Prenatal treatment with preimplantation factor improves early postnatal neurogenesis and cognitive impairments in a mouse model of Down syndrome.

Down syndrome (DS) is a genetic disease characterized by a supernumerary chromosome 21. Intellectual deficiency (ID) is one of the most prominent features of DS. Central nervous system defects lead to learning disabilities, motor and language delays, and memory impairments. At present, a prenatal treatment for the ID in DS is lacking. Subcutaneous administration of synthetic preimplantation factor (sPIF, a peptide with a range of biological functions) in a model of severe brain damage has shown neuroprotective and anti-inflammatory properties by directly targeting neurons and microglia. Here, we evaluated the effect of PIF administration during gestation and until weaning on Dp(16)1Yey mice (a mouse model of DS). Possible effects at the juvenile stage were assessed using behavioral tests and molecular and histological analyses of the brain. To test the influence of perinatal sPIF treatment at the adult stage, hippocampus-dependent memory was evaluated on postnatal day 90. Dp(16)1Yey pups showed significant behavioral impairment, with impaired neurogenesis, microglial cell activation and a low microglial cell count, and the deregulated expression of genes linked to neuroinflammation and cell cycle regulation. Treatment with sPIF restored early postnatal hippocampal neurogenesis, with beneficial effects on astrocytes, microglia, inflammation, and cell cycle markers. Moreover, treatment with sPIF restored the level of DYRK1A, a protein that is involved in cognitive impairments in DS. In line with the beneficial effects on neurogenesis, perinatal treatment with sPIF was associated with an improvement in working memory in adult Dp(16)1Yey mice. Perinatal treatment with sPIF might be an option for mitigating cognitive impairments in people with DS.

The collembolan Heteromurus nitidus grazes the wheat fungal pathogen Zymoseptoria tritici on infected tissues: opportunities and limitations for bioregulation.

BACKGROUND: Septoria tritici blotch (STB), caused by the fungus Zymoseptoria tritici, is a foliar disease affecting wheat crops against which conventional control methods are not totally effective. During inter-epidemic periods the fungus survives in wheat residues left on the ground. In this study, we tested the potential of the collembolan Heteromurus nitidus - a springtail species present in field soils and known to interact with different fungal species - as a potential bioregulation agent of Z. tritici on wheat residues through a choice and consumption experiment. RESULTS: Springtails preferred inoculated fresh residues but did not have a preference between inoculated and uninoculated old residues. Springtails grazed on Z. tritici fruiting bodies and reduced pycnidiospore numbers by ten-fold compared to control inoculated fresh residues. Attraction toward fresh inoculated residues and pycnidiospore reduction support the hypothesis that Z. tritici is a food source for springtails. Heteromurus nitidus showed no preference between inoculated and uninoculated 18-month-old residues, probably because they no longer produced ascospores. CONCLUSION: Attraction towards fresh residues and spore reduction support our hypothesis that H. nitidus may contribute to the bioregulation of Z. tritici. Perspectives for field application would be determined by the ability of H. nitidus and Z. tritici to interact at key epidemiological stages. The impact of H. nitidus on the quantity of pathogen primary inoculum over time should be estimated using residues of intermediate age. This would help to identify the optimal period for enhancing the effectiveness of springtails as consumers of Z. tritici. © 2024 The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

Methoprene-tolerant and Krüppel homolog 1 are actors of juvenile hormone-signaling controlling the development of male sexual behavior in the moth Agrotis ipsilon.

