Neonatal Stage Research Articles

Anatomical and histological characteristics of the hepatobiliary system in adult Sox17 heterozygote mice.

Biliary atresia (BA) is a rare neonatal disease characterized by inflammation and obstruction of the extrahepatic bile ducts (EHBDs). The Sox17-haploinsufficient (Sox17+/- ) mouse is an animal model of BA that encompasses bile duct injury and subsequent BA-like inflammation by the neonatal stage. Most Sox17+/- neonates die soon after birth, but some Sox17+/- pups reach adulthood and have a normal life span, unlike human BA. However, the phenotype and BA-derived scars in the hepatobiliary organs of surviving Sox17+/- mice are unknown. Here, we examined the phenotypes of the hepatobiliary organs in post-weaning and young adult Sox17+/- mice. The results confirmed the significant reduction in liver weight, together with peripheral calcinosis and aberrant vasculature in the hepatic lobule, in surviving Sox17+/- mice as compared with their wild-type (WT) littermates. Such hepatic phenotypes may be sequelae of hepatobiliary damage at the fetal and neonatal stages, a notion supported by the slight, but significant, increases in the levels of serum markers of liver damage in adult Sox17+/- mice. The surviving Sox17+/- mice had a shorter gallbladder in which ectopic hepatic ducts were more frequent compared to WT mice. Also, the surviving Sox17+/- mice showed neither obstruction of the EHBDs nor atrophy or inflammation of hepatocytes or the intrahepatic ducts. These data suggest that some Sox17+/- pups with BA naturally escape lethality and recover from fetal hepatobiliary damages during the perinatal period, highlighting the usefulness of the in vivo model in understanding the hepatobiliary healing processes after surgical restoration of bile flow in human BA.

Oral Ascorbic Acid And α-Tocopherol Protect On Di-(2-Ethyl Hexyl) Phthalate (DEHP) Induced Effects On Gonadotoxicity In The Adult Male Wistar Rats

Environmental pollutants such as di-(2-ethylhexyl) phthalate (DEHP) adversely affect reproductive system tissue differentiation and functions with exposure at intrauterine, neonatal or adult stages of life, thereby potentiating male infertility later in life. World health organization estimates a global infertility prevalent rate of 10-15%, and 20-30% among Nigerians, with male factor constituting about 40-50% of infertility cases. This study was designed to investigate the effect(s) of oral vitamins C and E on DEHP induced changes in some semen parameters and serum testosterone concentration in adult Wistar rats. Seventy (70) adult male Wistar rats weighing between 156-250 g were randomised into 7 experimental groups 1, 2, 3, 4, 5, 6 and 7 (group n=10). Animals in groups 1, 2 and 3 were treated with 0.02 mg, 20 mg, 200 mg oral DEHP/kg bw daily respectively, while those in groups 4, 5 and 6, in addition to the above DEHP treatments, were treated with 100 mg ascorbic acid and 67.5 mg α-tocopherol per kg bw daily respectively. Rats in group 7 served as Control and were treated with vehicle. All treatments lasted for 60 days. After, over night fasting, samples of semen and serum were obtained for analysis. Results obtained were expressed as mean ± standard deviation and analyzed for significant differences in means using one way ANOVA and Post Hoc test. Relative to the control reference values, groups exposed to oral DEHP had significant (p<0.05) reduction in sperm count, total sperm motility, active sperm motility, normal sperm morphology, serum testosterone concentration and serum super oxide dismutase levels to 31.70±18.68x106 cells/mL, 38.60±24.78%, 8.50±5.66%, 38.00±18.00%, 9.56±1.34 ng/mL and 0.017±0.0013 units respectively. Sluggish sperm motility and abnormal sperm morphology significantly (p˂0.01) increased to 39.70±13.05% and 68.50±18.42% respectively. In the groups that had DEHP co-treatments with oral ascorbic acid and α-tocopherol, all studied parameters tended to comparative indifference statistically, with the Controls values. This indicates a protective function against DEHP effects on the studied parameters. The study has shown therefore, that DEHP inflicts oxidative stress in the reproductive system which potentially suppresses serum testosterone concentration with attendant derangements in the qualitative and quantitative sperm cells in adult Wistar rats, and thereby enhancing male infertility. However, the antioxidants ascorbic acid and α-tocopherol protects the gonadal and sperm cells from the harmful effects of DEHP by ameliorating oxidative stress and improving male fertility. This implies that there is need to avoid prolonged exposure to DEHP while encouraging the daily intake of oral ascorbic acid and α-tocopherol.

