Neuropeptide Y attenuates anxiety- and depression-like effects of cholecystokinin-4 in mice.

We investigated the involvement of neuropeptide Y (NPY) in the modulation of cholecystokinin-4 (CCK-4)-evoked anxiety and depression. Adult male mice were injected with vehicle, CCK-4, NPY, NPY Y1 receptor agonist [Leu(31), Pro(34)]-NPY or antagonist BIBP3226, via intracerebroventricular route, and subjected to social interaction or forced swim test (FST) for the evaluation of anxiety- and depression-like phenotypes, respectively. To assess the interactions between the two systems, if any, NPYergic agents were administered prior to CCK-4 and the animals were subjected to these behavioral tests. Treatment with CCK-4 or BIBP3226 dose-dependently reduced social interaction time, while NPY or [Leu(31), Pro(34)]-NPY produced opposite effect. CCK-4 treatment increased immobility time in FST. This effect was reversed by NPY and [Leu(31), Pro(34)]-NPY, although BIBP3226 per se did not alter the immobility time. In a combination study, the anxiogenic or depressive effects of CCK-4 were attenuated by NPY or [Leu(31), Pro(34)]-NPY and potentiated by BIBP3226. The brains of CCK-4 treated rats were processed for NPY immunohistochemistry. Following CCK-4 treatment, the nucleus accumbens shell (AcbSh), ventral part of lateral division of the bed nucleus of stria terminalis (BSTLV), hypothalamic paraventricular nucleus and locus coeruleus showed a reduction in NPY-immunoreactive fibers. Population of NPY-immunopositive cells was also decreased in the AcbSh, BSTLV, prefrontal cortex and hypothalamic arcuate nucleus (ARC). However, NPY-immunoreaction in the fibers of the ARC and cells of the central nucleus of amygdala was unchanged. We conclude that, inhibition of NPY signaling in the brain by CCK-4 might be causal to anxiety- and depression-like behaviors.

Immunohistochemical localization and biochemical changes in catalase and superoxide dismutase during metamorphosis in the olfactory system of frog Microhyla ornata.

Amphibian metamorphosis is characterized by rapid tissue remodeling and drastic changes in the body structure and function. Like other organs, olfactory system also undergoes a dramatic rearrangement as the animal experiences transition from aquatic to terrestrial habitat. Reactive oxygen species (ROS) are known to play an important role during anuran metamorphosis and role of antioxidant enzymes like catalase and superoxide dismutase (SOD) are believed to play a major role in these processes. Therefore, we hypothesize that antioxidant enzymes in the olfactory system may undergo changes that reflect metamorphic processes. Immunohistochemical study revealed the presence of catalase and SOD in the olfactory receptor neurons and also granular reaction in olfactory epithelium of medial diverticulum during metamorphosis. Catalase and SOD immunoreactivity were seen in the epithelium of lateral diverticulum, vomeronasal organ as metamorphosis proceeds and in the apical lining of olfactory epithelium of adult frog. Biochemical study showed that catalase activity gradually increases in the olfactory system from metamorphic stage 40-46 and adult, while SOD activity decreases from stage 40 to 46 and increases in adult. Thus, the localization and relative levels of catalase and SOD during metamorphosis in the olfactory system suggests that these enzymes may be involved in protection from oxidative damage.

Agmatine in the hypothalamic paraventricular nucleus stimulates feeding in rats: involvement of neuropeptide Y.

