Low oxygen exposure does not cause pulmonary injury in the newborn rat.

BACKGROUND: Two recent studies have suggested that low levels of supplemental inspired oxygen may cause lung injury in preterm infants. AIMS: To assess lung injury of newborn rats exposed to 14 days of low-level variation of oxygen. STUDY DESIGN: Four groups were compared with 12 animals per group and 4 lung sections per animal. These were, a control group raised in room air and three groups raised in levels of inspired oxygen fluctuating around the following mean values: group Lo (mean FiO(2) 0.179), group N (mean FiO(2) 0.213), and group Hi (mean FiO(2) 0.247). The degree of oxygen variability was identical for each group. Lungs were inflated at 20 cm H(2)O, fixed and stained with H and E and Millers Elastin. SUBJECTS: Sprague Dawley albino newborn rats. OUTCOME MEASURES: Random alveolar areas were studied and analysed using imaging software to assess total amount of tissue and elastin, number of secondary septa, and mean linear intercept. RESULTS: There were no significant differences between the three experimental oxygen groups and the control group in terms of lung/body weight ratio and the measured markers of lung development. CONCLUSION: We conclude that low-level oxygen supplementation during early lung development does not affect alveolar development in the newborn rat.

A novel model of retinopathy of prematurity simulating preterm oxygen variability in the rat.

PURPOSE: To examine changes in the retinal vasculature of rat pups after 14 days of minute-by-minute small variations in oxygen. METHODS: Arterial oxygen data from a preterm infant who developed severe retinopathy of prematurity (ROP) was translated to equivalent values for the rat. Newborn rat pups were raised for 14 days in a cage in which a computer controlled the atmosphere to mimic the fluctuating oxygen profile (group V). Positive controls (P) of 12-hour cycles of 80% and 21% were run concurrently, as were room air controls (C). All were killed at day 14. RESULTS: Groups V and P had significantly larger avascular retinal areas than C [median, interquartile range (IQR) 1.7%, 0-7.9%; 10%, 8.1-13%; 0%, 0-0%, respectively; each group n = 30]. Group P had a higher capillary branch count than C (median, IQR: 310/mm(2); 253-311 mm(2); versus 277/mm(2), 272-364/mm(2), respectively), but this was not significant using a multilevel analysis. Group V had significantly reduced capillary counts compared with C (median, 261/mm(2); IQR, 215-290/mm(2); P < 0.05 multilevel analysis). No neovascularization was seen in any group, though abnormal terminal vessels were seen at the avascular/vascular retina interface in 73% of rats in group P and 21% of rats in group V. In situ hybridization on serial sections demonstrated VEGF in the inner nuclear layer of the retina in P and V, whereas C showed trace levels only. CONCLUSIONS: The vaso-obliterative stage of ROP can be induced in rats using clinically relevant oxygen levels.

Dissociation of osmoregulation from plasma arginine vasopressin levels following thermal injury in childhood.

Although the syndrome of inappropriate anti-diuretic hormone secretion has been recognised as a complication associated with burn and other trauma in adults, relatively little is known about its incidence in children. The objective of this study was to investigate whether it is a complication associated with burn injury in children. Plasma and urine levels of arginine vasopressin (anti-diuretic hormone), sodium and osmolality were measured in samples collected from 16 burn-injured children admitted to the burns unit of the regional children's hospital. No significant correlations were found between plasma vasopressin and plasma sodium or osmolality levels, but there were significant correlations between plasma vasopressin and urine osmolality, 36 (r=0.74, p=0. 009), 60 (r=0.92, p=0.000) and 84 h (r=0.84, p=0.001) after admission, respectively. There were also significant correlations between plasma sodium and plasma osmolality, 24 (r=0.7, p=0.005), 36 (r=0.57, p=0.04) and 84 h (r=0.84, p=0.004) after admission. The data suggest dissociation between the osmolar control of vasopressin secretion and vasopressin levels after burn injury in children, but do not support the incidence of inappropriate secretion of antidiuretic hormone.

Systemic hormonal, electrolyte, and substrate changes after non-thermal limb injury in children.