Neonatal sevoflurane exposure induces impulsive behavioral deficit through disrupting excitatory neurons in the medial prefrontal cortex in mice

Sevoflurane, in particular multiple exposures, has been reported to cause the abnormal neurological development including attention-deficit/hyperactivity disorder (ADHD). This study is to investigate ADHD-like impulsivity in adult mice after repeated sevoflurane exposures at the neonatal stage. Six-day-old pups were exposed to 60% oxygen in the presence or absence of 3% sevoflurane for 2 h and the treatment was administrated once daily for three consecutive days. To assess the impulsivity, the cliff avoidance reaction (CAR) was carried out at the 8th week. Our results showed that repeated sevoflurane treatment increased the number of jumps and shortened the jumping latency in the CAR test. The cortices were harvested for immunostaining to detect c-Fos and calmodulin-dependent protein kinase IIα (CaMKIIα) expression in the medial prefrontal cortex (mPFC). We found that mPFC neurons, especially excitatory neurons, were highly activated and related to impulsive behavior. The activation viruses (AAV-CaMKIIα-hM3Dq) were injected to evaluate the effects of specific activation of mPFC excitatory neurons on impulsive behavior in the presence of clozapine-N-oxide (CNO). Likewise, the inhibitory viruses (AAV-CaMKIIα-hM4Di) were injected in the sevoflurane group to explore whether the mPFC excitatory neuronal inhibition reduced the impulsivity. Our results revealed that chemogenetic activation of mPFC excitatory neurons induced impulsive behavior whereas inhibition of mPFC excitatory neurons partially rescued the deficit. These results indicate that repeated sevoflurane exposures at the critical time induce impulsive behavior accompanied with overactivation of mPFC excitatory neurons in adult stages. This work may further extend to understand the ADHD-like impulsive behavior of the anesthetic neurotoxicity.

Developmental mechanisms regulating the formation of smooth muscle layers in the mouse uterus†.

Uterine smooth muscle cells differentiate from mesenchymal cells, and gap junctions connect the muscle cells in the myometrium. At the neonatal stage, a uterine smooth muscle layer is situated away from the epithelium when smooth muscle cells are grafted near the epithelium, suggesting that the epithelium plays an important role in differentiation, proliferation, and/or migration of smooth muscle cells. In this study, developmental mechanisms regulating the formation of the smooth muscle layers in the mouse uterus were analyzed using an in vitro culture model. Differentiation of smooth muscle cells occurs at a neonatal stage because ACTA2 gene expression was increased at the outer layer, and GJA1 was not expressed in cellular membranes of uterine smooth muscle cells by postnatal day 15. To analyze the effects of the epithelium on the differentiation of smooth muscle cells, a bulk uterine mesenchymal cell line was established from p53-/- mice at postnatal day 3 (P3US cells). Co-culture with Müllerian ductal epithelial cells (E1 cells) induced repulsive migration of ACTA2-positive cells among bulk P3US cells from E1 cells, but it had no effects on the migration of any of 100% ACTA2-positive or negative smooth muscle cell lines cloned from P3US cells. Thus, uterine epithelial cells indirectly affected the repulsive migration of smooth muscle cells via mesenchymal cells. Conditioned medium by E1 cells inhibited differentiation into smooth muscle cells of clonal cells established from P3US cells. Therefore, the uterine epithelium inhibits the differentiation of stem-like progenitor mesenchymal cells adjacent to the epithelium into smooth muscle cells.

