Promoting teamwork may improve infant care processes during delivery room management: Florida perinatal quality collaborative's approach.

BACKGROUND: LOCAL PROBLEM: Inadequate understanding of compliance with standardized evidence-based DR management. INTERVENTIONS: Promote inter-professional teamwork and a bundle of interventions focusing on resuscitation team roles, equipment check, and debriefing using QI methodology. Optimize delivery room (DR) management to achieve 10-min SPO2 targets, delayed-cord clamping (DCC), team role assignment and debriefings in >50% of deliveries, and achieve normothermia in >75% of infants. METHODS: Over 15 months (Epoch 1 to 5), nine Florida hospitals implemented a DR management plan for infants <31 weeks gestational age or <1500 g (N=814) using quality improvement methodology. RESULTS: There was increased compliance of DCC (36 to 66%), role assignment (53 to 98%), debriefing rates (33 to 76%) and having all seven pre-delivery preparedness components fulfilled (34 to 75%). There were no significant improvements in admission temperatures or SPO2 targeting. When 7 vs 0 items of pre-delivery preparedness were completed, we saw improvements in thermoregulation (57% vs 72%), SPO2 targeting (60% vs 78%) and DCC compliance (43 to 67%). CONCLUSION: Promoting teamwork by increasing pre-delivery preparedness is associated with improvement of thermoregulation, SPO2 targeting and DCC compliance.

Red blood cell transfusions increase fecal calprotectin levels in premature infants.

OBJECTIVE: We hypothesized that red blood cell (RBC) transfusions influence intestinal inflammation in very low birth weight (VLBW) infants. We also suspected that hematocrit (Hct) at transfusions and RBC storage time correlate with intestinal inflammation. STUDY DESIGN: VLBW infants, without major congenital defects, intestinal perforation or necrotizing enterocolitis, were enrolled prospectively. Fecal calprotectin (FC) levels were measured from stool samples collected before and after RBC transfusions. Data on Hct and RBC storage time were collected. RESULT: Data from 42 RBC transfusions given to 26 infants revealed that FC levels increased faster than baseline after RBC transfusions (P=0.018) and were higher in multiple-transfused infants (0 to 48 and >48 h post transfusion, P=0.007 and P=0.005, respectively). Lower Hct and RBC storage >21 days correlated with higher FC levels (P=0.044 and P=0.013, respectively). CONCLUSION: RBC transfusions, anemia and prolonged RBC storage were associated with an increase in intestinal inflammation.

Effect of carotenoid supplementation on plasma carotenoids, inflammation and visual development in preterm infants.

OBJECTIVE: Dietary carotenoids (lutein, lycopene and ß-carotene) may be important in preventing or ameliorating prematurity complications. Little is known about carotenoid status or effects of supplementation. STUDY DESIGN: This randomized controlled multicenter trial compared plasma carotenoid levels among preterm infants (n=203, <33 weeks gestational age) fed diets with and without added lutein, lycopene and ß-carotene with human milk (HM)-fed term infants. We assessed safety and health. RESULT: Plasma carotenoid levels were higher in the supplemented group at all time points (P<0.0001) and were similar to those of term HM-fed infants. Supplemented infants had lower plasma C-reactive protein (P<0.001). Plasma lutein levels correlated with the full field electroretinogram-saturated response amplitude in rod photoreceptors (r=0.361, P=0.05). The supplemented group also showed greater rod photoreceptor sensitivity (least squares means 6.1 vs 4.1; P<0.05). CONCLUSION: Carotenoid supplementation for preterm infants raises plasma concentrations to those observed in HM-fed term infants. Carotenoid supplementation may decrease inflammation. Our results point to protective effects of lutein on preterm retina health and maturation.

Characterisation of amyloid-induced inflammatory responses in the rat retina.

