Fetal heart rate responses in chronic hypoxaemia with superimposed repeated hypoxaemia consistent with early labour: a controlled study in fetal sheep.

OBJECTIVE: Deceleration area (DA) and capacity (DC) of the fetal heart rate can help predict risk of intrapartum fetal compromise. However, their predictive value in higher risk pregnancies is unclear. We investigated whether they can predict the onset of hypotension during brief hypoxaemia repeated at a rate consistent with early labour in fetal sheep with pre-existing hypoxaemia. DESIGN: Prospective, controlled study. SETTING: Laboratory. SAMPLE: Chronically instrumented, unanaesthetised near-term fetal sheep. METHODS: One-minute complete umbilical cord occlusions (UCOs) were performed every 5 minutes in fetal sheep with baseline pa O2 <17 mmHg (hypoxaemic, n = 8) and >17 mmHg (normoxic, n = 11) for 4 hours or until arterial pressure fell <20 mmHg. MAIN OUTCOME MEASURES: DA, DC and arterial pressure. RESULTS: Normoxic fetuses showed effective cardiovascular adaptation without hypotension and mild acidaemia (lowest arterial pressure 40.7 ± 2.8 mmHg, pH 7.35 ± 0.03). Hypoxaemic fetuses developed hypotension (lowest arterial pressure 20.8 ± 1.9 mmHg, P < 0.001) and acidaemia (final pH 7.07 ± 0.05). In hypoxaemic fetuses, decelerations showed faster falls in FHR over the first 40 seconds of UCOs but the final deceleration depth was not different to normoxic fetuses. DC was modestly higher in hypoxaemic fetuses during the penultimate (P = 0.04) and final (P = 0.012) 20 minutes of UCOs. DA was not different between groups. CONCLUSION: Chronically hypoxaemic fetuses had early onset of cardiovascular compromise during labour-like brief repeated UCOs. DA was unable to identify developing hypotension in this setting, while DC only showed modest differences between groups. These findings highlight that DA and DC thresholds need to be adjusted for antenatal risk factors, potentially limiting their clinical utility.

Deceleration area and capacity during labour-like umbilical cord occlusions identify evolving hypotension: a controlled study in fetal sheep.

OBJECTIVE: Cardiotocography is widely used to assess fetal well-being during labour. The positive predictive value of current clinical algorithms to identify hypoxia-ischaemia is poor. In experimental studies, fetal hypotension is the strongest predictor of hypoxic-ischaemic injury. Cohort studies suggest that deceleration area and deceleration capacity of the fetal heart rate trace correlate with fetal acidaemia, but it is not known whether they are indices of fetal arterial hypotension. DESIGN: Prospective, controlled study. SETTING: Laboratory. SAMPLE: Near-term fetal sheep. METHODS: One minute of complete umbilical cord occlusions (UCOs) every 5 minutes (1:5 min, n = 6) or every 2.5 minutes (1:2.5 min, n = 12) for 4 hours or until fetal mean arterial blood pressure fell <20 mmHg. MAIN OUTCOME MEASURES: Deceleration area and capacity during the UCO series were related to evolving hypotension. RESULTS: The 1:5 min group developed only mild metabolic acidaemia, without hypotension. By contrast, 10/12 fetuses in the 1:2.5-min group progressively developed severe metabolic acidaemia and hypotension, reaching 16.8 ± 0.9 mmHg after 71.2 ± 6.7 UCOs. Deceleration area and capacity remained unchanged throughout the UCO series in the 1:5-min group, but progressively increased in the 1:2.5-min group. The severity of hypotension was closely correlated with both deceleration area (P < 0.001, R2  = 0.66, n = 18) and capacity (P < 0.001, R2  = 0.67, n = 18). Deceleration area and capacity predicted development of hypotension at a median of 103 and 123 minutes before the final occlusion, respectively. CONCLUSIONS: Both deceleration area and capacity were strongly associated with developing fetal hypotension, supporting their potential to improve identification of fetuses at risk of hypotension leading to hypoxic-ischaemic injury during labour. TWEETABLE ABSTRACT: Deceleration area and capacity of fetal heart rate identify developing hypotension during labour-like hypoxia.