Effects of electroacupuncture on stress-induced gastric dysrhythmia and mechanisms involving autonomic and central nervous systems in functional dyspepsia.

Electroacupuncture (EA) is widely used as an effective method to treat stress-related disorders. However, its mechanisms remain largely unknown. The aim of this study was to investigate the effects and mechanisms of EA on gastric slow wave (GSW) dysrhythmia and c-Fos expression in the nucleus of the solitary tract (NTS) induced by stress in a rodent model of functional dyspepsia (FD). Rats in the neonatal stage were treated using intragastric iodoacetamide. Eight weeks later, the rats were implanted with electrodes in the stomach for the measurement of GSW and electrodes into accupoints ST36 for EA. Autonomic functions were assessed by spectral analysis of heart rate variability. Rats were placed for 30 min in a cylindrical plastic tube for acute restraint stress. The involvement of a central afferent pathway was assessed by measuring c-Fos-immunoreactive cells in the NTS. 1) EA normalized restraint stress-induced impairment of GSW in FD rats. 2) EA significantly increased vagal activity (P = 0.002) and improved sympathovagal balance (P = 0.004) under stress in FD rats. 3) In FD rats under restraint stress, plasma norepinephrine concentration was increased substantially (P < 0.01), which was suppressed with EA. 4) The EA group showed increased c-Fos-positive cell counts in the NTS compared with the sham EA group (P < 0.05) in FD rats. Acute restraint stress induces gastric dysrhythmia in a rodent model of FD. EA at ST36 improves GSW under stress in FD rats mediated via the central and autonomic pathways, involving the NTS and vagal efferent pathway.

Pressure Overload Greatly Promotes Neonatal Right Ventricular Cardiomyocyte Proliferation: A New Model for the Study of Heart Regeneration.

BackgroundCurrent mammalian models for heart regeneration research are limited to neonatal apex amputation and myocardial infarction, both of which are controversial. RNAseq has demonstrated a very limited set of differentially expressed genes between sham and operated hearts in myocardial infarction models. Here, we investigated in rats whether pressure overload in the right ventricle, a common phenomenon in children with congenital heart disease, could be used as a better animal model for heart regeneration studies when considering cardiomyocyte proliferation as the most important index.Methods and ResultsIn the rat model, pressure overload was induced by pulmonary artery banding on postnatal day 1 and confirmed by echocardiography and hemodynamic measurements at postnatal day 7. RNA sequencing analyses of purified right ventricular cardiomyocytes at postnatal day 7 from pulmonary artery banding and sham‐operated rats revealed that there were 5469 differentially expressed genes between these 2 groups. Gene ontology and Kyoto Encyclopedia of Genes and Genomes analysis showed that these genes mainly mediated mitosis and cell division. Cell proliferation assays indicated a continuous overproliferation of cardiomyocytes in the right ventricle after pulmonary artery banding, in particular for the first 3 postnatal days. We also validated the model using samples from overloaded right ventricles of human patients. There was an approximately 2‐fold increase of Ki67/pHH3/aurora B‐positive cardiomyocytes in human‐overloaded right ventricles compared with nonoverloaded right ventricles. Other features of this animal model included cardiomyocyte hypotrophy with no fibrosis.ConclusionsPressure overload profoundly promotes cardiomyocyte proliferation in the neonatal stage in both rats and human beings. This activates a regeneration‐specific gene program and may offer an alternative animal model for heart regeneration research.

Influence of in utero di-n-hexyl phthalate and di-cyclohexyl phthalate exposure on the endocrine glands and T3, T4, and TSH hormone levels of male and female rats: Postnatal outcomes.