Amyloid-induced inflammation is thought to play a critical and early role in the pathophysiology of Alzheimer's disease. As such, robust models with relevant and accessible compartments that provide a means of assessing anti-inflammatory agents are essential for the development of therapeutic agents. In the present work, we have characterised the induction of inflammation in the rat retina following intravitreal administration of amyloid-beta protein (Aß). Histology and mRNA endpoints in the retina demonstrate Aß1-42-, but not Aß42-1-, induced inflammatory responses characterised by increases in markers for microglia and astrocytes (ionised calcium-binding adaptor molecule 1 (iba-1), GFAP and nestin) and increases in mRNA for inflammatory cytokines and chemokines such as IL1-ß, MIP1α and TNFα. Likewise, analysis of vitreal cytokines also revealed increases in inflammatory cytokines and chemokines, including IL1-ß, MIP1α and MCP1, induced by Aß1-42 but not Aß42-1. This profile of pro-inflammatory gene and protein expression is consistent with that observed in the Alzheimer's disease brain and suggest that this preclinical model may provide a useful relevant tool in the development of anti-inflammatory approaches directed towards Alzheimer's disease therapy.

Bone ultrasound velocity in small- versus appropriate-for-gestational age preterm infants.

OBJECTIVE: To compare bone status of small-for-gestational age (SGA) versus appropriate-for-gestational age (AGA) newborn preterm infants. STUDY DESIGN: Tibial speed of sound (SOS) was measured in 144 infants categorized as SGA or AGA using the reference tables of Lubchenco et al. and Alexander et al. RESULTS: By the Lubchenco tables, 22% of infants were SGA and 75% were AGA. The mean gestational ages of SGA and AGA were similar (33.3+/-2.6 and 32.5+/-2.4 weeks, respectively, P = 0.09); however, SGA infant birth weights were lower (1329+/-392 and 1829+/-481 g, respectively, P<0.001). SOS values were higher for SGA versus AGA infants (3098+/-135 and 3003+/-122 m/s, respectively. P<0.001). Use of the Alexander tables yielded a twofold increase in the percent of infants categorized as SGA; SOS values remained significantly greater for SGA infants (P<0.001). CONCLUSION: Higher tibial SOS values in SGA versus AGA infants indicate greater bone strength.

Central effects of urotensin-II following ICV administration in rats.

RATIONALE: Urotensin-II (U-II) has recently been identified as an agonist for the G-protein-coupled receptor, GPR14. Detection of both U-II and GPR14 mRNA in the brain and spinal cord is consistent with a role for U-II in the CNS. However, the effects of central administration of U-II in rodents have not been reported previously. OBJECTIVES: To determine the localisation of GPR14 mRNA in rat tissues and to investigate the behavioural and endocrine effects of human U-II (hU-II) following intracerebroventricular (ICV) administration in rats. METHODS: Experiments were carried out in male Sprague-Dawley rats. Expression of GPR14 mRNA in rat brain was determined by semi-quantitative RT-PCR. Effects of hU-II on general behaviours were assessed by an observer and the motor activity response was measured by an automated activity monitor. Plasma hormones and [DOPAC + HVA]/[DA] and [5-HIAA]/[5-HT] ratios in five brain areas were measured 20 min post-hU-II (ICV). RESULTS: GPR14 mRNA expression was found in whole brain tissue and in all CNS regions tested. GPR14 mRNA expression was also detected in the periphery; highest levels were found in the heart. Following ICV administration, hU-II (3-10 micrograms ICV) increased rearing and grooming, and increased motor activity in a familiar environment. Further, hU-II increased plasma prolactin and TSH but did not affect levels of corticosterone. hU-II had no effects on dopamine or 5-HT levels or their metabolites in the frontal cortex, hippocampus, hypothalamus, striatum and nucleus accumbens. CONCLUSIONS: These data provide further insight into the distribution of GPR14 mRNA within the CNS and show for the first time that hU-II causes marked behavioural and endocrine effects.

Effects of centrally administered orexin-B and orexin-A: a role for orexin-1 receptors in orexin-B-induced hyperactivity.