In insects, juvenile hormone (JH) is critical for the orchestration of male reproductive maturation. For instance, in the male moth, Agrotis ipsilon, the behavioral response and the neuronal sensitivity within the primary olfactory centers, the antennal lobes (ALs), to the female-emitted sex pheromone increase with fertility during adulthood and the coordination between these events is governed by JH. However, the molecular basis of JH action in the development of sexual behavior remains largely unknown. Here, we show that the expression of the paralogous JH receptors, Methoprene-tolerant 1 and 2 (Met1, Met2) and of the JH-inducible transcription factor, Krüppel homolog 1 (Kr-h1) within ALs raised from the third day of adult life and this dynamic is correlated with increased behavioral responsiveness to sex pheromone. Met1-, Met2- and Kr-h1-depleted sexually mature males exhibited altered sex pheromone-guided orientation flight. Moreover, injection of JH-II into young males enhanced the behavioral response to sex pheromone with increased AL Met1, Met2 and Kr-h1 mRNA levels. By contrast, JH deficiency suppressed the behavioral response to sex pheromone coupled with reduced AL Met1, Met2 and Kr-h1 mRNA levels in allatectomized old males and these inhibitions were compensated by an injection of JH-II in operated males. Our results demonstrated that JH acts through Met-Kr-h1 signaling pathway operating in ALs, to promote the pheromone information processing and consequently the display of sexual behavior in synchronization with fertility to optimize male reproductive fitness. Thus, this study provides insights into the molecular mechanisms underlying the hormonal regulation of reproductive behavior in insects.

Neuroligin 1 expression is linked to plasticity of behavioral and neuronal responses to sex pheromone in the male moth Agrotis ipsilon.

In the moth Agrotis ipsilon, the behavioral response of males to the female-emitted sex pheromone increases throughout adult life and following a prior exposure to sex pheromone, whereas it is temporally inhibited after the onset of mating. This behavioral flexibility is paralleled with changes in neuronal sensitivity to pheromone signal within the primary olfactory centers, the antennal lobes. In the present study, we tested the hypothesis that neuroligins, post-synaptic transmembrane proteins known to act as mediators of neuronal remodeling, are involved in the olfactory modulation in A. ipsilon males. We cloned a full-length cDNA encoding neuroligin 1, which is expressed predominantly in brain and especially in antennal lobes. The level of neuroligin 1 expression in antennal lobes gradually raised from day-2 until day-4 of adult life, as well as at 24 h, 48 h and 72 h following pre-exposure to sex pheromone, and the temporal dynamic of these changes correlated with increased sex pheromone responsiveness. By contrast, there was no significant variation in antennal lobe neuroligin 1 expression during the post-mating refractory period. Taken together, these results highlight that age- and odor experience-related increase in sex pheromone responsiveness is linked to the overexpression of neuroligin 1 in antennal lobes, thus suggesting a potential role played by this post-synaptic cell-adhesion molecule in mediating the plasticity of the central olfactory system in A. ipsilon.

Obstructive Apneas in a Mouse Model of Congenital Central Hypoventilation Syndrome.

Rationale: Congenital central hypoventilation syndrome (CCHS) is characterized by life-threatening sleep hypoventilation and is caused by PHOX2B gene mutations, most frequently the PHOX2B27Ala/+ mutation, with patients requiring lifelong ventilatory support. It is unclear whether obstructive apneas are part of the syndrome. Objectives: To determine if Phox2b27Ala/+ mice, which present the main symptoms of CCHS and die within hours after birth, also express obstructive apneas, and to investigate potential underlying mechanisms. Methods: Apneas were classified as central, obstructive, or mixed by using a novel system combining pneumotachography and laser detection of abdominal movement immediately after birth. Several respiratory nuclei involved in airway patency were examined by immunohistochemistry and electrophysiology in brainstem-spinal cord preparations. Measurements and Main Results: The median (interquartile range) of obstructive apnea frequency was 2.3 (1.5-3.3)/min in Phox2b27Ala/+ pups versus 0.6 (0.4-1.0)/min in wild types (P < 0.0001). Obstructive apnea duration was 2.7 seconds (2.3-3.9) in Phox2b27Ala/+ pups versus 1.7 seconds (1.1-1.9) in wild types (P < 0.0001). Central and mixed apneas presented similar significant differences. In Phox2b27Ala/+ preparations, the hypoglossal nucleus had fewer (P < 0.05) and smaller (P < 0.01) neurons, compared with wild-type preparations. Importantly, coordination of phrenic and hypoglossal motor activities was disrupted, as evidenced by the longer and variable delay of hypoglossal activity with respect to phrenic activity onset (P < 0.001). Conclusions: The Phox2b27Ala/+ mutation predisposed pups not only to hypoventilation and central apneas, but also to obstructive and mixed apneas, likely because of hypoglossal dysgenesis. These results thus demand attention toward obstructive events in infants with CCHS.

