Interleukin-10 reverses acute detrimental effects of endotoxin-induced inflammation on perinatal cerebral hypoxia-ischemia

Dithiocarbamates, a class of compounds widely used in medicine and agriculture, have been reported to impair sleep structure. These effects have been attributed to the decrease in norepinephrine levels induced by these drugs. However, it has also been recently demonstrated that most of the mechanisms by which dithiocarbamates damage cell function involve changes in oxidative environment. To verify the potential relevance of the latter mechanism in the sleep impairment, we examined the sleep response of adult rats to an acute administration of diethyldithiocarbamate (DDTC). At the dose of 0.6 g/kg, DDTC induced fragmentation and a decrease in slow wave sleep (SWS), and a dramatic loss of paradoxical sleep (PS). These changes occurred soon after the treatment (day 0), persisted the following day (day 1), partially recovered on day 3, and regained near basal values on day 6. No sleep anomalies were observed with a lower dose of DDTC (0.06 mg/kg). On the other hand, when the higher dose of DDTC was given in association with either one of two antioxidants, alpha-tocopherol or melatonin, the amounts of SWS and PS significantly improved even on day 1, suggesting that the DDTC effects on sleep involved an impairment of the brain oxidative balance. Likewise, administration of the lower dose of DDTC 5 days before the higher dose induced a much earlier recovery of normal sleep, presumably due to the development of a tolerance to DDTC. On the whole, the data suggest that the brain oxidative environment may play a role in the mechanisms subserving sleep regulation.     

Does nitric oxide prevent oxidative mediated lung injury?

The US Food and Drug Administration recently approved nitric oxide (NO) inhalation therapy for newborn infants >34 wk of gestation with hypoxic respiratory failure associated with pulmonary hypertension. In clinical trials, this therapy has reduced the need for extracorporeal membrane oxygenation. It has not reduced mortality, however. A body of accumulating data indicates that NO may act as an antioxidant as well as a prooxidant, depending on a number of known and unknown factors, e.g. the concentration of NO itself and the concentration of other oxidants. In low doses, NO is an antioxidant and in high doses its prooxidant effects are more pronounced. In this issue of Acta Paediatrica, new information regarding this question has come to light. Turanlanthi et al. have found that NO in relatively high doses induces free radical mediated injury in the lungs of 10-wk-old Wistar rats, while in combination with hyperoxia it attenuates the oxidative stress of hyperoxia alone. Recently, it has also become clear that NO acts as a second messenger activating a number of cytokines and inducing apoptosis. There therefore seems to be a close relation between NO, oxidative stress, regulation of growth and inflammation. For these reasons, long-term follow-up studies of newborn infants treated with NO inhalation are needed. So far, NO therapy has not been successful in premature infants. Conclusions: NO inhalation has a number of both short-term and long-term potential adverse effects, and is still at the experimental stage in premature infants. Consequently, there is a need for further clinical studies monitoring also the long-term consequences of this therapy.     

Sodium nitroprusside prevents oxygen-free-radical-induced pulmonary vasoconstriction in newborn piglets

The aim of the present study was to test whether hypoxanthine-xanthine oxidase (XO) induced a pulmonary vasoconstriction in newborn piglets, and whether this vasoconstriction could be attenuated or abolished by pretreatment of nitric oxide (NO) donor sodium nitroprusside (SNP). Twenty-five anesthetized newborn piglets (1-3 days old) were randomly assigned to the following four groups: the control group received saline intravenously only; the XO group received 0.1 mmol/kg of hypoxanthine subsequent with XO (1.5 U/kg); the SNP group received the same dosages of hypoxanthine/ XO together with SNP intravenously, allopurinol (ALP) group received ALP intravenously prior to hypoxanthine and XO injection. After giving XO, the pulmonary arterial pressure (PAP) and vascular resistance (PVR) increased, while the cardiac index decreased significantly in the XO group. By contrast, these variables were not significantly modified by XO injection in the SNP and ALP groups. The data suggest that oxygen free radicals induce a pulmonary vasoconstriction in newborn piglets, and this vasoconstriction can be prevented by infusion of the NO donor SNP.     