RATIONALE: Orexin-A and orexin-B are hypothalamic neuropeptides derived from a 130-amino acid precursor, prepro-orexin, and are potent agonists at both the orexin-1 (OX1) and orexin-2 (OX2) receptors. Orexin-A has been ascribed a number of in vivo functions in the rat after intracerebroventricular (ICV) administration, including hyperphagia, neuroendocrine modulation and a role in the regulation of sleep-wake function. The in vivo role of orexin-B is not as clear. OBJECTIVES: To investigate the behavioural, endocrine and neurochemical effects of orexin-B in in-vivo tests. In a number of experiments, these effects were compared with those of orexin-A. METHODS: Experiments were carried out in male, Sprague-Dawley rats with a guide cannula directed towards the lateral ventricle. The effects of orexin-B (ICV) upon grooming behaviour were compared with those of orexin-A. The effects of orexin-B upon the motor activity response to both novel and familiar environments were assessed in an automated activity monitor. Orexin-B was tested upon startle reactivity and body temperature. Further, plasma hormones and [DOPAC+ HVA]/[DA] and [5-HIAA]/[5-HT] ratios in six brain areas were measured 40 min post-orexin-B or orexin-A. RESULTS: The clearest behavioural response to orexin-B was increased motor activity in both novel and familiar environments. Orexin-B-induced hyperactivity was blocked by an OX1 receptor antagonist, SB-334867-A, implicating OX1 receptors in this behavioural response. In common with orexin-A, orexin-B reduced plasma prolactin and failed to influence startle reactivity. However, in contrast with orexin-A, orexin-B increased head grooming but failed to cause a robust whole body grooming response or increase plasma corticosterone levels. Further, orexin-B, but not orexin-A, increased plasma TSH and increased hypothalamic and striatal [5-HIAA]/[5-HT] ratios. CONCLUSIONS: The present study has demonstrated a number of behavioural, neuroendocrine and neurochemical effects of orexin-B that distinguish it from orexin-A. Further, we have demonstrated a role for OX1 receptors in the actions of orexin-B upon motor activity.

Transcutaneous absorption of vitamin A in newborn rats.

Very low birth weight neonates have low tissue concentrations of vitamin A, which may contribute to the development of lung disease. These infants, however, may not receive vitamin A supplementation for several days after birth. We determined if the relatively permeable skin of a newborn could be used to administer vitamin A. 25 control rat pups were killed and lungs and livers were collected. 20 microl (1,000 IU) of retinyl palmitate were applied to the skin surface of an additional 50 two-day-old pups. At 2.5 and 5 h after application, 25 pups were killed, and lungs and livers were collected. Concentrations of retinyl palmitate and retinol were significantly higher in the lungs of pups 5 h after administration of vitamin A compared with controls. There were no differences in concentrations of retinyl palmitate or retinol in livers. We conclude that transcutaneous administration may be an effective means of delivering vitamin A to the lungs of newborn rats.

Pharmacological actions of a novel, high-affinity, and selective human dopamine D(3) receptor antagonist, SB-277011-A.

SB-277011-A (trans-N-[4-[2-(6-cyano-1,2,3, 4-tetrahydroisoquinolin-2-yl)ethyl]cyclohexyl]-4-quinolininecarboxamide), is a brain-penetrant, high-affinity, and selective dopamine D(3) receptor antagonist. Radioligand-binding experiments in Chinese hamster ovary (CHO) cells transfected with human dopamine D(3) or D(2 long) (hD(3), hD(2)) receptors showed SB-277011-A to have high affinity for the hD(3) receptor (pK(i) = 7.95) with 100-fold selectivity over the hD(2) receptor and over 66 other receptors, enzymes, and ion channels. Similar radioligand-binding data for SB-277011-A were obtained from CHO cells transfected with rat dopamine D(3) or D(2). In the microphysiometer functional assay, SB-277011-A antagonized quinpirole-induced increases in acidification in CHO cells overexpressing the hD(3) receptor (pK(b) = 8.3) and was 80-fold selective over hD(2) receptors. Central nervous system penetration studies showed that SB-277011-A readily entered the brain. In in vivo microdialysis studies, SB-277011-A (2. 8 mg/kg p.o.) reversed the quinelorane-induced reduction of dopamine efflux in the nucleus accumbens but not striatum, a regional selectivity consistent with the distribution of the dopamine D(3) receptor in rat brain. SB-277011-A (2-42.3 mg/kg p.o.) did not affect spontaneous locomotion, or stimulant-induced hyperlocomotion. SB-277011-A (4.1-42.2 mg/kg p.o.) did not reverse prepulse inhibition deficits in apomorphine- or quinpirole-treated rats, but did significantly reverse the prepulse inhibition deficit in isolation-reared rats at a dose of 3 mg/kg p.o. SB-277011-A (2.5-78. 8 mg/kg p.o.) was noncataleptogenic and did not raise plasma prolactin levels. Thus, dopamine D(3) receptor blockade produces few of the behavioral effects characteristic of nonselective dopamine receptor antagonists. The effect of SB-277011-A on isolation-induced prepulse inhibition deficit suggests that blockade of dopamine D(3) receptors may benefit the treatment of schizophrenia.