A plant volatile alters the perception of sex pheromone blend ratios in a moth.

Mate finding in most moths is based on male perception of a female-emitted pheromone whose species specificity resides in component chemistry and proportions. Components are individually detected by specialized olfactory receptor neurons (ORNs) projecting into the macroglomerular complex (MGC) of the male brain. We asked how robust ratio recognition is when challenged by a plant volatile background. To test this, we investigated the perception of the pheromone blend in Agrotis ipsilon, a moth species whose females produce a blend of Z7-dodecenyl acetate (Z7-12:Ac), Z9-tetradecenyl acetate (Z9-14:Ac), and Z11-hexadecenyl acetate in a 4:1:4 ratio optimally attractive for males. First, we recorded the responses of specialist ORNs for Z7 and Z9 and showed that heptanal, a flower volatile, activated Z7 but not Z9 neurons. Then, we recorded intracellularly the responses of MGC neurons to various ratios and showed that heptanal altered ratio responses of pheromone-sensitive neurons. Finally, we analyzed the behavior of males in a wind tunnel and showed that their innate preference for the 4:1:4 blend was shifted in the presence of heptanal. Pheromone ratio recognition may thus be altered by background odorants. Therefore, the olfactory environment might be a selective force for the evolution of pheromone communication systems.

A critical role for Dop1-mediated dopaminergic signaling in the plasticity of behavioral and neuronal responses to sex pheromone in a moth.

Most animal species, including insects, are able to modulate their responses to sexual chemosignals and this flexibility originates from the remodeling of olfactory areas under the influence of the dopaminergic system. In the moth Agrotis ipsilon, the behavioral response of males to the female-emitted sex pheromone increases throughout adult life and after a prior exposure to pheromone signal, and this change is accompanied by an increase in neuronal sensitivity within the primary olfactory centers, the antennal lobes (ALs). To identify the underlying neuromodulatory mechanisms, we examined whether this age- and experience-dependent olfactory plasticity is mediated by dopamine (DA) through the Dop1 receptor, an ortholog of the vertebrate D1-type dopamine receptors, which is positively coupled to adenylyl cyclase. We cloned A. ipsilon Dop1 (AiDop1), which is expressed predominantly in brain and especially in ALs; its knockdown induced a decrease in AL cAMP and altered sex pheromone-orientated flight. The levels of DA, AiDop1 expression and cAMP in ALs increased from the third day of adult life and at 24 and 48 h following pre-exposure to sex pheromone, and the dynamic of these changes correlated with the increased responsiveness to sex pheromone. These results demonstrate that Dop1 is required for the display of male sexual behavior and that age- and experience-related neuronal and behavioral changes are sustained by DA-Dop1 signaling that operates within ALs, probably through cAMP-dependent mechanisms in A. ipsilon Thus, this study expands our understanding of the neuromodulatory mechanisms underlying olfactory plasticity, mechanisms that appear to be highly conserved between insects and mammals.

Breathing under Anesthesia: A Key Role for the Retrotrapezoid Nucleus Revealed by Conditional Phox2b Mutant Mice.