Relatively little is known regarding the hormonal changes after injury in children. Adult protocols are often applied to children, although the latter often have different physiological responses to trauma. Twenty children with an angulated displaced fracture of the radius and/or ulna (injury severity score 9) were studied prospectively for changes in adrenaline, noradrenaline, cortisol, angiotensin II, arginine vasopressin, urea, electrolytes, and glucose. Two blood samples were taken: one an arrival at the accident and emergency department and one preoperatively several hours later. There were marked increases in adrenaline, noradrenaline, cortisol, and arginine vasopressin above the normal range. Five (25%) cases demonstrated greater early increases in adrenaline than those reported for adult injuries of similar severity. Early hypokalaemia in four cases had corrected towards normal within a few hours, without potassium supplementation.

The systemic stress response to thermal injury in children.

OBJECTIVE: Thermal injury is extremely stressful, but data characterizing the endocrine stress response to this injury in children are sparse. The objective of this study was to measure the effects of thermal injury on the levels of stress hormones in children and to assess the temporal changes associated with them. PATIENTS: Twenty-three children, 13 girls and 10 boys aged between 5 months and 12 years 3 months (mean, 2 years 11 months), with burns covering 10-61% of their body surface (mean, 20.5%) were studied during the first 5 days following injury. MEASUREMENTS: The levels of arginine vasopressin, angiotensin II, cortisol, adrenaline, noradrenaline and dopamine were measured in sequential blood samples obtained from thermally injured children on admission and at specified time intervals during the 5 days of the investigation. RESULTS: At admission the concentrations of all the hormones were high, and varied widely between individual patients. The geometric mean and 95% confidence intervals of admission hormone levels were as follows: arginine vasopressin 18.3 (8.3-40.7) pmol/l; angiotensin II 122.0 (56.0-266.2) pmol/l; cortisol 650.6 (473.0-895.0) nmol/l; dopamine 1.0 (0.1-8.0) nmol/l; adrenaline 6.4 (3.2-12.5) nmol/l and noradrenaline 2.3 (1.3-4.3) nmol/l. Although the concentrations of arginine vasopressin and cortisol returned to normal 24 to 36 h after admission, the levels of angiotensin II, adrenaline and dopamine fluctuated and remained higher than normal throughout the study (108 h). CONCLUSIONS: Thermal injury results in the release of abnormally high levels of stress hormones in children. Although there are similarities between some of the data reported here and those reported in adults, higher levels of adrenaline and lower levels of noradrenaline than reported in adults suggest important differences too. These differences may need to be taken into account in the management of burn-injured children.

The bigger the burn, the greater the stress.

Data characterizing the endocrine stress response to burn injury in children are sparse. We have measured the levels of the stress hormones arginine vasopressin, catecholamines-adrenaline, noradrenaline and dopamine-atrial natriuretic peptide and hormones of the renin-angiotensin-aldosterone system in admission blood samples taken from 35 children admitted to the burns unit of the regional children's hospital. Hormone levels were compared with the size of burn injury. With the exception of adrenaline, there were significant positive correlations between vasopressin (r = 0.707, p < 0.0001), plasma renin activity (r = 0.721, P < 0.0001), angiotensin II (r = 0.512, P = 0.002), aldosterone (r = 0.620, P < 0.0001), noradrenaline (r = 0.430, P = 0.0189), dopamine (r = 0.627, P = 0.0024) and percentage burn surface area, and a negative correlation between atrial natriuretic peptide (r = 0.548, P = 0.0008) and burn surface area. It is concluded that the hormones which react to stress are very sensitive to burn injury in children, and that the magnitude of their response is closely related to the size of the burn surface area.

Beta B2-crystallin in the mammalian retina.

beta-crystallins are abundant lens proteins in most, if not all vertebrate species. We have previously reported the presence of low levels of beta-crystallins in chick non-lens tissues, both ocular and extra-ocular, including the expression of beta B2-crystallin in the retina. Here we report that extralenticular beta-crystallin expression is also found in mammals. beta B2-crystallin is expressed in mouse and cat neural and pigmented retinas and in cat iris. Although present at levels lower than those found in the lens, the appearance and accumulation of beta B2-crystallin in the neural retina coincides with the functional maturation of this tissue.

A mouse model of early social interactions after prenatal drug exposure: a genetic investigation.

