 1 week post-TX to a diffuse reticulated pattern of individual fibers emerging from bundles at maturity. The OMP-reactive fiber bundles of the TX OB also contained GAP-43-reactive fibers, but GAP-43 reactivity also extended to other (OMP-negative) bundles and fields. Reactivity for GAP-43 in the TX OB was nearly ubiquitous at 2 weeks post-TX but, as development progressed (in both the TX and normal OB), such reactivity gradually decreased. Thus, while maturation in sensory afferent fiber systems in the TX OB may be delayed, it eventually follows a pattern similar to that in the normal OB, suggesting that factors other than the timing of fiber extension may be responsible for the laminar disorganization of the TX OB.

Olfactory ensheathing glia and platelet-derived growth factor B-chain reactivity in the transplanted rat olfactory bulb.

Using a monoclonal antibody against the B-chain of platelet-derived growth factor as a marker, we have examined the behavior of olfactory ensheathing glia in the normal and transplanted rat olfactory bulb. In the normal postnatal olfactory bulb, these glia are found to ensheath the bundles of incoming primary olfactory nerve fibers as well as those in the olfactory nerve layer. Olfactory marker protein antibody was used to identify the olfactory nerve proper. Within the transplant, the same glia: (1) ensheath bundles of both primary olfactory and non-primary olfactory axons, (2) ensheath axonal bundles deep within the donor tissue, and (3) eventually permit radiation of individual axons from bundles to surrounding neuropil. We believe that ensheathing glia (being rich in growth-related factors and extracellular matrix molecules) may be useful in providing trophic support and guidance for the reconstruction of developmentally or traumatically damaged neuronal pathways not directly related to the olfactory system. The evidence presented here indicates that ensheathing glia are capable of existing in deep brain areas and ensheathing other than primary olfactory axons. The special molecular characteristics of these glia along with the morphological findings presented here provide a foundation for further studies of these unique glia and their potential utility in the restoration of damaged neural pathways.

Platelet-derived growth factor B-chain-like immunoreactivity in the developing and adult rat brain.

Platelet-derived growth factors (PDGFs) are growth-regulatory molecules that stimulate chemotaxis, proliferation and increased metabolism, primarily of connective tissue cells. In our previous paper, we have demonstrated the ubiquitous localization of PDGF B-chain-containing proteins in neurons and expression of transcripts for PDGF A-chain, B-chain and the two forms of the PDGF receptor in the brains of non-human primates. In the present study, the cellular localization of PDGF B-chain in developing and adult rat brains was analyzed using immunocytochemistry with a PDGF B-chain-specific monoclonal antibody. Intense PDGF B-chain immunoreactivity (PDGFB-I) was distributed around the continuously regenerating primary olfactory neurons at all stages of development from embryo to adult. The major part of PDGFB-I associated with neurons appeared some time after birth and increased with age. PDGFB-I appeared in several nerve fiber systems during earlier stages of development and gradually decreased with age. In conjunction with other data showing the existence of functional PDGF receptor beta-subunits in the neurons, these data suggest a possible role for PDGF B-chain as a neurotrophic or neuroregulatory factor in both developing and mature brains.

Fetal olfactory bulb transplants send projections to host olfactory cortex in the rat.

We are using the rat olfactory system to study developmental details of neurotransplantation. Tritiated [3H]thymidine-labeled fetal olfactory bulbs (OBs), were transplanted immediately into sites from which the neonatal host OB was removed. Subsequently, a small lesion was placed in the region of the transplanted OB and the tissue studied, using degeneration methods and autoradiography. Only OB's with extensive [3H]-label and precise lesions confined to the labeled areas were used. Degeneration was found mainly in the ipsilateral piriform cortex with lesser amounts at other nearby sites. The results demonstrate successfully transplanted donor OBs that send axons to specific and appropriate target areas of the host brain.

Exploration of selected brachial plexus lesions by the posterior subscapular approach.

The application of an old surgical technique, previously employed for treatment of thoracic outlet syndromes, to lesions of the brachial plexus is discussed. Positioning of the patient, the surgical procedure, and selected indications for a posterior subscapular approach with resection of the first rib are discussed. The indications for the use of this approach are: proximal plexus lesions involving roots and/or trunks believed to be repairable, complicated thoracic outlet syndromes, prior anterior exploration for vascular or nervous structure disease, and progressive plexus palsy associated with damage to the soft tissue of the anterior chest wall and supraclavicular regions secondary to irradiation. The authors' experience to date with 12 such cases is presented in chart form, while five cases are presented in some detail.

Diet selection following area postrema/nucleus of the solitary tract lesions.

Ten adult Long-Evans male rats were offered access to fat, protein and carbohydrate from separate sources. After adaptation to this diet, 5 animals received thermal lesions of the area postrema and adjacent caudal-medial portion of the nucleus of the solitary tract (AP/cmNTS). The remainder were sham-operated. AP/cmNTS lesioned rats ate significantly less and lost more weight than controls during the first postsurgery measurement period (Days 4-13 after lesioning). The decrease of food intake of AP/cmNTS lesioned rats was due to reduced fat consumption. Carbohydrate and protein intakes of lesioned animals did not differ from those of controls. Food intakes and weight changes of lesioned rats did not differ from those of controls during days 14-23 after lesioning. Intake of fat by lesioned animals remained low but was no longer significantly different from that of controls. Carbohydrate and protein intakes of lesioned rats increased slightly but did not differ significantly from those of nonlesioned controls.

Area postrema/nucleus of the solitary tract ablations: analysis of the effects of hypophagia.

The effect of hypophagia following lesions of the area postrema and caudal-medial aspect of the nucleus of the solitary tract AP/cmNTS) on body-weight, water intake and preference for palatable diets was examined. Following AP/cmNTS ablation, rats reduced pelleted-food intake to a degree which was sufficient to account for the weight loss and increased water:food ratios observed. Restricting food intakes of intact rats to levels taken by lesioned animals resulted in similar weight losses and increased water:food ratios. When offered both pelleted food and milk, lesioned rats took more calories as milk than did previously food-restricted intact rats. Thus, the hypophagia of AP/cmNTS lesioned rats does not account for their increased preference for milk diets. Lesioned rats ate less high-fat diet than did intact or sham-lesioned controls and did not increase their intakes when this diet was sweetened. At autopsy, retroperitoneal and epididymal fat-pad weights accounted for less of the total body weight of lesioned animals than controls suggesting that body-fat levels are reduced following AP/cmNTS ablation.

Response to chronic insulin administration: effect of area postrema ablation.

The effects of daily administration of protamine zinc insulin (PZI) on plasma insulin and glucose levels and on food intake and body weight of rats with lesions of the area postrema and adjacent caudal-medial portions of the nucleus of the solitary tract (APX rats) were examined. Prior to insulin treatment, APX rats weighted less and had lower plasma immunoreactive insulin (IRI) levels than nonlesioned controls but did not differ from controls in plasma glucose levels. Five daily injections of 5 U/kg PZI raised plasma IRI and lowered plasma glucose levels similarly for both lesioned and nonlesioned rats. When injected with increasing doses of PZI over a 30-day period, both lesioned and nonlesioned rats showed increases of food intake and rate of weight gain in response to 8 U/kg PZI. These data indicate that APX does not affect either physiological or behavioral responses to chronic peripheral insulin administration.