The present study was designed to evaluate the effects of di-n-hexyl phthalate (DHP) and di-cyclohexyl phthalate (DCHP) on endocrine organs in rats. Oil control, 20-, 100-, and 500 mg/kg dose groups were selected and administered to pregnant rats on gestational days 6-19 by oral gavage. The neonatal stages of rats continued until postnatal day 20 and the- juvenile stages of rats continued until postnatal day of 32. The rats were allowed to mature until the neonatal and juvenile stages and there after, they were divided into four groups corresponding to the treatment levels. Body and organ weights were recorded, serum was collected, and thyroid, pancreas, pituitary gland, and adrenal gland were removed. There was a decrease in body weights in the 20- and 500mg/kg DHP and in the 20-mg/kg DCHP dose groups in neonatal male rats. In contrast, for female rats, there was an increase in body weights in the 100-mg/kg DCHP dose group and there was a decrease in body weights in the 500-mg/kg DHP dose group. Body weights were increased at 20 and 500 mg/kg in the DHP-exposed juvenile male rats. Serum thyroid-stimulating hormone (TSH) levels were increased in neonatal male rats, while they were increased in the 100-mg/kg DHP group of neonatal and juvenile female rats. Serum triiodothyronine (T3) levels were increased at the high dose of DHP for neonatal male rats and at the low and high dose levels of DCHP for female rats. Serum thyroxine (T4) levels were increased in neonatal rats for DHP. Also, some histopathological changes were observed in the thyroid, pancreas, adrenal, and pituitary gland. In conclusion, it was shown that DHP and DCHP caused negative effects on T3, T4, and TSH hormone levels.

Neonatal EEG sleep stage classification based on deep learning and HMM

Objective. Automatic sleep stage scoring is of great importance for investigating sleep architecture during infancy. In this work, we introduce a novel multichannel approach based on deep learning networks and hidden Markov models (HMM) to improve the accuracy of sleep stage classification in term neonates. Approach. The classification performance was evaluated on quiet sleep (QS) and active sleep (AS) stages, each with two sub-states, using multichannel EEG data recorded from sixteen neonates with postmenstrual age of 38–40 weeks. A comprehensive set of linear and nonlinear features were extracted from thirty-second EEG segments. The feature space dimensionality was then reduced by using an evolutionary feature selection method called MGCACO (Modified Graph Clustering Ant Colony Optimization) based on the relevance and redundancy analysis. A bi-directional long-short time memory (BiLSTM) network was trained for sleep stage classification. The number of channels was optimized using the sequential forward selection method to reduce the spatial space. Finally, an HMM-based postprocessing stage was used to reduce false positives by incorporating the knowledge of transition probabilities between stages into the classification process. The method performance was evaluated using the K-fold (KFCV) and leave-one-out cross-validation (LOOCV) strategies. Main results. Using six-bipolar channels, our method achieved a mean kappa and an overall accuracy of 0.71–0.76 and 78.9%–82.4% using the KFCV and LOOCV strategies, respectively. Significance. The presented automatic sleep stage scoring method can be used to study the neurodevelopmental process and to diagnose brain abnormalities in term neonates.

Astrocytes of the early postnatal brain.

In the rodent forebrain, the majority of astrocytes are generated during the early postnatal phase. Following differentiation, astrocytes undergo maturation which accompanies the development of the neuronal network. Neonate astrocytes exhibit a distinct morphology and domain size which differs to their mature counterparts. Moreover, many of the plasma membrane proteins prototypical for fully developed astrocytes are only expressed at low levels at neonatal stages. These include connexins and Kir4.1, which define the low membrane resistance and highly negative membrane potential of mature astrocytes. Newborn astrocytes moreover express only low amounts of GLT-1, a glutamate transporter critical later in development. Furthermore, they show specific differences in the properties and spatio-temporal pattern of intracellular calcium signals, resulting from differences in their repertoire of receptors and signalling pathways. Therefore, roles fulfilled by mature astrocytes, including ion and transmitter homeostasis, are underdeveloped in the young brain. Similarly, astrocytic ion signalling in response to neuronal activity, a process central to neuron-glia interaction, differs between the neonate and mature brain. This review describes the unique functional properties of astrocytes in the first weeks after birth and compares them to later stages of development. We conclude that with an immature neuronal network and wider extracellular space, astrocytic support might not be as demanding and critical compared to the mature brain. The delayed differentiation and maturation of astrocytes in the first postnatal weeks might thus reflect a reduced need for active, energy-consuming regulation of the extracellular space and a less tight control of glial feedback onto synaptic transmission.