BACKGROUND AND PURPOSE: Agmatine, a multifaceted neurotransmitter, is abundantly expressed in the hypothalamic paraventricular nucleus (PVN). Our aim was to assess (i) the effect of agmatine on feeding behaviour and (ii) its association, if any, with neuropeptide Y (NPY). EXPERIMENTAL APPROACH: Satiated rats fitted with intra-PVN cannulae were administered agmatine, alone or jointly with (i) α2-adrenoceptor agonist, clonidine, or antagonist, yohimbine; (ii) NPY, NPY Y1 receptor agonist, [Leu³¹, Pro³4]-NPY, or antagonist, BIBP3226; or (iii) yohimbine and NPY. Cumulative food intake was monitored at different post-injection time points. Furthermore, the expression of hypothalamic NPY following i.p. treatment with agmatine, alone or in combination with yohimbine (i.p.), was evaluated by immunocytochemistry. KEY RESULTS: Agmatine robustly increased feeding in a dose-dependent manner. While pretreatment with clonidine augmented, yohimbine attenuated the orexigenic response to agmatine. Similarly, NPY and [Leu³¹, Pro³4]-NPY potentiated the agmatine-induced hyperphagia, whereas BIBP3226 inhibited it. Moreover, yohimbine attenuated the synergistic orexigenic effect induced by the combination of NPY and agmatine. Agmatine increased NPY immunoreactivity in the PVN fibres and in the cells of the hypothalamic arcuate nucleus (ARC) and this effect was prevented by pretreatment with yohimbine. NPY immunoreactivity in the fibres of the ARC, dorsomedial, ventromedial and lateral nuclei of the hypothalamus was not affected by any of the above treatments. CONCLUSIONS AND IMPLICATIONS: The orexigenic effect of agmatine is coupled to increased NPY activity mediated by stimulation of α2-adrenoceptors within the PVN. This signifies the importance of agmatine or α2-adrenoceptor modulators in the development of novel therapeutic agents to treat feeding-related disorders.

Central regulation of feeding behavior during social isolation of rat: evidence for the role of endogenous CART system.

OBJECTIVE: Although hyperphagia and body weight gain are well-recognized consequences of social isolation, the underlying mechanisms are not understood. The aim of this work is to test the possibility that the endogenous cocaine- and amphetamine-regulated transcript peptide (CART) may be involved in the process. DESIGN: Socially isolated rats were screened for increase in food intake and body weight, and the modifications of these parameters by CART were evaluated. Furthermore, isolated animals were re-socialized and screened for reversal of these effects. Response of the endogenous CART system, in certain hypothalamic nuclei of the isolated and re-socialized rats, was evaluated with immunohistochemistry. SUBJECTS: Fifty days old naive male Sprague-Dawley rats were used. MEASUREMENTS: The effects of CART/CART antibody on the social isolation and subsequent re-socialization on feeding and body weight changes were monitored. Moreover, the immunohistochemical response of endogenous CART system to social isolation and re-socialization was analyzed morphometrically. RESULTS: While social isolation of rats for a period of 6 weeks caused progressive increase in food consumption and body weight gain, these rats showed a significant reduction in food intake and body weight when injected daily with CART via intracerebroventricular (i.c.v.) route, for the following 7 days. The re-socialization of isolated rats reduced food intake and body weight to the control levels. These effects of re-socialization were attenuated by immunoneutralization of the endogenous CART by i.c.v. CART antibody. Social isolation also resulted in a drastic reduction in CART immunoreactivity in the cells and/or fibers in the hypothalamic areas like dorsomedial, ventromedial, lateral, paraventricular and arcuate nuclei, recognized for their role in feeding. On the other hand, the CART immunoreactivity profile was fully restored following 7 days of re-socialization of the isolation-reared rats. CONCLUSION: Social isolation might down-regulate the hypothalamic CART-containing system, which in turn may lead to increase in food intake and body weight.

Lung function measurement in prematurely born preschool children with and without chronic lung disease.

OBJECTIVE: Prematurely born infants often have recurrent wheeze and long-term respiratory morbidity at follow-up. Assessment of airways obstruction in preschool children is feasible using the interrupter resistance (Rint) but has rarely been examined in preterm children with and without chronic lung disease (CLD). The objective of this study was to determine lung function measured by the interrupter technique, its feasibility in the ambulatory setting and respiratory health in prematurely born preschool children with and without CLD. STUDY DESIGN: Preterm children of 2 to 4 years with severe CLD (>30% oxygen at 36 weeks and discharged home receiving supplemental oxygen) (n=43, median gestational age 27 weeks and median birth weight 995 g) and without CLD (n=33, median gestational age 29 weeks and median birth weight 1366 g) attempting lung function test for the first time were enrolled. Respiratory symptoms score was calculated using a questionnaire. A single set of 10 consecutive Rint measurements was obtained using a portable device (MicroRint). Median of at least five occlusions with consistent shape of mouth pressure-time curves was taken to be a Rint measurement. To assess feasibility the children were categorized as 'satisfactory', 'failure' and 'rejected' depending on the outcome of the test. Outcome variables were respiratory symptoms score and Rint. RESULT: Satisfactory Rint measurement was obtained in 46 (61%) children, 9 (36%) 2-year olds, 17 (65%) 3-year olds and 20 (80%) 4-year olds. As compared with the preterm control children (n=18), CLD children (n=28) had significantly higher respiratory symptoms score (18.5 vs 6, P<0.01) and Rint expressed as absolute values (kPa l(-1)) and z-scores (1.33 vs 1.16 and 1.42 vs 1.0, P<0.01), respectively. CONCLUSION: Rint measurement is feasible in prematurely born children of preschool age in the ambulatory setup. Preschool children with severe CLD may be identified from preterm children without CLD by increased Rint that may be used as a screening tool and as an outcome measure for interventions.