Fluoride and Oral Health.

The discovery during the first half of the 20th century of the link between natural fluoride, adjusted fluoride levels in drinking water and reduced dental caries prevalence proved to be a stimulus for worldwide on-going research into the role of fluoride in improving oral health. Epidemiological studies of fluoridation programmes have confirmed their safety and their effectiveness in controlling dental caries. Major advances in our knowledge of how fluoride impacts the caries process have led to the development, assessment of effectiveness and promotion of other fluoride vehicles including salt, milk, tablets, toothpaste, gels and varnishes. In 1993, the World Health Organization convened an Expert Committee to provide authoritative information on the role of fluorides in the promotion of oral health throughout the world (WHO TRS 846, 1994). This present publication is a revision of the original 1994 document, again using the expertise of researchers from the extensive fields of knowledge required to successfully implement complex interventions such as the use of fluorides to improve dental and oral health. Financial support for research into the development of these new fluoride strategies has come from many sources including government health departments as well as international and national grant agencies. In addition, the unique role which industry has played in the development, formulation, assessment of effectiveness and promotion of the various fluoride vehicles and strategies is noteworthy. This updated version of 'Fluoride and Oral Health' has adopted an evidence-based approach to its commentary on the different fluoride vehicles and strategies and also to its recommendations. In this regard, full account is taken of the many recent systematic reviews published in peer reviewed literature.

Does tongue size contribute to risk of airway narrowing in preterm infants sitting in a car safety seat?

BACKGROUND: Preterm infants are at risk of narrowing of the upper airway while restrained in infant car seats, leading to secondary apnea. However, some infants are able to maintain a normal airway. We hypothesized that this might reflect relatively smaller tongue size. METHODS: We retrospectively analyzed previously reported respiration-timed lateral radiographs of the upper airways of 17 preterm infants ready for discharge (32.6 ± 1.0 weeks gestation at birth, and 37.8 ± 9.7 days old at study) taken during sleep, first in a car safety seat with an insert that allowed the head to remain upright, and then without the insert, when the head slumped forward. The presence of air above the tongue was used as an index of relative tongue size. RESULTS: A smaller airspace around the tongue (relatively larger tongue) was associated with greater narrowing of the upper airway when the head was flexed forward in sleep (p < 0.002). In contrast, there was no significant correlation between baseline airway size and change in airway size (r (2) = 0.16, p = 0.11). CONCLUSION: The present study supports the hypothesis that the vulnerability of preterm infants to airways compromise while restrained in a car safety seat may be in part related to relative tongue size.

Scoping Review of Oral Health-Related Birth Cohort Studies: Toward a Global Consortium.

The multidisciplinary nature and long duration of birth cohort studies allow investigation of the relationship between general and oral health and indicate the most appropriate stages in life to intervene. To date, the worldwide distribution of oral health-related birth cohort studies (OHRBCSs) has not been mapped, and a synthesis of information on methodological characteristics and outcomes is not available. We mapped published literature on OHRBCSs, describing their oral health-related data and methodological aspects. A 3-step search strategy was adopted to identify published studies using PubMed, Embase, Web of Science, and OVID databases. Studies with baseline data collection during pregnancy or within the first year of life or linked future oral health data to exposures during either of these 2 life stages were included. Studies examining only mothers' oral health and specific populations were excluded. In total, 1,721 articles were suitable for initial screening of titles and abstracts, and 528 articles were included in the review, identifying 120 unique OHRBCSs from 34 countries in all continents. The review comprised literature from the mid-1940s to the 21st century. Fifty-four percent of the OHRBCSs started from 2000 onward, and 75% of the cohorts were from high-income and only 2 from low-income countries. The participation rate between the baseline and the last oral health follow-up varied between 7% and 93%. Ten cohorts that included interventions were mostly from 2000 and with fewer than 1,000 participants. Seven data-linkage cohorts focused mostly on upstream characteristics and biological aspects. The most frequent clinical assessment was dental caries, widely presented as decayed, missing, and filled teeth (DMFT/dmft). Periodontal conditions were primarily applied as isolated outcomes or as part of a classification system. Socioeconomic classification, ethnicity, and country- or language-specific assessment tools varied across countries. Harmonizing definitions will allow combining data from different studies, adding considerable strength to data analyses; this will be facilitated by forming a global consortium.