BACKGROUND: Optimal management of anesthesia-induced respiratory depression requires identification of the neural pathways that are most effective in maintaining breathing during anesthesia. Lesion studies point to the brainstem retrotrapezoid nucleus. We therefore examined the respiratory effects of common anesthetic/analgesic agents in mice with selective genetic loss of retrotrapezoid nucleus neurons (Phox2b mice, hereafter designated "mutants"). METHODS: All mice received intraperitoneal ketamine doses ranging from 100 mg/kg at postnatal day (P) 8 to 250 mg/kg at P60 to P62. Anesthesia effects in P8 and P14 to P16 mice were then analyzed by administering propofol (100 and 150 mg/kg at P8 and P14 to P16, respectively) and fentanyl at an anesthetic dose (1 mg/kg at P8 and P14 to P16). RESULTS: Most mutant mice died of respiratory arrest within 13 min of ketamine injection at P8 (12 of 13, 92% vs. 0 of 8, 0% wild type; Fisher exact test, P < 0.001) and P14 to P16 (32 of 42, 76% vs. 0 of 59, 0% wild type; P < 0.001). Cardiac activity continued after terminal apnea, and mortality was prevented by mechanical ventilation, supporting respiratory arrest as the cause of death in the mutants. Ketamine-induced mortality in mutants compared to wild types was confirmed at P29 to P31 (24 of 36, 67% vs. 9 of 45, 20%; P < 0.001) and P60 to P62 (8 of 19, 42% vs. 0 of 12, 0%; P = 0.011). Anesthesia-induced mortality in mutants compared to wild types was also observed with propofol at P8 (7 of 7, 100% vs. 0 of 17,7/7, 100% vs. 0/17, 0%; P < 0.001) and P14 to P16 (8 of 10, 80% vs. 0 of 10, 0%; P < 0.001) and with fentanyl at P8 (15 of 16, 94% vs. 0 of 13, 0%; P < 0.001) and P14 to P16 (5 of 7, 71% vs. 0 of 11, 0%; P = 0.002). CONCLUSIONS: Ketamine, propofol, and fentanyl caused death by respiratory arrest in most mice with selective loss of retrotrapezoid nucleus neurons, in doses that were safe in their wild type littermates. The retrotrapezoid nucleus is critical to sustain breathing during deep anesthesia and may prove to be a pharmacologic target for this purpose.

Myelination induction by a histamine H3 receptor antagonist in a mouse model of preterm white matter injury.

Fifteen million babies are born preterm every year and a significant number suffer from permanent neurological injuries linked to white matter injury (WMI). A chief cause of preterm birth itself and predictor of the severity of WMI is exposure to maternal-fetal infection-inflammation such as chorioamnionitis. There are no neurotherapeutics for this WMI. To affect this healthcare need, the repurposing of drugs with efficacy in other white matter injury models is an attractive strategy. As such, we tested the efficacy of GSK247246, an H3R antagonist/inverse agonist, in a model of inflammation-mediated WMI of the preterm born infant recapitulating the main clinical hallmarks of human brain injury, which are oligodendrocyte maturation arrest, microglial reactivity, and hypomyelination. WMI is induced by mimicking the effects of maternal-fetal infection-inflammation and setting up neuroinflammation. We induce this process at the time in the mouse when brain development is equivalent to the human third trimester; postnatal day (P)1 through to P5 with i.p. interleukin-1ß (IL-1ß) injections. We initiated GSK247246 treatment (i.p at 7 mg/kg or 20 mg/kg) after neuroinflammation was well established (on P6) and it was administered twice daily through to P10. Outcomes were assessed at P10 and P30 with gene and protein analysis. A low dose of GSK247246 (7 mg/kg) lead to a recovery in protein expression of markers of myelin (density of Myelin Basic Protein, MBP & Proteolipid Proteins, PLP) and a reduction in macro- and microgliosis (density of ionising adaptor protein, IBA1 & glial fibrillary acid protein, GFAP). Our results confirm the neurotherapeutic efficacy of targeting the H3R for WMI seen in a cuprizone model of multiple sclerosis and a recently reported clinical trial in relapsing-remitting multiple sclerosis patients. Further work is needed to develop a slow release strategy for this agent and test its efficacy in large animal models of preterm infant WMI.