Neonatal ventilation with inhaled nitric oxide vs. ventilatory support without inhaled nitric oxide for infants with severe respiratory failure born at or near term: the INNOVO multicentre randomised controlled trial.

BACKGROUND: Evidence from European centres to support the use of nitric oxide (NO) in mature newborns with evidence of severe respiratory failure is sparse. METHODS: Infants of >33 weeks' gestation, <28 days old, and with severe respiratory failure requiring ventilatory support were randomised to receive or not to receive inhaled NO (iNO). The study was not blinded. RESULTS: Sixty infants were recruited (29 allocated iNO, 31 no iNO) from 15 neonatal units in the UK, Finland, Belgium and the Republic of Ireland. 15/60 recruited babies died, and 8.1% of the survivors (4/45) were classified as severely disabled at 1 year. There was no statistically significant difference between the randomised groups in terms of the primary outcome of death or severe disability by the corrected age of 1 year (relative risk = 0.96 (95% confidence interval = 0.46-2.03); p = 0.86) (Fisher's exact p = 1.00). The costs of NO were outweighed by reduced extra corporeal membrane oxygenation costs in the iNO group. The mean total hospitalisation costs were lower in the iNO group, although the mean difference (1,697 pounds) was not statistically significant (95% confidence interval = -14,472 to 11,478). CONCLUSIONS: The results complement those of previous studies that suggest NO is cost-effective and reduces the need for extra corporeal membrane oxygenation in this group of babies. Overall survival rates compare unfavourably with results of US trials.

Corticosteroids for treating hypotension in preterm infants.

BACKGROUND: Systemic hypotension is a relatively common complication of preterm birth and is associated with periventricular haemmorhage, periventricular white matter injury and adverse neurodevelopmental outcome. Corticosteroid treatment has been used as an alternative, or an adjunct, to conventional treatment with volume expansion and vasopressor/inotropic therapy. OBJECTIVES: To determine the effectiveness and safety of corticosteroids used either as primary treatment of hypotension or for the treatment of refractory hypotension in preterm infants. SEARCH STRATEGY: Randomized or quasi-randomized controlled trials were identified by searching the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 1, 2005), MEDLINE (1996 - June 2005), EMBASE (1974 - June 2005), reference lists of published papers and abstracts from the Pediatric Academic Societies and the European Society for Pediatric Research meetings published in Pediatric Research (1995 - 2004). SELECTION CRITERIA: We included all randomised or quasi-randomised controlled trials investigating the effect of corticosteroid therapy in the treatment of hypotension in preterm infants (< 37 weeks gestation) less than 28 days old. Studies using corticosteroids as primary treatment were included as well as studies using corticosteroids in babies with hypotension resistant to inotropes/pressors and volume therapy. We included studies comparing oral/intravenous corticosteroids with placebo, other drugs used for providing cardiovascular support or no therapy in this review. DATA COLLECTION AND ANALYSIS: Methodological quality of eligible studies was assessed according to the methods used for minimising selection bias, performance bias, attrition bias and detection bias. Studies that evaluated corticosteroids (1) as primary treatment for hypotension or (2) for refractory hypotension unresponsive to prior use of inotropes/pressors and volume therapy, were analysed using separate comparisons. Data were analysed using the standard methods of the Neonatal Review Group using Rev Man 4.2.7. Treatment effect was analysed using relative risk, risk reduction, number needed to treat for categorical outcomes and weighted mean difference for outcomes measured on a continuous scale, with 95% confidence intervals. MAIN RESULTS: Two studies were included in this review enrolling a total of 57 babies. In the first study, persistent hypotension was more common in hydrocortisone treated infants as compared to those who received dopamine as primary treatment for hypotension (RR 8.2, 95% CI 0.47 to 142.6; RD 0.19, 95% CI 0.01 to 0.37). In the second study, persistent hypotension (defined as a continuing need for epinephrine infusion) was less common in dexamethasone treated infants as compared to controls who received placebo for refractory hypotension (RR 0.42 , 95% CI 0.17 to 1.06; RD -0.51, 95% CI - 0.91 to - 0.12). There were no statistically significant effects on any other short or long-term outcome. It was not considered appropriate to perform a meta-analysis. A further two studies that have only been published in abstract form to date, may be eligible for inclusion in a future update of this review. AUTHORS' CONCLUSIONS: There is insufficient evidence to support the routine use of steroids in the treatment of primary or refractory neonatal hypotension. Hydrocortisone may be as effective as dopamine in treating primary hypotension, but there are no data regarding the long-term safety of steroids used for this indication.A single dose of dexamethasone may be effective in treating preterm infants with refractory hypotension receiving epinephrine. However, given the lack of data on long-term safety dexamethasone cannot be recommended for routine use in preterm hypotension.