White matter protection with insulin-like growth factor 1 and hypothermia is not additive after severe reversible cerebral ischemia in term fetal sheep.

Moderate cerebral hypothermia significantly improves survival without disability from perinatal hypoxia-ischemia. However, protection is partial. Insulin-like growth factor 1 (IGF-1) plays a key role in oligodendrocyte survival and myelination. The purpose of this study was to test the hypothesis that the combination of IGF-1 plus hypothermia could reduce postischemic white matter damage compared with hypothermia alone. Unanesthetized near-term fetal sheep received 30 min of cerebral ischemia, followed by either an infusion of 3 µg of IGF-1 intracerebroventricularly from 4.5 to 5.5 h plus cooling from 5.5 to 72 h (IGF-1 + hypothermia; n = 8), vehicle infusion plus cooling from 5.5 to 72 h (vehicle + hypothermia; n = 12), sham cooling plus sham infusion (ischemia control; n = 12) or sham ischemia (n = 5). The fetal extradural temperature was reduced from 39.4 ± 0.1°C to between 30 and 33°C. White matter was assessed after 5 days. Ischemia was associated with severe loss of CNPase-positive oligodendrocytes in white matter compared with sham ischemia (380 ± 138 vs. 1,180 ± 152 cells/field; mean ± SD; p < 0.001). Delayed hypothermia reduced cell loss (847 ± 297 cells/field, p < 0.01, vs. ischemia control), but there was no significant difference between vehicle + hypothermia and IGF-1 + hypothermia (1,015 ± 211 cells/field; NS). Ischemia was associated with increased caspase 3 expression in white matter (216 ± 41 vs. 19 ± 18 cells/field; p < 0.001). Hypothermia reduced numbers of activated caspase 3-positive cells (116 ± 81 cells/field; p < 0.05), with no significant difference between vehicle + hypothermia and IGF-1 + hypothermia (91 ± 27 cells/field; NS). In conclusion, delayed cotreatment with IGF-1 plus hypothermia after ischemia was associated with an improvement in white matter damage similar to that achieved by hypothermia alone.

Adenosine A(1) receptor mediated suppression of adrenal activity in near-term fetal sheep.

Activation of the hypothalamic-pituitary-adrenal (HPA) axis is a critical response to perinatal hypoxia. Recent data show that adenosine appears to inhibit baseline levels of fetal cortisol and to restrict the increase in ACTH and cortisol during moderate hypoxia. Because adenosine increases substantially during profound asphyxia, it is possible, but untested, that counterintuitively it might restrict the HPA response to more severe insults. It is unclear which receptors mediate the effects of adenosine on the HPA axis; however, adenosine A(1) receptor activation is important for adaptation to hypoxia. We therefore investigated whether adenosine A(1) receptor blockade modulates ACTH and cortisol levels in fetal sheep at 118 to 126 days gestation, randomly allocated to receive an intravenous infusion of either vehicle (vehicle-occlusion, n = 7) or 8-cyclopentyl-1,3-dipropylxanthine (DPCPX, an A(1) receptor antagonist, DPCPX-occlusion, n = 7) infused 60 min before and during 10 min of umbilical cord occlusion, or infusion of DPCPX for 70 min without occlusion (DPCPX-sham, n = 6). Experiments were terminated after 72 h. Fetal ACTH levels increased significantly (P < 0.01) during occlusion, but not sham occlusion, and returned to baseline values by 60 min after occlusion. In the vehicle-occlusion group, fetal cortisol and cortisone plasma levels increased significantly (P < 0.05) 60 min after the occlusion and returned to baseline values by 24 h. In contrast, there was a marked increase in both fetal cortisol and cortisone during DPCPX infusion before occlusion to a level greater even than the maximum rise seen after occlusion alone. This increase was sustained after occlusion, with increased cortisol levels compared with occlusion alone up to 72 h. In conclusion, fetal cortisol concentrations are suppressed by adenosine A(1) receptor activity, largely though a direct adrenal mechanism. This suppression can be partially overcome by supraphysiological stimuli such as asphyxia.