MiRNAs Expression Profiling of Bovine (Bos taurus) Testes and Effect of bta-miR-146b on Proliferation and Apoptosis in Bovine Male Germline Stem Cells.

Spermatogenesis is a complex biological process regulated by well-coordinated gene regulation, including MicroRNAs (miRNAs). miRNAs are endogenous non-coding ribonucleic acids (ncRNAs) that mainly regulate the gene expression at post-transcriptional levels. Several studies have reported miRNAs expression in bull sperm and the process of spermatogenic arrest in cattle and yak. However, studies for the identification of differential miRNA expression and its mechanisms during the developmental stages of testis still remain uncertain. In the current study, we comprehensively analyzed the expression of miRNA in bovine testes at neonatal (3 days after birth, n = 3) and mature (13 months, n = 3) stages by RNA-seq. Moreover, the role of bta-miR-146b was also investigated in regulating the proliferation and apoptosis of bovine male germline stem cells (mGSCs) followed by a series of experiments. A total of 652 miRNAs (566 known and 86 novel miRNAs) were identified, whereas 223 miRNAs were differentially expressed between the two stages. Moreover, an elevated expression level of bta-miR-146b was found in bovine testis among nine tissues, and the functional studies indicated that the overexpression of bta-miR-146b inhibited the proliferation of bovine mGSCs and promoted apoptosis. Conversely, regulation of bta-miR-146b inhibitor promoted bovine mGSCs proliferation. This study provides a basis for understanding the regulation roles of miRNAs in bovine testis development and spermatogenesis.

The lack of terminal tubule cells in the submandibular gland of mice deficient in submandibular gland protein C.

The submandibular gland (SMG) of newborn mice has no mature acini but has the rudiments of acini called terminal tubules (TT). The TT are composed of TT cells with dark secretory granules and proacinar cells with lighter secretory granules, the latter being considered the immediate precursor of mature acinar cells. TT cells contain a specific secretory protein, submandibular gland protein C (SMGC) and they decrease in number postnatally at a higher rate in males than in females. In the present study, in order to clarify the biological roles of TT cells and their secretory product SMGC, we generated a knockout (KO) mouse strain deficient in SMGC. The KO mice of both sexes grew normally, had normal reproductive capacity and had normal acinar and duct systems in the SMG in adult ages. However, through the neonatal and early postnatal stages, the KO mice were deficient not only in the production of SMGC but also in TT cells. With electron microscopy of the SMG of newborn KO mice, TT cells with characteristic granules were absent and replaced by undifferentiated ductal cells, whereas proacinar cells were normal. These results suggested that the absence of SMGC inhibits the development of TT cells and that the absence of SMGC and TT cells has no notable influence on the postnatal development of the acinar and duct systems in the SMG.

HOME VISITS DURING THE FIRST MONTH OF DELIVERY FOR RECENTLY DELIVERED WOMEN IN UTTAR PRADESH, INDIA

HOME VISITS DURING THE FIRST MONTH OF DELIVERY FOR RECENTLY DELIVERED WOMEN IN UTTAR PRADESH, INDIA

Meningitic &lt;i&gt;Escherichia Coli&lt;/i&gt; α-Hemolysin Facilitates Blood-Brain Barrier Disruption Via Targeting Tgfβ1-Induced Hedgehog Signaling