Temporal gene expression profiles of target-ablated olfactory epithelium in mice with disrupted expression of scavenger receptor A: impact on macrophages.

Target ablation [removal of the olfactory bulb (OBX)] induces apoptotic death of olfactory sensory neurons (OSNs) and an immune response in which activation and recruitment of macrophages (ms) into the olfactory epithelium (OE) occupy a central role. Ms phagocytose apoptotic neurons and secrete cytokines/growth factors that regulate subsequent progenitor cell proliferation and neurogenesis. Scavenger receptor A (SR-A) is a pattern recognition receptor that mediates binding of ms to apoptotic cells and other relevant immune response functions. The aim of this study was to determine the impact of the absence of SR-A on the immune response to OBX. The immune response to OBX was evaluated in mice in which functional expression of the m scavenger receptor (MSR) was eliminated by gene disruption (MSR-/-) and wild-type (wt) mice of the same genetic background. OBX induced significant apoptotic death of mature OSNs in the two strains. However, subsequent m infiltration and activation and progenitor cell proliferation were significantly reduced in MSR-/- vs. wt mice. Gene expression profiling at short intervals after OBX demonstrated significant differences in temporal patterns of expression of several gene categories, including immune response genes. Many immune response genes that showed different temporal patterns of expression are related to m function, including cytokine and chemokine secretion, phagocytosis, and m maturation and activation. These studies suggest that impairment of the immune response to OBX in the OE of MSR-/- mice most likely resulted from decreased m adhesion and subsequent reduced infiltration and activation, with a resultant decrease in neurogenesis.

Reproduction phase-related expression of beta-endorphin-like immunoreactivity in the nucleus lateralis tuberis of the female Indian major carp Cirrhinus mrigala: correlation with the luteinising hormone cells-ovary axis.

The present study aimed to determine whether beta-endorphin immunoreactivity (bEP-ir) in the neurones of the nucleus lateralis tuberis (NLT) is linked to the seasonal cycle and shows correlation with the number of luteinising hormone (LH) cells in the pituitary gland and ovaries in the teleost, Cirrhinus mrigala. Although LH cells were moderately immunostained during the resting phase (December to January), the morphological profile suggested increased synthetic and secretory activity during the preparatory (February to April) and prespawning (May to June) phases. However, LH immunoreactivity was greatly reduced (P < 0.001) in the spawning (July to August) phase, suggesting massive discharge of the hormone; this pool was partly replenished in the postspawning (September to November) phase. The ovaries grew rapidly in the preparatory and prespawning phases; maximal size was attained during spawning, when ovulation occurred. Thereafter, the ovaries regressed. The NLT of C. mrigala is divisible into the pars lateralis (NLTl) and medialis (NLTm). During the postspawning and resting phases, bEP-ir was readily detectable in the NLTm as well as NLTl neurones. However, a steady reduction in the immunoreactivity was observed in the NLTm neurones during the preparatory through spawning phases (P < 0.001), suggesting a negative correlation with the LH cells-ovary axis. Thus, the inhibitory influence of beta-endorphin on the gonadotrophin-releasing hormone (GnRH)-LH axis appears to be attenuated during the preparatory through spawning phases. This may be necessary for the rapid stimulation of the axis culminating in spawning. Neurones of the NLTl also showed a gradual reduction in bEP-ir during the preparatory and prespawning phases (P < 0.01) and may therefore play a similar role. However, significant augmentation of the immunoreactivity was noticed in these neurones during the spawning phase (P < 0.001), the physiological significance of which is unknown. Although the present study demonstrated a temporal correlation between the beta-endorphin in the NLT, LH cells and the ovary, we suggest that the peptide in the NLTl and NLTm may show functional duality during the spawning phase.