The neural and vascular effects of killed Su-Streptococcus pyogenes (OK-432) in preterm fetal sheep.

Fetal exposure to inflammatory mediators is associated with a greater risk of brain injury and may cause endothelial dysfunction; however, nearly all the evidence is derived from gram-negative bacteria. Intrapleural injections of OK-432, a killed Su-strain of Streptococcus pyogenes, has been used to treat fetal chylothorax. In this study, we evaluated the neural and cardiovascular effects of OK-432 in preterm fetal sheep (104 +/- 1 days, term 147 days). OK-432 (0.1 mg, n = 6) or saline vehicle (n = 7) was infused in the fetal pleura, and fetuses were monitored for 7 days. Blood samples were taken routinely for plasma nitrite measurement. Fetal brains were taken for histological assessment at the end of the experiment. Between 3 and 7 h postinjection, OK-432 administration was associated with transient suppression of fetal body and breathing movements and electtroencephalogram activity (P < 0.05), increased carotid and femoral vascular resistance (P < 0.05), but no change in blood pressure. Brain activity and behavior then returned to normal except in one fetus that developed seizures. OK-432 fetuses showed progressive, sustained vasodilatation (P < 0.05), with lower blood pressure after 4 days (P < 0.05), but normal heart rate. There were no changes in plasma nitrite levels. Histological studies showed bilateral infarction in the dorsal limb of the hippocampus of the fetus that developed seizures, but no injury in other fetuses. We conclude that a single low-dose injection of OK-432 can be associated with risk of focal cerebral injury in the preterm fetus and chronic central and peripheral vasodilatation that does not appear to be mediated by nitric oxide.

Hydroureteronephrosis and fetal mummification secondary to uterine torsion in a Merino ewe.

A 6 year old pluriparous Merino ewe was presented for investigation of a large intra-abdominal mass. Post-mortem examination revealed a 360° clockwise uterine torsion was present with a mummifying fetus. The torsion involved the left ureter resulting in a severe hydroureteronephrosis. Uterine torsion is uncommon in the ewe, occurring in less than 0.1% of pregnancies in one report (Mahmoud et al. Livest Res Rural Dev 2018;30), but cases are likely to be undiagnosed, particularly under the extensive management conditions typical of Australia. The chronicity of the condition in this ewe would support this statement. To the authors' knowledge this is the first reported case of hydroureteronephrosis secondary to uterine torsion in any species.

Oral Health Birth Cohort Studies: Achievements, Challenges, and Potential.

Birth cohorts are those among observational studies that provide understanding of the natural history and causality of diseases since early in life. Discussions during an International Association for Dental Research symposium in London, United Kingdom, in 2018, followed by a workshop in Bangkok, Thailand, in 2019, concluded that there are few birth cohort studies that consider oral health and that a broader discussion on similarities and differences among those studies would be valuable. This article aims to 1) bring together available long-term data of oral health birth cohort studies from the low, middle, and high-income countries worldwide and 2) describe similarities and differences among these studies. This work comprises 15 studies from all 5 continents. The most studied dental conditions and exposures are identified; findings are summarized; and methodological differences and similarities among studies are presented. Methodological strengths and weaknesses are also highlighted. Findings are summarized in 1) the negative impact of detrimental socioeconomic status on oral health changes over time, 2) the role of unfavorable patterns of dental visiting on oral health, 3) associations between general and oral health, 4) nutritional and dietary effects on oral health, and 5) intergenerational influences on oral health. Dental caries and dental visiting patterns have been recorded in all studies. Sources of fluoride exposure have been documented in most of the more recent studies. Despite some methodological differences in the way that the exposures and outcomes were measured, some findings are consistent. Predictive models have been used with caries risk tools, periodontitis occurrence, and permanent dentition orthodontic treatment need. The next steps of the group's work are as follows: 1) establishing a consortium of oral health birth cohort studies, 2) conducting a scoping review, 3) exploring opportunities for pooled data analyses to answer pressing research questions, and 4) promoting and enabling the development of the next generation of oral health researchers.