Design and synthesis of trans-N-[4-[2-(6-cyano-1,2,3, 4-tetrahydroisoquinolin-2-yl)ethyl]cyclohexyl]-4-quinolinecarboxamide (SB-277011): A potent and selective dopamine D(3) receptor antagonist with high oral bioavailability and CNS penetration in the rat.

A selective dopamine D(3) receptor antagonist offers the potential for an effective antipsychotic therapy, free of the serious side effects of currently available drugs. Using clearance and brain penetration studies as a screen, a series of 1,2,3, 4-tetrahydroisoquinolines, exemplified by 13, was identified with high D(3) affinity and selectivity against the D(2) receptor. Following examination of molecular models, the flexible butyl linker present in 13 was replaced by a more conformationally constrained cyclohexylethyl linker, leading to compounds with improved oral bioavailability and selectivity over other receptors. Subsequent optimization of this new series to improve the cytochrome P450 inhibitory profile and CNS penetration gave trans-N-[4-[2-(6-cyano-1, 2,3, 4-tetrahydroisoquinolin-2-yl)ethyl]cyclohexyl]-4-quinolinecarbo xamide (24, SB-277011). This compound is a potent and selective dopamine D(3) receptor antagonist with high oral bioavailability and brain penetration in the rat and represents an excellent new chemical tool for the investigation of the role of the dopamine D(3) receptor in the CNS.

Orexin A activates locus coeruleus cell firing and increases arousal in the rat.

The localization of orexin neuropeptides in the lateral hypothalamus has focused interest on their role in ingestion. The orexigenic neurones in the lateral hypothalamus, however, project widely in the brain, and thus the physiological role of orexins is likely to be complex. Here we describe an investigation of the action of orexin A in modulating the arousal state of rats by using a combination of tissue localization and electrophysiological and behavioral techniques. We show that the brain region receiving the densest innervation from orexinergic nerves is the locus coeruleus, a key modulator of attentional state, where application of orexin A increases cell firing of intrinsic noradrenergic neurones. Orexin A increases arousal and locomotor activity and modulates neuroendocrine function. The data suggest that orexin A plays an important role in orchestrating the sleep-wake cycle.

Evidence to suggest that agonist modulation of hyperlocomotion is via post-synaptic dopamine D2 or D3 receptors.

It has been suggested that a sub-population of dopamine D3 receptors is located pre-synaptically and these serve as autoreceptors in dopamine projection areas such as the nucleus accumbens/ventral striatum. To study further the physiological role and synaptic location of the dopamine D3 receptor, we have investigated the in vivo effect of the D3/D2 receptor agonist quinelorane on amphetamine-induced hyperactivity and extracellular dopamine release from the nucleus accumbens of the conscious rat. Amphetamine increased dopamine release to 202 +/- 34% of pre-injection control values, but quinelorane at 2.5 micrograms/kg, a dose which effectively blocked amphetamine-induced hyperlocomotion, had no significant effect on amphetamine-induced dopamine release. These data suggest that hyperlocomotion is mediated via post-synaptic rather than pre-synaptic dopamine receptors. Since quinelorane has significant affinity for the dopamine D3 receptor, these effects may be via post-synaptic D3 receptors; however, D2 receptor effects cannot be disregarded. In summary, these data indicate that the quinelorane effect on amphetamine-stimulated hyperlocomotion is not mediated via D3 or D2 autoreceptors, but rather a population of receptors located post-synaptically, which appear to mediate the inhibition of rat locomotor activity.