Role of neuropeptide Y in the regulation of gonadotropin releasing hormone system in the forebrain of Clarias batrachus (Linn.): immunocytochemistry and high performance liquid chromatography-electrospray ionization-mass spectrometric analysis.

Although the importance of neuropeptide Y (NPY) in the regulation of gonadotropin releasing hormone (GnRH) and reproduction has been highlighted in recent years, the neuroanatomical substrate within which these substances might interact has not been fully elucidated. Present work was undertaken with a view to define the anatomical-physiological correlates underlying the role exercised by NPY in the regulation of GnRH in the forebrain of the teleost Clarias batrachus. Application of double immunocytochemistry revealed close associations as well as colocalizations of the two peptides in the olfactory receptor neurons (ORNs), olfactory nerve fibers and their terminals in the glomeruli, ganglion cells of nervus terminalis, medial olfactory tract, fibers in the area ventralis telencephali/pars supracommissuralis and cells as well as fibers in the pituitary. NPY containing axons were found to terminate in the vicinity of GnRH cells in the pituitary with light as well as electron microscopy. Double immunoelectron microscopy demonstrated gold particles for NPY and GnRH colocalized on the membrane and in dense core of the secretory granules in the cells distributed in all components of the pituitary gland. To assess the physiological implication of these observations, NPY was injected via the intracranial route and the response of GnRH immunoreactive system was evaluated by relative quantitative morphometry as well as high performance liquid chromatography (HPLC) analysis. Two hours following NPY (20 ng/g body weight) administration, a dramatic increase was observed in the GnRH immunoreactivity in the ORNs, in the fibers of the olfactory bulb (163%) and medial olfactory tract (351%). High performance liquid chromatography-electrospray ionization-mass spectrometric analysis confirmed the immunocytochemical data. Significant rise in the salmon GnRH (sGnRH)-like peptide content was observed in the olfactory organ (194.23%), olfactory bulb (146.64%), telencephalon+preoptic area (214.10%) and the pituitary (136.72%) of the NPY-treated fish. However, GnRH in the hypothalamus was below detection limit in the control as well as NPY-treated fish. Present results suggest the involvement of NPY in the up-regulation of sGnRH containing system at different level of neuraxis extending from the olfactory epithelium to the pituitary in the forebrain of C. batrachus.

Neonatal Ventilation With Inhaled Nitric Oxide Versus Ventilatory Support Without Inhaled Nitric Oxide for Preterm Infants With Severe Respiratory Failure: the INNOVO multicentre randomised controlled trial (ISRCTN 17821339).

BACKGROUND: Although inhaled nitric oxide (iNO) may be a promising treatment for newborn infants with severe respiratory failure, the results from 3 previous small trials were inconclusive. METHODS: Infants of <34 weeks' gestation, <28 days old, and with severe respiratory failure requiring ventilatory support were randomized to receive or not receive iNO. The study was not blinded. FINDINGS: Recruited were 108 infants (55 allocated to receive iNO and 53 not allocated to receive iNO) from 15 neonatal units in the United Kingdom and Republic of Ireland. Fifty-nine percent (64 of 108) died, and 84% of the survivors (37 of 44) had signs of some impairment or disability, 9 (20%) of them classified as severely disabled. There was no evidence of an effect of iNO on the primary outcomes: death or severe disability at 1 year corrected age (relative risk [RR]: 0.99; 95% confidence interval [CI]: 0.76 to 1.29); death or supplemental oxygen on expected date of delivery (RR: 0.84; 95% CI: 0.68 to 1.02); or death or supplemental oxygen at 36 weeks' postmenstrual age (RR: 0.98; 95% CI: 0.87 to 1.12). There was a trend for infants allocated to the iNO group to spend more time on the ventilator (log rank: 3.6), on supplemental oxygen (log rank: 1.4), and in hospital (log rank: 3.5) than those allocated to receive no iNO. This pattern predominantly reflected the infants who died. Mean total costs at 1 year corrected age were significantly higher in the iNO group, partly because of the costs of the gas but mainly because of the difference in initial hospitalization costs. INTERPRETATION: Evidence of prolongation of intensive care and increased costs of such care, without clear beneficial effects, implies that iNO cannot be recommended for preterm infants with severe hypoxic respiratory failure.