The insect HR38 nuclear receptor, a member of the NR4A subfamily, is a synchronizer of reproductive activity in a moth.

In the male moth, Agrotis ipsilon, the behavioural response and neuron sensitivity within the olfactory centres, the antennal lobes (ALs), to female sex pheromone increase with age, in correlation with the maturation of sex accessory glands (SAGs). By contrast, newly mated males cease to be attracted to sex pheromone and remate when their SAGs are refilled during the next night. The insect hormone receptor 38 (HR38), an ortholog of the vertebrate NR4A receptors, is a component of ecdysteroid signalling pathway which controls adult male physiology and behaviour. Here, we cloned the A. ipsilon HR38 (AiHR38) and explored its function in the coordination of reproductive events in the male. AiHR38 was detected in SAGs and ALs, and where its amount raised with age, in parallel with SAG protein content and sex pheromone responsiveness. By contrast, the AL and SAG AiHR38 expressions declined at 0-2 h after mating, in linking with depletion of SAG protein reserves and loss of sensitivity to sex pheromone. The increased AL and SAG AiHR38 expressions at 20-24 h postmating coincided with replenishing of SAGs and recovery of sensitivity to sex pheromone for a new mating. Moreover, AiHR38 knockdown resulted in reduction in SAG protein amount and disruption of sex pheromone-orientated flight. These results show that the insect HR38 is essential both for SAG activity, probably by controlling the protein synthesis, and display of male sexual behaviour, and that the concomitant regulation of its expression within SAGs and olfactory centres contributes to synchronisation between fertility and sexual activity. DATABASE: The nucleotide sequence of Agrotis ipsilon HR38 is available in the DDBJ/EMBL/GenBank databases under the accession number MF402845.

Acetylcholine Modulates the Hormones of the Growth Hormone/Insulinlike Growth Factor-1 Axis During Development in Mice.

Pituitary growth hormone (GH) and insulinlike growth factor (IGF)-1 are anabolic hormones whose physiological roles are particularly important during development. The activity of the GH/IGF-1 axis is controlled by complex neuroendocrine systems including two hypothalamic neuropeptides, GH-releasing hormone (GHRH) and somatostatin (SRIF), and a gastrointestinal hormone, ghrelin. The neurotransmitter acetylcholine (ACh) is involved in tuning GH secretion, and its GH-stimulatory action has mainly been shown in adults but is not clearly documented during development. ACh, together with these hormones and their receptors, is expressed before birth, and somatotroph cells are already responsive to GHRH, SRIF, and ghrelin. We thus hypothesized that ACh could contribute to the modulation of the main components of the somatotropic axis during development. In this study, we generated a choline acetyltransferase knockout mouse line and showed that heterozygous mice display a transient deficit in ACh from embryonic day 18.5 to postnatal day 10, and they recover normal ACh levels from the second postnatal week. This developmental ACh deficiency had no major impact on weight gain and cardiorespiratory status of newborn mice. Using this mouse model, we found that endogenous ACh levels determined the concentrations of circulating GH and IGF-1 at embryonic and postnatal stages. In particular, serum GH level was correlated with brain ACh content. ACh also modulated the levels of GHRH and SRIF in the hypothalamus and ghrelin in the stomach, and it affected the levels of these hormones in the circulation. This study identifies ACh as a potential regulator of the somatotropic axis during the developmental period.

A Background of a Volatile Plant Compound Alters Neural and Behavioral Responses to the Sex Pheromone Blend in a Moth.