Letter to the Editor

The present study comprises all deaths in Norwegian psychiatric hospitals in 1950-74 with the diagnosis of non-organic (functional) psychosis: 5106 deaths. Mortality declined in both sexes as did excess mortality which is now 1.7 times the general population in the male, and 2.3 times in the female sex. However, a significant rise in unnatural deaths (suicides and accidents) took place in both sexes during 1963-74, as mortality increased 2-3 times in comparison with 1950-62. This rise in unnatural deaths is probably directly related to the introduction of drug therapy, which created an increased need for protection of the hospital population. A challenge which the accompanying changes in the hospital environment have failed to meet. Cardio-vascular mortality increased considerably during 1963-74 in both sexes. The rise is most likely the combined result of an adverse effect of drug therapy in individual patients (obesity, physical inactivity, increased smoking habits), the reduced stress-relieving effect of hospitalisation through shorter stays in hospital and the liberalization policy. We may not yet have experienced the total adverse effect on mortality of the increase in behavioural risk factors in psychiatric patients. It is suggested that future mortality studies include psychiatric out-patients.     

The determination of inosine and hypoxanthine in rat brain during normothermic and hypothermic anoxia

Since hypoxanthine and xanthine are metabolized by xanthine oxidase to urate in the presence of an adequate oxygen supply, the concentration of the precursors of urate may be used as markers of the oxygen supply to the central nervous system. the present paper intends to elucidate this question.
Brain anoxia was induced in rats by decapitation. the purine metabolites inosine (hypoxanthine-riboside) and hypoxanthine were determined in brain-tissue following anoxia which lasted from 1 min up to 24 h.
A new method for the determination of hypoxanthine in plasma was modified for the determination of these metabolites in brain tissue. This method has been evaluated with regard to precision and recovery.
The hypoxanthine level was significantly augmented after 8 min of normothermic (37°C) anoxia compared to control values. A steady increase in the concentration of this metabolite was found up to 24 h of anoxia, although the rate of increase tapered off after approximately 30 min of anoxia. A similar pattern was found with regard to alteration in inosine concentrations. the inosine level was, however, significantly increased compared to the control level already after one minute of anoxia.
During hypothermic (29°C) anoxia up to 2 h, the increase of brain tissue hypoxanthine concentration was slower compared to values found during normothermic anoxia. It is concluded that measurements of these metabolites in brain tissue are useful indicators of the degree of brain tissue hypoxia.     

Positive factors associated with promoting health in low-risk and high-risk populations of 15- and 16-year-old pupils in Oslo, Norway

AIM: To explore possible risk-reducing factors associated with the incidence of common illnesses and use of healthcare services among adolescents. METHODS: Cross-sectional questionnaire study conducted in all Oslo schools among all 15- and 16-y-olds in 2000 and 2001. The adolescent population was divided into a low-risk (LR) and a high-risk (HR) group, and into quartiles, based on a sum score of different negative life experiences. The groups were compared with respect to potential risk-reducing factors. RESULTS: 88% of the 8316 pupils filled in the questionnaires. The difference between the LR and HR groups was largest for the possible risk-reducing factor "my family values my opinion" (LR group = 92%; HR group = 82%), and "I manage to solve serious problems myself" (LR = 91%; HR = 86%). The family valuing the adolescents' opinions was the risk-reducing factor most often associated with lower incidences of illness and healthcare utilization. Among the adolescents at highest risk, less depression was strongly related to positive relationships with friends, boys: odds ratio = 0.1 (CI 95%: 0.0-0.7); and girls: 0.2 (0.1-0.5). Adolescents reporting that they managed their own problems had about half the risk of depression. CONCLUSION: Good relations with family and friends, and a feeling of managing one's own life, are significantly related to lower rates of illness, in particular depression, and less healthcare-seeking behaviour. The risk-reducing effects increase with increasing risk. Healthcare workers therefore need to pay more attention to HR patients.     