Nasal potential difference increases with gestation in moderately preterm neonates on the first postnatal day.

At birth the mammalian airway switches from liquid secretion to absorption, an important mechanism in lung liquid clearance. Airway ion transport was examined on the first postnatal day in 38 moderately preterm infants (29-36 weeks gestation). The absorptive airway ion transport capacity was well developed regardless of respiratory condition and there was little capacity for Cl- secretion.

Treated threshold stage 3 versus spontaneously regressed subthreshold stage 3 retinopathy of prematurity: a study of motility, refractive, and anatomical outcomes at 6 months and 36 months.

AIM: To compare the visual acuity (VA), spherical equivalent refractive error, motility, and anatomical outcomes in children with treated regressed threshold stage 3 retinopathy of prematurity (ROP) and those with spontaneously regressed subthreshold stage 3 ROP. METHOD: 6 month and 3 year data collected from infants examined between 1989 and 1999 with regressed stage 3 ROP, with or without treatment were retrospectively reviewed. RESULTS: 85 infants were included in this study. 40 eyes received cryotherapy, 81 eyes laser photocoagulation, and 34 eyes had spontaneously regressed subthreshold stage 3 ROP. Grating acuity score > or =2 cycles/degree (c/d) at 6 months was predictive of optotype acuity > or =6/9 in 69% of eyes and a score <2 c/d at 6 months was predictive of acuity < 6/9 in 88% of eyes. Eyes with subthreshold stage 3 ROP were twice as likely to have VA of 6/9 or better at 36 months than the treated eyes. The mean spherical equivalent refractive error at 36 months was -6.5 dioptres (D) (-21.5D to +1.38D) in cryotherapy treated eyes, -2.4D (-13D to +4D) in the laser group, and -0.22D (-9D to +2.25D) in the subthreshold group. Eyes within the treated groups were more myopic than the eyes within the spontaneously regressed group (p = 0.005). At 36 months, 42 out of the 85 infants (that is, 49%) had strabismus (44% in the cryotherapy group, 26% in the laser group, and 25% in the subthreshold group). There was a statistically significant association between the presence of strabismus and anisometropia (p = 0.016) and strabismus and intraventricular haemorrhage (IVH) (p = 0.005). There was a statistically significant difference in the incidence of strabismus between mild and moderate and severe grade IVH (p = 0.01). Eight out of 40 eyes in the cryotherapy group and six out of the 81 eyes in the laser group developed macular ectopia. None of the eyes in the spontaneously regressed group had macular dragging. CONCLUSIONS: In this study, the grating acuity at 6 months was a good predictor of the 3 year optotype acuity in all groups. Eyes with spontaneously regressed subthreshold stage 3 ROP were associated with better vision at 3 years of age and a lesser degree of myopia compared to the treated groups. Strabismus developed predominantly in the treated groups and was frequently associated with neurological damage and/or anisometropia. The spontaneously regressed subthreshold stage 3 group had a better anatomical outcome compared to the groups in which the retinopathy regressed following treatment.

Betamimetics for inhibiting preterm labour.