Recognition of intra-specific olfactory signals within a complex environment of plant-related volatiles is crucial for reproduction in male moths. Sex pheromone information is detected by specific olfactory receptor neurons (Phe-ORNs), highly abundant on the male antenna. The information is then transmitted to the pheromone processing macroglomerular complex (MGC) within the primary olfactory center, the antennal lobe, where it is processed by local interneurons and projection neurons. Ultimately a behavioral response, orientation toward the pheromone source, is elicited. Volatile plant compounds (VPCs) are detected by other functional types of olfactory receptor neurons (ORNs) projecting in another area of the antennal lobe. However, Phe-ORNs also respond to some VPCs. Female-produced sex pheromones are emitted within a rich environment of VPCs, some of which have been shown to interfere with the detection and processing of sex pheromone information. As interference between the different odor sources might depend on the spatial and temporal features of the two types of stimuli, we investigated here behavioral and neuronal responses to a brief sex pheromone blend pulse in a VPC background as compared to a control background in the male noctuid moth Agrotis ipsilon. We observed male orientation behavior in a wind tunnel and recorded responses of Phe-ORNs and MGC neurons to a brief sex pheromone pulse within a background of individual VPCs. We also recorded the global input signal to the MGC using in vivo calcium imaging with the same stimulation protocol. We found that VPCs eliciting a response in Phe-ORNs and MGC neurons masked responses to the pheromone and decreased the contrast between background odor and the sex pheromone at both levels, whereas α-pinene did not interfere with first order processing. The calcium signal produced in response to a VPC background was tonic, lasting longer than the VPC stimulus duration, and masked entirely the pheromone response. One percent heptanal and linalool, in addition to the masking effect, caused a clear delay in responses of MGC neurons to the sex pheromone. Upwind flight toward the pheromone in a wind tunnel was also delayed but otherwise not altered by different doses of heptanal.

Corrigendum: Protective effects of intermittent hypoxia on brain and memory in a mouse model of apnea of prematurity.

[This corrects the article on p. 313 in vol. 6, PMID: 26582992.].

Safety study of Ciprofloxacin in newborn mice.

Ciprofloxacin, a broad-spectrum antimicrobial agent belonging to the fluoroquinolone family, is prescribed off-label in infants less than one year of age. Ciprofloxacin is included in the European Medicines Agency priority list of off-patent medicinal products requiring evaluation in neonates. This evaluation is undergoing within the TINN (Treat Infections in Neonates) FP7 EU project. As part of the TINN project, the present preclinical study was designed to assess the potential adverse effects of Ciprofloxacin on neurodevelopment, liver and joints in mice. Newborn mice received subcutaneous Ciprofloxacin at 10, 30 and 100 mg/kg/day from 2 to 12 postnatal days. Peak plasma levels of Ciprofloxacin were in the range of levels measured in human neonates. We examined vital functions in vivo, including cardiorespiratory parameters and temperature, psychomotor development, exploratory behavior, arthro-, nephro- and hepato-toxic effects. We found no effect of Ciprofloxacin at 10 and 30 mg/kg/day. In contrast, administration at 100 mg/kg/day delayed weight gain, impaired cardiorespiratory and psychomotor development, caused inflammatory infiltrates in the connective tissues surrounding the knee joint, and moderately increased extramedullary hematopoiesis. The present study pleads for careful watching of cardiorespiratory and motor development in neonates treated with Ciprofloxacin, in addition to the standard surveillance of arthrotoxicity.

Influence of low direct electric currents and chlorhexidine upon human dental biofilms.