Differential effects of slow rewarming after cerebral hypothermia on white matter recovery after global cerebral ischemia in near-term fetal sheep.

It is widely believed that rewarming slowly after therapeutic hypothermia for hypoxic-ischemic (HI) encephalopathy can improve outcomes, but its impact on white matter injury after HI is unclear. Fetal sheep (0.85 gestation) received 30 min ischemia-normothermia (n = 8), or hypothermia from 3-48 h with rapid spontaneous rewarming over 1 h (ischemia-48 h hypothermia, n = 8), or 48 h with slow rewarming over 24 h (ischemia-slow rewarming, n = 7) or 72 h with rapid rewarming (ischemia-72 h hypothermia, n = 8). Ischemia was associated with loss of total and mature oligodendrocytes and reduced area fraction of myelin basic protein (MBP) and 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNPase; immature/mature oligodendrocytes) and increased microglia and astrocytes. Total numbers of oligodendrocytes were increased by all hypothermia protocols but only ischemia-72 h hypothermia attenuated loss of mature oligodendrocytes. All hypothermia protocols similarly increased the area fraction of MBP, whereas there was only an intermediate effect on the area fraction of CNPase. Microglia were suppressed by all hypothermia protocols, with the greatest reduction after ischemia-72 h hypothermia, and an intermediate effect after ischemia-slow rewarming. By contrast, induction of astrocytes was significantly reduced only after ischemia-slow rewarming. In conclusion, slow rewarming after hypothermia did not improve oligodendrocyte survival or myelination or suppression of microgliosis compared to fast rewarming, but modestly reduced astrocytosis.

Fluoride Revolution and Dental Caries: Evolution of Policies for Global Use.

Epidemiological studies over 70 y ago provided the basis for the use of fluoride in caries prevention. They revealed the clear relation between water fluoride concentration, and therefore fluoride exposure, and prevalence and severity of dental fluorosis and dental caries. After successful trials, programs for water fluoridation were introduced, and industry developed effective fluoride-containing toothpastes and other fluoride vehicles. Reductions in caries experience were recorded in many countries, attributable to the widespread use of fluoride. This is a considerable success story; oral health for many was radically improved. While previously, water had been the only significant source of fluoride, now there are many, and this led to an increase in the occurrence of dental fluorosis. Risks identified for dental fluorosis were ingestion of fluoride-containing toothpaste, water fluoridation, fluoride tablets (which were sometimes ingested in areas with water fluoridation), and infant formula feeds. Policies were introduced to reduce excessive fluoride exposure during the period of tooth development, and these were successful in reducing dental fluorosis without compromising caries prevention. There is now a much better understanding of the public perception of dental fluorosis, with mild fluorosis being of no aesthetic concern. The advantages of water fluoridation are that it provides substantial lifelong caries prevention, is economic, and reduces health inequalities: it reaches a substantial number of people worldwide. Fluoride-containing toothpastes are by far the most important way of delivering the beneficial effect of fluoride worldwide. The preventive effects of conjoint exposure (e.g., use of fluoride toothpaste in a fluoridated area) are additive. The World Health Organization has informed member states of the benefits of the appropriate use of fluoride. Many countries have policies to maximize the benefits of fluoride, but many have yet to do so.

Fluoridated Water Modifies the Effect of Breastfeeding on Dental Caries.

