Hypoxia-ischemia before or around the time of birth occurs in approximately 2/1000 live births and is associated with a high risk of death or lifelong disability. Therapeutic hypothermia is now well established as standard treatment for infants with moderate to severe hypoxic-ischemic encephalopathy but is only partially effective. There is compelling preclinical and clinical evidence that hypothermia is most protective when it is started as early as possible after hypoxia-ischemia. Further improvements in outcome from therapeutic hypothermia are very likely to arise from strategies to reduce the delay before starting treatment of affected infants. In this review we examine evidence that current protocols are reasonably close to the optimal depth and duration of cooling, but that the optimal rate of rewarming after hypothermia is unclear. The potential for combination treatments to augment hypothermic neuroprotection has considerable promise, particularly with endogenous targets such as melatonin and erythropoietin and noble gases such as xenon. We dissect the critical importance of preclinical studies using realistic delays in treatment and clinically relevant cooling protocols when examining combination treatment, and that for many strategies overlapping mechanisms of action can substantially attenuate any effects.

A six-month trial was conducted to compare the effects of high and low make-up water flushing rates on rainbow trout performance and water quality in replicated water reuse aquaculture systems (WRAS). Six identical 9.5m3 WRAS, containing a single 5.3m3 tank and operated at a total recirculating flow of 380L/min were stocked with 1000 rainbow trout each (133±1g). Three WRAS were operated at high flushing rates (2.6% of total flow) and three were operated at low flushing rates (0.26% of total flow), providing system hydraulic retention times of 0.67 and 6.7 days, respectively. During a one-week period when fish were at maximum feeding (i.e., mean feed loadings of 0.53 and 5.3kg/m3 make-up water flow high and low make-up conditions, respectively) and maximum densities (80kg/m3), water samples were collected across all unit processes. All typical water quality parameters measured at the culture tank outlet during this week were significantly different between treatments, except for dissolved oxygen, carbon dioxide, and temperature, which were controlled. Within the low exchange WRAS, total suspended solids (TSS), carbonaceous biochemical oxygen demand, total ammonia nitrogen, un-ionized ammonia nitrogen, nitrite nitrogen, nitrate nitrogen, dissolved organic carbon, particle counts, true color, and total heterotrophic plate counts were significantly greater, whereas UV transmittance (%) and alkalinity were significantly reduced. Of these parameters, TSS, fine particles, and heterotrophic bacteria counts were the only parameters of concern within the low exchange WRAS. The potential impacts of each water quality constituent are discussed. Element analysis indicated that concentrations of nine metals were significantly greater within the low exchange WRAS. The highest metal concentrations measured at low exchange were within safe recommended limits, with the exception of copper (0.037–0.056mg/L), which could have reached chronically toxic levels. Although cumulative mortality was relatively low for all WRAS, a linear trend between copper concentration and mortality was evident. The highest mortality, which occurred within a low exchange WRAS, coincided with the highest copper (0.056mg/L); and the lowest mortality, which occurred within a high exchange WRAS, coincided with non-detectable copper levels. A comparison of survival between treatments bordered significance, 99.5±0.1 and 98.9±0.4% for the high and low exchange WRAS, respectively. There was no significant difference in rainbow trout weight at the conclusion of the study, i.e., approximately one year post-hatch: 1401±23 and 1366±33g for the high and low exchange WRAS, respectively. There were no differences in thermal growth coefficients or feed conversion ratios between the high and low exchange treatments. Rainbow trout condition factor was significantly greater within the low exchange WRAS

Preterm birth is associated with a high risk of morbidity and mortality including brain damage and cerebral palsy. The development of brain injury in the preterm infant may be influenced by many factors including perinatal asphyxia, infection/inflammation, chronic hypoxia and exposure to treatments such as mechanical ventilation and corticosteroids. There are currently very limited treatment options available. In clinical trials, magnesium sulfate has been associated with a small, significant reduction in the risk of cerebral palsy and gross motor dysfunction in early childhood but no effect on the combined outcome of death or disability, and longer-term follow up to date has not shown improved neurological outcomes in school-age children. Recombinant erythropoietin has shown neuroprotective potential in preclinical studies but two large randomized trials, in extremely preterm infants, of treatment started within 24 or 48 h of birth showed no effect on the risk of severe neurodevelopmental impairment or death at 2 years of age. Preclinical studies have highlighted a number of promising neuroprotective treatments, such as therapeutic hypothermia, melatonin, human amnion epithelial cells, umbilical cord blood and vitamin D supplementation, which may be useful at reducing brain damage in preterm infants. Moreover, refinements of clinical care of preterm infants have the potential to influence later neurological outcomes, including the administration of antenatal and postnatal corticosteroids and more accurate identification and targeted treatment of seizures.