Dental biofilms have been widely associated with biological complications of oral implants. Currently, no consensus exists regarding the most reliable anti-infective approach to treat peri-implantitis. This study aimed to investigate whether low direct electric currents (DC) could influence chlorhexidine (CHX) 0.2% antimicrobial efficacy against human dental biofilms. To support biofilm accumulation, discs made with machined titanium (Ti) or hydroxyapatite (HA) were used. Five volunteers wore during 24 h an intraoral thermoformed splint on which ten specimens were bonded. Biofilms were then collected and treated ex vivo. During each antimicrobial experiment (N = 20 replicates), two modalities of treatment (CHX/PBS = control groups and CHX/PBS+5mA = test groups) were tested (n = 5 discs each) and the number of viable bacteria evaluated in LogCFU/mL at baseline, 0.5, 1, 2 and 5 min. The proportion of killed bacteria was also estimated and compared statistically at each time point between control and test groups. CHX+/-5mA induced a mean viability reduction around 90-95% after 5 min of treatment whatever the surface considered (Ti/HA). A significant difference regarding the bactericidal effect was noted on Ti surfaces after 0.5, 1 and 2 min in favor of the CHX+5mA modality when compared to CHX alone (p < 0.05). PBS+5mA also had a certain antimicrobial effect (58%) after 5 min on Ti surfaces. This effect was significantly higher than that observed with PBS (25%) (p < 0.05). This study showed that low DC (5mA) can have an antibiofilm effect and are also able to enhance chlorhexidine 0.2% efficacy against human dental biofilms grown on titanium surfaces.

Protective effects of intermittent hypoxia on brain and memory in a mouse model of apnea of prematurity.

Apnea of prematurity (AOP) is considered a risk factor for neurodevelopmental disorders in children based on epidemiological studies. This idea is supported by studies in newborn rodents in which exposure to intermittent hypoxia (IH) as a model of AOP significantly impairs development. However, the severe IH used in these studies may not fully reflect the broad spectrum of AOP severity. Considering that hypoxia appears neuroprotective under various conditions, we hypothesized that moderate IH would protect the neonatal mouse brain against behavioral stressors and brain damage. On P6, each pup in each litter was randomly assigned to one of three groups: a group exposed to IH while separated from the mother (IH group), a control group exposed to normoxia while separated from the mother (AIR group), and a group of untreated unmanipulated pups left continuously with their mother until weaning (UNT group). Exposure to moderate IH (8% O2) consisted of 20 hypoxic events/hour, 6 h per day from postnatal day 6 (P6) to P10. The stress generated by maternal separation in newborn rodents is known to impair brain development, and we expected this effect to be smaller in the IH group compared to the AIR group. In a separate experiment, we combined maternal separation with excitotoxic brain lesions mimicking those seen in preterm infants. We analyzed memory, angiogenesis, neurogenesis and brain lesion size. In non-lesioned mice, IH stimulated hippocampal angiogenesis and neurogenesis and improved short-term memory indices. In brain-lesioned mice, IH decreased lesion size and prevented memory impairments. Contrary to common perception, IH mimicking moderate apnea may offer neuroprotection, at least in part, against brain lesions and cognitive dysfunctions related to prematurity. AOP may therefore have beneficial effects in some preterm infants. These results support the need for stratification based on AOP severity in clinical trials of treatments for AOP, to determine whether in patients with moderate AOP, these treatments are beneficial or deleterious.

First dose in neonates: are juvenile mice, adults and in vitro-in silico data predictive of neonatal pharmacokinetics of fluconazole.

BACKGROUND AND OBJECTIVES: Selection of the first-dose-in-neonates is challenging. The objective of this proof-of-concept study was to evaluate a pharmacokinetic bridging approach to predict a neonatal dosing regimen. METHODS: We selected fluconazole as a paradigm compound. We used data from studies in juvenile mice and adults to develop population pharmacokinetic models using NONMEM. We also develop a physiologically-based pharmacokinetic model from in vitro-in silico data using Simcyp. These three models were then used to predict neonatal pharmacokinetics and dosing regimens for fluconazole. RESULTS: From juvenile mice to neonates, a correction factor of maximum lifespan potential should be used for extrapolation, while a "renal factor" taking into account renal maturation was required for successful bridging based on adult and in vitro-in silico data. Simulations results demonstrated that the predicted drug exposure based on bridging approach was comparable to the observed value in neonates. The prediction errors were -2.2, +10.1 and -4.6 % for juvenile mice, adults and in vitro-in silico data, respectively. CONCLUSION: A model-based bridging approach provided consistent predictions of fluconazole pharmacokinetic parameters in neonates and demonstrated the feasibility of this approach to justify the first-dose-in-neonates, based on all data available from different sources (including physiological informations, preclinical studies and adult data), allowing evidence-based decisions of neonatal dose rather than empiricism.