BACKGROUND: Preterm birth is a major contributor to perinatal mortality and morbidity worldwide. Tocolytic agents are drugs used to inhibit uterine contractions. The most widely used tocolytic agents are betamimetics especially in resource-poor countries. OBJECTIVES: To assess the effects of betamimetics given to women with preterm labour. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group trials register (May 2003) without language restrictions. SELECTION CRITERIA: Randomised controlled trials of betamimetics, administered by any route or any dose, in the treatment of women in preterm labour where betamimetics are compared with other betamimetics, placebo or no treatment. DATA COLLECTION AND ANALYSIS: Two reviewers evaluated independently methodological quality and extracted the data. We sought additional information to enable assessment of methodology and conduct intention-to-treat analyses. We present the results using the relative risk for categorical data and the weighted mean difference for continuous data. MAIN RESULTS: Eleven randomised controlled trials, involving 1332 women, compared betamimetics with placebo. Betamimetics decreased the number of women in preterm labour giving birth within 48 hours (relative risk (RR) 0.63; 95% confidence interval (CI) 0.53 to 0.75) but there was no decrease in the number of births within seven days after carrying out a sensitivity analysis of studies with adequate allocation of concealment. No benefit was demonstrated for betamimetics on perinatal death (RR 0.84; 95% CI 0.46 to 1.55, 7 trials, n = 1332), or neonatal death (RR 1.00; 95% CI 0.48 to 2.09, 5 trials, n = 1174). No significant effect was demonstrated for respiratory distress syndrome (RR 0.87; 95% CI 0.71 to 1.08, 8 trials, n = 1239). A few trials reported the following outcomes, with no difference detected: cerebral palsy, infant death and necrotizing enterocolitis. Betamimetics were significantly associated with the following: withdrawal from treatment due to adverse effects; chest pain; dyspnoea; tachycardia; palpitation; tremor; headaches; hypokalemia; hyperglycemia; nausea/vomiting; and nasal stuffiness; and fetal tachycardia. Other betamimetics were compared with ritodrine in five trials (n = 948). Trials were small, varied and of insufficient quality to delineate any consistent patterns of effect. REVIEWERS' CONCLUSIONS: Betamimetics help to delay delivery for women transferred to tertiary care or completed a course of antenatal corticosteroids. However, multiple adverse effects must be considered. The data are too few to support the use of any particular betamimetics.

Concentrations of cardiac troponin T in neonates with and without respiratory distress.

AIMS: To establish a practical postnatal reference range for cardiac troponin T in neonates and to investigate concentrations in neonates with respiratory distress. METHODS: Prospective investigation in a tertiary neonatal unit, recruiting infants with and without respiratory distress (sick and healthy infants respectively). Concentrations of cardiac troponin T were compared between sick and healthy infants, accounting for confounding variables. RESULTS: A total of 162 neonates (113 healthy and 49 sick infants) had samples taken. The median (interquartile range) cardiac troponin T concentration in the healthy infants was 0.025 (0.01-0.062) ng/ml, and the 95th centile was 0.153 ng/ml. There were no significant relations between cardiac troponin T and various variables. The median (interquartile range) cardiac troponin T concentration in the sick infants was 0.159 (0.075-0.308) ng/ml. This was significantly higher (p < 0.0001) than in the healthy infants. In a linear regression model, the use of inotropes and oxygen requirement were significant associations independent of other basic and clinical variables in explaining the variation in cardiac troponin T concentrations. CONCLUSIONS: Cardiac troponin T is detectable in the blood of many healthy neonates, but no relation with important basic and clinical variables was found. Sick infants have significantly higher concentrations than healthy infants. The variations in cardiac troponin T concentration were significantly associated with oxygen requirement or the use of inotropic support in a regression model. Cardiac troponin T may be a useful marker of neonatal and cardiorespiratory morbidity.

Recent advances in diagnosis and management of pulmonary hypertension in chronic lung disease.

Pulmonary hypertension with elevated pulmonary vascular resistance is a common cardiovascular complication associated with increased morbidity and mortality in preterm infants with chronic lung disease. Injury to the developing pulmonary circulation results in structural and functional abnormalities of the pulmonary vasculature. Animal studies have demonstrated that disruption of angiogenesis may contribute to the failure of normal alveolarisation in chronic lung disease. Levels of vascular endothelial growth factor in bronchoalveolar lavage fluid are lower in infants with chronic lung disease compared to preterm controls. Supplemental oxygen is commonly used to prevent and treat pulmonary hypertension, although optimal arterial oxygen saturation levels remain uncertain. Other vasodilators such as inhaled nitric oxide appear promising, but as yet have not been evaluated in the form of randomised controlled trials. Further studies are required to investigate the long-term effectiveness of pulmonary vasodilator therapy.

Right ventricular volume measurements in ventilated preterm neonates.