Inflammation increases vulnerability to hypoxia in newborn piglets: effect of reoxygenation with 21% and 100% O2

OBJECTIVE: The purpose of this study was to assess whether inflammation increases vulnerability to hypoxia, and influences the effect of 100% O(2) and 21% O 2 reoxygenation on brain. STUDY DESIGN: Newborn piglets (n = 31) were randomized to 4 interventional groups: pretreatment with saline or endotoxin. After hypoxia they were reoxygenated with 21% or 100% oxygen for 30 minutes, followed by 21% oxygen for all groups. To assess brain injury we measured extracellular brain tissue glucose, glycerol, and lactate/pyruvate by microdialysis, brain tissue oxygen tension, and laser Doppler flow. RESULTS: Administration of endotoxin reduced the time to reach base excess (BE) -20 mmol/L by median 32 minutes compared with saline ( P < .05). We found no differences in changes in biochemical markers, brain tissue microcirculation, or oxygen tension between piglets in the 4 groups. CONCLUSION: Endotoxin and hypoxia acted synergistically in inducing metabolic acidosis. In the presence of experimental inflammation, 21% oxygen seems as effective as 100% O(2) in reoxygenating piglets.     

Resuscitation with 100% O2 increases cerebral injury in hypoxemic piglets

Perinatal asphyxia is a major cause of immediate and postponed brain injury in the newborn. We hypothesized that resuscitation with 100% O2 compared with ambient air is detrimental to the cerebral tissue. We assessed cerebral injury in newborn piglets that underwent global hypoxia and subsequent resuscitation with 21 or 100% O2 by extracellular glycerol, matrix metalloproteinase (MMP) expression levels, and oxidative stress. Extracellular glycerol was sampled by cerebral microdialysis. MMP levels were analyzed in cerebral tissue by gelatin zymography, broad matrix degrading capacity, and real-time PCR. Total endogenous antioxidant capacity was measured by the oxygen radical absorbance capacity assay. Extracellular glycerol increased 50% after resuscitation with 100% O2 compared with 21% O2. Total MMP activity was doubled in resuscitated animals at endpoint compared with baseline (p=0.018), and the MMP-2 activity was significantly increased in piglets that were resuscitated with 21% O(2) (p=0.003) and 100% O2 (p=0.001) compared with baseline. MMP-2 mRNA level was 100% increased in piglets that were resuscitated with 100% O2 as compared with 21% O2 (p < 0.05). Oxygen radical absorbance capacity values in piglets that were resuscitated with 100% O2 were considerably reduced compared with both baseline (p=0.001) and piglets that were resuscitated with 21% O2 (p=0.001). In conclusion, our data show increased MMP-2 activity at both gene and protein levels, accompanied with cerebral leakage of glycerol, presumably triggered by augmented oxidative stress. Our findings suggest that resuscitation of asphyxiated piglets with 100% O2 is detrimental to the piglet brain compared with resuscitation with 21% O2.     

Treatment strategies for bronchopulmonary dysplasia with postnatal corticosteroids in Europe: the EURAIL survey

AIM: To survey practices in 14 European countries and describe strategies for the prevention and treatment of bronchopulmonary dysplasia with postnatal steroids (PNS). METHODS: In 1999-2000 questionnaires covering the use of PNS were sent to every neonatal unit taking very preterm newborns in charge, in population-based areas covering at least 20000 births annually. One questionnaire was sent to surveyed unit. The participating areas were chosen by an expert from each country participating in the Europe Against Immature Lung (EURAIL) study group. RESULTS: Responses to 331 questionnaires were received; the mean response rate by countries was 84% (range 64-100%). Teaching hospitals accounted for 19% of the responding units. The number of extremely premature newborns (less than 28 wk of gestation) admitted yearly to these units was 0 in 16%, < 20 in 62%, 20-39 in 11% and > 39 in 11%. Overall, 67% of the centres used PNS: 48% initiated treatment in non-intubated infants and 53% at 7-14 d. Treatment duration was 4-15 d in 62% and > 15 d in 21%. PNS administration was limited to intubated infants less often in smaller units [odds ratio (OR) 0.2, 95% confidence interval (95% CI) 0.1-0.6] and more often in non-teaching hospitals (OR 2.5, 95% CI 2.5-5.0). CONCLUSIONS: Although PNS have important side effects, they were still widely used in 1999 to treat or prevent chronic lung disease. Surprisingly, steroids are still prescribed in non-ventilated infants. PNS use should be based on guidelines derived from the evidence from randomized controlled trials. This evidence should be regularly updated and disseminated.