Hyperactivation of Alk induces neonatal lethality in knock-in AlkF1178L mice.

The ALK (Anaplastic Lymphoma Kinase) gene encodes a tyrosine kinase receptor preferentially expressed in the central and peripheral nervous systems. A syndromic presentation associating congenital neuroblastoma with severe encephalopathy and an abnormal shape of the brainstem has been described in patients harbouring de novo germline F1174V and F1245V ALK mutations. Here, we investigated the phenotype of knock-in (KI) mice bearing the AlkF1178L mutation (F1174L in human). Although heterozygous KI mice did not reproduce the severe breathing and feeding difficulties observed in human patients, behavioral tests documented a reduced activity during dark phases and an increased anxiety of mutated mice. Matings of heterozygotes yielded the expected proportions of wild-type, heterozygotes and homozygotes at birth but a high neonatal lethality was noticed for homozygotes. We documented Alk expression in several motor nuclei of the brainstem involved in the control of sucking and swallowing. Evaluation of basic physiological functions 12 hours after birth revealed slightly more apneas but a dramatic reduced milk intake for homozygotes compared to control littermates. Overall, our data demonstrate that Alk activation above a critical threshold is not compatible with survival in mice, in agreement with the extremely severe phenotype of patients carrying aggressive de novo ALK germline mutations.

Sildenafil mediates blood-flow redistribution and neuroprotection after neonatal hypoxia-ischemia.

BACKGROUND AND PURPOSE: The best conceivable treatment for hypoxia-ischemia (HI) is the restoration of blood flow to the hypoxic-ischemic region(s). Our objective was to examine whether boosting NO-cGMP signaling using sildenafil citrate, a phosphodiesterase-type 5 inhibitor, could modify cerebral blood flow and reduce lesions in the developing brain. METHODS: HI was induced in P7 Sprague-Dawley rats by unilateral carotid artery occlusion and hypoxia, and followed by either PBS or sildenafil. Blood-flow velocities were measured by ultrasound imaging with sequential Doppler recordings to evaluate collateral recruitment. Cell death, blood-brain barrier integrity, and glial activation were analyzed by immunohistochemistry. Motor behavior was evaluated using an open-field device adapted to neonatal animals. RESULTS: Sildenafil citrate (10 mg/kg) induced collateral patency, reduced terminal dUTP nick-end labeling-positive cells, reactive astrogliosis, and macrophage/microglial activation at 72 hours and 7 days post-HI. Sildenafil also reduced the number of terminal dUTP nick-end labeling-positive endothelial cells within lesion site. Seven days after HI and sildenafil treatment, tissue loss was significantly reduced, and animals recovered motor coordination. CONCLUSIONS: Our findings strongly indicate that sildenafil citrate treatment, associated with a significant increase in cerebral blood flow, reduces HI damage and improves motor locomotion in neonatal rats. Sildenafil may represent an interesting therapeutic strategy for neonatal neuroprotection.

Creating markets for combined heat and power and clean distributed generation in New York State.

Combined heat and power (CHP) is the simultaneous production of electrical or mechanical power and thermal energy from in a single process. Because thermal output from the generation of electricity is captured and utilized onsite, CHP systems can achieve efficiencies from 60% to as high as 90%. In contrast generation of electric power at sites remote from the loads served often results in efficiencies of 33% or less due to losses in generation and transmission and distribution of the power to ultimate end users. A well designed CHP system is the essence of energy efficiency. It may also provide significant environmental benefits. However, the full promise of CHP for improving the efficiency and productivity of businesses and the quality of the environment is unlikely to be realized given the current market structure and regulatory environment in which CHP projects are forced to compete. This paper examines the market structure and regulatory obstacles that hinder the development of more robust markets for CHP in New York State.