Pulmonary hypertension is associated with worse perinatal outcomes in infants with respiratory disorders. In these infants, right ventricular dysfunction may result in poor pulmonary blood flow. The objective of this study was to follow changes in right ventricular volumes during the first 2 days of life in infants with respiratory distress syndrome. Serial echocardiographic examinations were performed on days 0-2 on infants ventilated for respiratory distress syndrome. Two-dimensional echocardiography with the ellipsoid approximation was used to calculate systolic and diastolic volumes. In 17 ventilated preterm infants, right ventricular volumes were significantly lower on day 2 compared with day 0 and decreased from a median (interquartile range) end systolic volume of 0.80 ml/kg (0.66-0.91 ml/kg) to 0.45 ml/kg (0.39-0.54 ml/kg) ( p < 0.001). End diastolic volume decreased from a median (interquartile range) of 1.54 ml/kg (1.44-1.65 ml/kg) to 1.30 ml/kg (1.22-1.60 ml/kg) ( p = 0.039). Right ventricular ejection fraction increased from a median (interquartile range) of 0.48 ml/kg (0.44-0.56 ml/kg) to 0.62 ml/kg (0.58-0.71 ml/kg) during the same period ( p < 0.001), as did right ventricular output from a median (interquartile range) 120 ml/kg/min (96-125 ml/kg/min) to 140 ml/kg/min (113-168 ml/kg/min) ( p = 0.044). Right ventricular volume decreases during the first 2 days of life in ventilated preterm infants. However, right ventricular performance is maintained.

Dopamine versus dobutamine for hypotensive preterm infants.

BACKGROUND: Inotropes are widely used in preterm infants to treat systemic hypotension. The most commonly used drugs are dopamine and dobutamine. These agents have different modes of action which may result in different haemodynamic effects. OBJECTIVES: To compare the effectiveness and safety of dopamine and dobutamine in the treatment of systemic hypotension in preterm infants. SEARCH STRATEGY: Searches of electronic and other databases were performed including MEDLINE (1966-2002), EMBASE (1988-2002), Science Citation Index (1981-2002), the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 2, 2003). Previous reviews were searched for references to relevant trials and leading authors in the field were contacted for information about other published and unpublished studies. SELECTION CRITERIA: Randomised controlled trials where short and/or long term effects of treatment with dopamine and dobutamine for the treatment of systemic arterial hypotension were compared were selected for this review. Trials studying newborn infants born before 37 completed weeks gestation and less than 28 days of age were eligible for inclusion. Systemic arterial hypotension was not defined specifically, but accepted as defined in individual studies. Studies were not limited by birthweight, lower gestational age threshold or by route or duration of administration of inotropic agents. Study quality and eligibility were assessed independently by each reviewer. DATA COLLECTION AND ANALYSIS: Data extraction was performed independently by each reviewer, with differences being resolved by discussion. The following outcomes were determined: mortality in the neonatal period, long term neurodevelopmental outcome, radiological evidence of severe neurological injury, short term haemodynamic changes and incidence of adverse effects. The effect of interventions was expressed either as Relative Risk (RR), Risk Difference (RD) or as Weighted Mean Difference (WMD) with their 95% Confidence Interval (CI). MAIN RESULTS: Five trials met the pre-defined criteria for inclusion in this review. There was no evidence of a significant difference between dopamine and dobutamine in terms of neonatal mortality (RD 0.02 95% CI -0.12 to 0.16), incidence of periventricular leukomalacia (RD -0.08, 95% CI -0.19 to 0.04), or severe periventricular haemorrhage (RD -0.02, 95% CI -0.13 to 0.09). Dopamine was more successful than dobutamine in treating systemic hypotension, with fewer infants having treatment failure (RD -0.23, 95% CI -0.34 to -0.13; NNT = 4.4, 95% CI 2.9 to 7.7). Treatment with dobutamine was associated with a significantly greater increase in left ventricular output in the single study reporting that outcome. There was no evidence of a significant difference between the two agents with respect to the incidence of tachycardia (RD -0.06, 95% CI -0.25 to 0.14). None of the studies reported the incidence of adverse long term neurodevelopmental outcome. REVIEWER'S CONCLUSIONS: Dopamine is more effective than dobutamine in the short term treatment of systemic hypotension in preterm infants. There was no evidence of an effect on the incidence of adverse neuroradiological sequelae (severe periventricular haemorrhage and/or periventricular leucomalacia), or on the incidence of tachycardia. However, in the absence of data confirming long term benefit and safety of dopamine compared to dobutamine, no firm recommendations can be made regarding the choice of drug to treat hypotension.