Breastfeeding is important for health and development. Yet, the interaction between breastfeeding duration and usage of fluoridated water on caries experience has not been investigated. This study examined exposure to fluoridation as an effect modifier of the association between breastfeeding duration and caries. The 2012 to 2014 national population-based study of Australian children involved parental questionnaires and oral epidemiological assessment. Children were grouped by parent-reported breastfeeding duration into minimal (none or <1 mo), breastfed for 1 to <6 mo, breastfed for 6 to 24 mo, and sustained (>24 mo). Residential history and main water source used for the first 2 y of life were collected to group children into exposed (WF) and nonexposed (NF) to fluoridation. Socioeconomic status, infant formula feeding, and sugar-sweetened beverage (SSB) consumption data were collected. The prevalence and severity of caries in children aged 5 to 6 y were primary outcomes. Multivariable regression models with robust error estimation were generated to compute prevalence ratios (PRs) and mean ratios (MRs) for 3 breastfeeding groups against the reference (breastfed for 6-24 mo). Of the 5- to 6-y-old children, 2,721 were in the WF and 1,737 were in the NF groups. The groups had comparable distributions of socioeconomic factors, infant formula feeding, and SSB consumption. There were U-shape distributions of caries experience among breastfeeding groups, being more pronounced among NF children. Among NF children, the minimal and sustained breastfeeding groups had significantly higher PR (1.4 [1.1-1.9] and 1.8 [1.4-2.4]) and MR (2.1 [1.4-3.3] and 2.4 [1.4-4.1]) than the reference group. However, among the WF children, this association between breastfeeding duration and caries attenuated after adjustment for other factors. The study contributes evidence of a nonlinear (U-shape) association between breastfeeding duration and dental caries. Early life exposure to fluoridated drinking water attenuated the potential cariogenic effect of both lack of and sustained breastfeeding.

Dramatic neuronal rescue with prolonged selective head cooling after ischemia in fetal lambs.

Hypothermia has been proposed as a neuroprotective strategy. However, short-term cooling after hypoxia-ischemia is effective only if started immediately during resuscitation. The aim of this study was to determine whether prolonged head cooling, delayed into the late postinsult period, improves outcome from severe ischemia. Unanesthetized near term fetal sheep were subject to 30 min of cerebral ischemia. 90 min later they were randomized to either cooling (n = 9) or sham cooling (n = 7) for 72 h. Intrauterine cooling was induced by a coil around the fetal head, leading initially to a fall in extradural temperature of 5-10 degrees C, and a fall in esophageal temperature of 1.5-3 degrees C. Cooling was associated with mild transient systemic metabolic effects, but not with hypotension or altered fetal heart rate. Cerebral cooling reduced secondary cortical cytotoxic edema (P < 0.001). After 5 d of recovery there was greater residual electroencephalogram activity (-5.2+/-1.6 vs. -15.5+/-1.5 dB, P < 0.001) and a dramatic reduction in the extent of cortical infarction and neuronal loss in all regions assessed (e.g., 40 vs. 99% in the parasagittal cortex, P < 0.001). Selective head cooling, maintained throughout the secondary phase of injury, is noninvasive and safe and shows potential for improving neonatal outcome after perinatal asphyxia.

Oesophageal lumen pH in yearling horses and effects of management and administration of omeprazole.