The aim of the present study was to (i) characterise the mouse behavioural profile (particularly social interactions) during the preweaning period, (ii) assess the effects of prenatal exposure to an anticonvulsant drug widely used in clinical practice, (iii) examine possible genetic differences both in baseline behavioural profiles and in sensitivity to drug-induced effects. Following a balanced intra-strain fostering procedure, the offspring of C57BL/6J and CBA inbred mouse strains from mothers exposed during pregnancy to either phenobarbitone (PHB, 60 mg/kg) or vehicle (VEH) given intraperitoneally (IP) during days 10-16 of gestation, were observed for early social interactions in the home cage during the last part of the preweaning period (days 20 and 21). The behavioural repertoires of the two strains differed markedly, in that C57 pups were more involved in Play soliciting, Locomotor-rotational play, and in Maintenance activities, while CBA mice spent much more time being inactive or exploring the environment. C57 and CBA mice also differed in the sensitivity to PHB exposure. On the whole, time spent in Investigative/Affiliative behaviours was increased, while the frequency of Play soliciting patterns was reduced in PHB-treated mice. The treatment of the fostering mother had only negligible effects, suggesting that PHB-induced changes in behaviour were largely due to direct effects of the substance on the foetus. These results indicate that specific items of the preweaning behavioural profile, and particularly social interactions, are influenced by early PHB exposure, and that the responses are heavily affected by the genotype.

Behavioural effects of gestational exposure to aluminium.

The involvement of aluminium in the aetiology of a number of human pathological diseases has altered its status from being a nontoxic, nonabsorbable, harmless element. This maybe of particular concern to the developing foetus which is more susceptible to agents and at lower levels than the adult. Little attention has been given to aluminium's potential reproductive toxicity until recently and further research is required for a full evaluation of its toxicity. Our preliminary results demonstrate behavioural and neurochemical alterations in the offspring of mice exposed to aluminium during gestation. Further, the effects of such exposure are also present in the adult animal suggesting persistent changes in behaviour following prenatal exposure.

Genetic differences in maternal behaviour patterns in mice administered phenobarbital during pregnancy.

In a study designed to examine the role of the genotype on sensitivity to drug-induced behavioural changes, pregnant C57BL/6J and CBA mice were administered 60 mg/kg phenobarbital (PHB) intraperitoneally during days 10-16 of gestation. Following a balanced intrastrain fostering procedure, the behaviour of lactating dams was observed in their home cage at 2, 3, 5, 7 and 14 days postpartum. As the pups became older, maternal behaviour declined in control groups, whereas PHB dams of the CBA strain persisted in nursing their pups. C57 dams were generally affected in an opposite way by PHB exposure. For example, treated dams spent significantly less time in licking behaviour. Nest quality score was especially elevated in PHB dams of the CBA strain, while in C57 dams, nest-building was inhibited and nest quality unaffected by the previous PHB exposure. These results indicate that specific items of maternal behaviour can be differently affected by PHB exposure, and that the responses are affected by the genotype. To summarise, pups raised by treated dams may receive either exaggerated or insufficient maternal attention, as a result of changes in neurotransmitter systems and behavioural regulation following phenobarbital exposure. These results point to the need for a better understanding of mother/pup interactions in studies aimed at characterizing drug and toxicant effects on postnatal development.

Activation of a procollagenase by low-molecular-weight angiogenesis factor.

Avascular tumours have the ability to establish a blood supply for themselves by secreting a humoral factor which stimulates their host's endothelial cells to proliferate and to migrate towards the tumour source. The mechanism of action of such a humoral angiogenesis factor is more than that of an endothelial-cell growth factor since it requires an oriented migration of cells towards the tumour. We report here the activation of pure skin-fibroblast procollagenase by a low-molecular-weight angiogenesis factor capable of stimulating endothelial-cell growth in vitro. The activation was observed when either Type I or III collagen was used as substrate. It is suggested that at least one function of angiogenesis factor is to promote limited degradation of the connective tissue through which it passes causing channeling in the matrix along which stimulated endothelial cells may migrate.

Collagenolytic enzyme systems in human intervertebral disc: their control, mechanism, and their possible role in the initiation of biomechanical failure.

Changes in the macromolecular matrix of the intervertebral disc may predispose to biomechanical failure of the disc. Such changes would involve extracellular enzymes capable of altering the collagen and proteoglycan of the disc matrix. In this study, extracts from homogenates of both annuli fibrosi and nuclei pulposi of human lumbar discs were found to contain neutral collagenolytic, gelatinolytic, and elastinolytic enzymes in all samples assayed. The specific activity of the collagenase was higher in extracts from nuclear than from annular tissue, a difference not seen with gelatinase or elastase. The collagenase was present as both a latent and active enzyme, the other enzymes being fully active. Human intervertebral discs therefore contain enzymes capable of degrading their extracellular macromolecular matrix.