Neuromonitoring in neonatal critical care part II: extremely premature infants and critically ill neonates

Abstract: Neonatal intensive care has expanded from cardiorespiratory care to a holistic approach emphasizing brain health. To best understand and monitor brain function and physiology in the neonatal intensive care unit (NICU), the most commonly used tools are amplitude-integrated EEG, full multichannel continuous EEG, and near-infrared spectroscopy. Each of these modalities has unique characteristics and functions. While some of these tools have been the subject of expert consensus statements or guidelines, there is no overarching agreement on the optimal approach to neuromonitoring in the NICU. This work reviews current evidence to assist decision making for the best utilization of these neuromonitoring tools to promote neuroprotective care in extremely premature infants and in critically ill neonates. Neuromonitoring approaches in neonatal encephalopathy and neonates with possible seizures are discussed separately in the companion paper. Impact: For extremely premature infants, NIRS monitoring has a potential role in individualized brain-oriented care, and selective use of aEEG and cEEG can assist in seizure detection and prognostication.For critically ill neonates, NIRS can monitor cerebral perfusion, oxygen delivery, and extraction associated with disease processes as well as respiratory and hypodynamic management. Selective use of aEEG and cEEG is important in those with a high risk of seizures and brain injury.Continuous multimodal monitoring as well as monitoring of sleep, sleep–wake cycling, and autonomic nervous system have a promising role in neonatal neurocritical care

Kaposi's Sarcoma Herpesvirus microRNAs Target Caspase 3 and Regulate Apoptosis

Kaposi's sarcoma herpesvirus (KSHV) encodes a cluster of twelve micro (mi)RNAs, which are abundantly expressed during both latent and lytic infection. Previous studies reported that KSHV is able to inhibit apoptosis during latent infection; we thus tested the involvement of viral miRNAs in this process. We found that both HEK293 epithelial cells and DG75 cells stably expressing KSHV miRNAs were protected from apoptosis. Potential cellular targets that were significantly down-regulated upon KSHV miRNAs expression were identified by microarray profiling. Among them, we validated by luciferase reporter assays, quantitative PCR and western blotting caspase 3 (Casp3), a critical factor for the control of apoptosis. Using site-directed mutagenesis, we found that three KSHV miRNAs, miR-K12-1, 3 and 4-3p, were responsible for the targeting of Casp3. Specific inhibition of these miRNAs in KSHV-infected cells resulted in increased expression levels of endogenous Casp3 and enhanced apoptosis. Altogether, our results suggest that KSHV miRNAs directly participate in the previously reported inhibition of apoptosis by the virus, and are thus likely to play a role in KSHV-induced oncogenesis

Resistance of a Rodent Malaria Parasite to a Thymidylate Synthase Inhibitor Induces an Apoptotic Parasite Death and Imposes a Huge Cost of Fitness

BACKGROUND: The greatest impediment to effective malaria control is drug resistance in Plasmodium falciparum, and thus understanding how resistance impacts on the parasite's fitness and pathogenicity may aid in malaria control strategy. METHODOLOGY/PRINCIPAL FINDINGS: To generate resistance, P. berghei NK65 was subjected to 5-fluoroorotate (FOA, an inhibitor of thymidylate synthase, TS) pressure in mice. After 15 generations of drug pressure, the 2% DT (the delay time for proliferation of parasites to 2% parasitaemia, relative to untreated wild-type controls) reduced from 8 days to 4, equalling the controls. Drug sensitivity studies confirmed that FOA-resistance was stable. During serial passaging in the absence of drug, resistant parasite maintained low growth rates (parasitaemia, 15.5%±2.9, 7 dpi) relative to the wild-type (45.6%±8.4), translating into resistance cost of fitness of 66.0%. The resistant parasite showed an apoptosis-like death, as confirmed by light and transmission electron microscopy and corroborated by oligonucleosomal DNA fragmentation. CONCLUSIONS/SIGNIFICANCE: The resistant parasite was less fit than the wild-type, which implies that in the absence of drug pressure in the field, the wild-type alleles may expand and allow drugs withdrawn due to resistance to be reintroduced. FOA resistance led to depleted dTTP pools, causing thymineless parasite death via apoptosis. This supports the tenet that unicellular eukaryotes, like metazoans, also undergo apoptosis. This is the first report where resistance to a chemical stimulus and not the stimulus itself is shown to induce apoptosis in a unicellular parasite. This finding is relevant in cancer therapy, since thymineless cell death induced by resistance to TS-inhibitors can further be optimized via inhibition of pyrimidine salvage enzymes, thus providing a synergistic impact. We conclude that since apoptosis is a process that can be pharmacologically modulated, the parasite's apoptotic machinery may be exploited as a novel drug target in malaria and other protozoan diseases of medical importance

Neuromonitoring in neonatal critical care part I: neonatal encephalopathy and neonates with possible seizures

Abstract: The blooming of neonatal neurocritical care over the last decade reflects substantial advances in neuromonitoring and neuroprotection. The most commonly used brain monitoring tools in the neonatal intensive care unit (NICU) are amplitude integrated EEG (aEEG), full multichannel continuous EEG (cEEG), and near-infrared spectroscopy (NIRS). While some published guidelines address individual tools, there is no consensus on consistent, efficient, and beneficial use of these modalities in common NICU scenarios. This work reviews current evidence to assist decision making for best utilization of neuromonitoring modalities in neonates with encephalopathy or with possible seizures. Neuromonitoring approaches in extremely premature and critically ill neonates are discussed separately in the companion paper. Impact: Neuromonitoring techniques hold promise for improving neonatal care.For neonatal encephalopathy, aEEG can assist in screening for eligibility for therapeutic hypothermia, though should not be used to exclude otherwise eligible neonates. Continuous cEEG, aEEG and NIRS through rewarming can assist in prognostication.For neonates with possible seizures, cEEG is the gold standard for detection and diagnosis. If not available, aEEG as a screening tool is superior to clinical assessment alone. The use of seizure detection algorithms can help with timely seizures detection at the bedside

Overfishing of small pelagic fishes increases trophic overlap between immature and mature striped dolphins in the Mediterranean Sea

The interactions among diet, ecology, physiology, and biochemistry affect N and C stable isotope signatures in animal tissues. Here, we examined if ecological segregation among animals in relation to sex and age existed by analyzing the signatures of δ15N and δ13C in the muscle of Western Mediterranean striped dolphins. Moreover, we used a Bayesian mixing model to study diet composition and investigated potential dietary changes over the last two decades in this population. For this, we compared isotope signatures in samples of stranded dolphins obtained during two epizootic events occurring in 1990 and 2007–2008. Mean δ13C values for females and males were not significantly different, but age-related variation indicated δ13C enrichment in both sexes, suggesting that females and males most likely fed in the same general areas, increasing their consumption of benthic prey with age. Enrichment of δ15N was only observed in females, suggesting a preference for larger or higher trophic level prey than males, which could reflect different nutritional requirements. δ13C values showed no temporal variation, although the mean δ15N signature decreased from 1990 to 2007–2008, which could indicate a dietary shift in the striped dolphin over the last two decades. The results of SIAR indicated that in 1990, hake and sardine together contributed to 60% on the diet of immature striped dolphins, and close to 90% for mature striped dolphins. Conversely, the diet of both groups in 2007–2008 was more diverse, as hake and sardine contributed to less than 40% of the entire diet. These results suggest a dietary change that was possibly related to changes in food availability, which is consistent with the depletion of sardine stocks by fishing