BACKGROUND: In human subjects, arytenoid chondritis can be caused by chemical trauma of mucosa attributable to gastro-oesophageal reflux. Although a similar process may be involved in the aetiopathogenesis of arytenoid chondritis in horses, the oesophageal lumen pH in this species is poorly understood. OBJECTIVES: To determine if gastro-oesophageal reflux occurs in horses by characterising oesophageal lumen pH. STUDY DESIGN: Blinded, randomised, placebo-controlled, crossover, experimental study. METHODS: Luminal oesophageal pH in six yearling horses was recorded over four 24 h periods using an ambulatory pH recorder attached to a catheter with two electrodes (proximal and distal) inserted into the oesophagus. Recordings of pH were made during three management protocols. Initially, horses grazed in a paddock (Protocol A). Horses were then moved to stables to simulate sale preparation of Thoroughbred yearlings, and were given either omeprazole (Protocol B) or placebo paste (Protocol C) orally once per day. Protocol A was repeated for each horse (after a 13 day washout period) between Protocols B and C. Summary statistics described pH range and frequency of pH changes. Associations with predictor variables were investigated using linear mixed-effects models. Data are presented as the mean ± s.d. RESULTS: Oesophageal lumen pH ranged from 4.90 to 9.70 (7.36 ± 0.27 and 7.18 ± 0.24 for the proximal and distal electrodes, respectively) and varied frequently (1.2 ± 0.9 changes/min and 0.8 ± 0.8 changes/min for the proximal and distal electrodes, respectively). Oesophageal lumen pH was associated with time since concentrate feeding, activity and time of day, but not with treatment of omeprazole. MAIN LIMITATIONS: A small number of horses were used and measurement periods were limited. CONCLUSIONS: Gastro-oesophageal reflux occurs in clinically normal yearling horses. Although omeprazole had no detectable effect, oesophageal lumen pH recorded during this study did not fall within the therapeutic range of omeprazole.

Endogenous alpha2-adrenergic receptor-mediated neuroprotection after severe hypoxia in preterm fetal sheep.

Central alpha-adrenergic receptor activity is important for fetal adaptation to hypoxia before birth. It is unclear whether it is also important during recovery. We therefore tested the hypothesis that an infusion of the specific alpha(2)-adrenergic receptor antagonist idazoxan (1 mg/kg/h i.v.) from 15 min to 4 h after profound hypoxia induced by 25 min umbilical cord occlusion in fetal sheep at 70% of gestation (equivalent to the 28-32 weeks in humans) would increase neural injury. After 3 days' recovery, idazoxan infusion was associated with a significant increase in neuronal loss in the hippocampus (P<0.05), expression of cleaved caspase-3 (P<0.05), and numbers of activated microglia (P<0.05). There was no significant effect on other neuronal regions or on loss of O4-positive premyelinating oligodendrocytes in the subcortical white matter. Idazoxan was associated with an increase in evolving epileptiform electroencephalographic (EEG) transient activity after occlusion (difference at peak 2.5+/-1.0 vs. 11.7+/-4.7 counts/min, P<0.05) and significantly reduced average spectral edge frequency, but not EEG intensity, from 54 until 72 h after occlusion (P<0.05). Hippocampal neuronal loss was correlated with total numbers of epileptiform transients during idazoxan infusion (P<0.01; r(2)=0.7). In conclusion, endogenous inhibitory alpha(2)-adrenergic receptor activation after severe hypoxia appears to significantly limit evolving hippocampal damage in the immature brain.

Insulin-like growth factor-1 and post-ischemic brain injury.

Insulin-like growth factor-1 (IGF-1) is a naturally occurring neurotrophic factor that plays an important role in promoting cell proliferation and differentiation during normal brain development and maturation. The present review examines recent evidence that endogenous IGF-1 also plays a significant role in recovery from insults such as hypoxia-ischemia and that giving additional exogenous IGF-1 can actively ameliorate damage. It is now well established that neurons and other cell types die many hours or even days after initial injury due to activation of programmed cell death pathways. IGF-1 and its binding proteins and receptors are intensely induced within damaged brain regions following brain injury, suggesting a possible a role for IGF-1 in brain recovery. Exogenous administration of IGF-1 within a few hours after brain injury is now known to be protective in both gray and white matter and leads to improved somatic function. In contrast, pre-treatment is ineffective, likely reflecting limited intracerebral penetration of IGF-1 into the uninjured brain. The neuroprotective effects of IGF-1 are mediated by IGF-1 receptors and its binding proteins and are specific to particular cellular phenotypes and brain regions. The window of opportunity for treatment with IGF-1 is limited to a few hours after normothermic brain injury, reflecting its specific actions on early, intracellular events in the apoptotic cascade. However, injury-associated mild post-hypoxic hypothermia, which delays the development of cell death, can shift and dramatically extend the window of opportunity for delayed treatment with IGF-1. Such a combined approach is likely to be essential for any clinical treatment.