Meningitic Escherichia coli is the major etiological agent of bacterial meningitis in neonatal stage, which is a life-threatening infection disease with severe neurological sequelae and high mortality. Blood-brain barrier (BBB) disruption is an important hallmark during this infection. Here, we showed that astrocyte-derived TGFβ1 maintained the BBB integrity via activating hedgehog signaling in endothelium, while meningitic E. coli infection could effectively subvert BBB by attenuating TGFBRII/Gli2-mediated such signaling. By high-throughput screening, we demonstrated E. coli α-hemolysin was the key determinant responsible for this attenuation through Sp1-dependent TGFBRII reduction, as well as triggering Ca2+ influx and protein kinase A activation, thus leading to Gli2 suppression. Additionally, the exogenous hedgehog agonist SAG showed a promising protection against meningitic E. coli-caused BBB dysfunction. Our work revealed a hedgehog-involved mechanism of E. coli-caused BBB disruption, and suggested that activating hedgehog signaling could be a potential protective strategy for future therapy of bacterial meningitis.

Neonatal sleep stage identification using long short-term memory learning system.

Neonatal sleep analysis at the neonatal intensive care units (NICU) is critical for the diagnosis of any brain growth risks during the early stages of life. In this paper, an investigation is carried out on the use of a long short-term memory (LSTM) learning system in automatic sleep stage scoring in neonates. The developed algorithm automatically classifies sleep stages based on inputs from a single channel EEG recording. Up to this date, only a single study have developed an approach for automatic sleep stage scoring in neonatal sleep signals using deep neural network (DNN). A total of 5095 sleep stages signals acquired from EEG recordings of the University of Pittsburgh are used in this study. The sleep stages are annotated by a medical doctor from the Pediatric Neurology Department of Case Western Reserve University for three neonatal sleep stages including the awake (W), active sleep (AS), and quiet sleep (QS) stages on every 60-s epoch. The signals are pre-processed through normalization and filtering. The resulted signals are divided following 4-, 6-, and 10-fold cross-validation schemes. The training and classification process is done using a bi-directional LSTM network classifier built with pre-defined training parameters. At the end, the developed algorithm is evaluated along with a complete summary table that reports the results of this study and other state-of-the-art studies. The current study achieved high levels of Cohen's kappa (κ), accuracy, and F1 score with 91.37%, 96.81%, and 94.43%, respectively. Based on the confusion matrix, the overall true positives percentage reached 95.21%. The developed algorithm gave promising results in automatic sleep stage scoring in neonatal sleep signals. Future work include LSTM architecture and training parameters improvements to enhance the overall accuracy of the classifier.

Tissue‐specific Humanized Models Expressing Human UGT1A1

The human UDP‐glucuronosyltransferases (UGTs) represent an important family of drug‐metabolizing enzymes. Among the nine UGT1A proteins, UGT1A1 has been the most extensively studied. UGT1A1 is the sole enzyme responsible for the glucuronidation of bilirubin and is involved in the conjugation of endogenous and many exogenous substances, including pharmaceutical drugs. Although the liver is considered a major organ for detoxification, intestinal UGT1A1 is also an important contributor for drug clearance. In order to investigate the role of both intestinal and hepatic human UGT1A1, we generated humanized strains that express only the UGT1A1 gene in either liver (hAlb1A1) or small intestine (hVil1A1). The two models were characterized by demonstrating hepatic and intestinal tissue specific expression of human UGT1A1. Body weight (BW) and total serum bilirubin (TSB) levels were monitored during different developmental stage. Both humanized models exhibited similar BW and normal TSB values in the adult stages. Differences between the two animal models were observed in the neonatal stage where hVil1A1 pups presented significantly lower TSB levels than hAlb1A1 mice, confirming that the intestinal expression of UGT1A1 is crucial in preventing bilirubin toxicity during development. Of importance is the finding that we have new humanized UGT1A1 mouse models to examine tissue‐specific glucuronidation. Given the importance of the intestinal tract in xenobiotic activation, metabolism and detoxification, we subsequently have isolated intestinal crypt organoids from these same animal models. The use of these in vivo models and their in vitro complementary primary cell models provide important tools for studying intestinal and hepatic toxicity of drugs and environmental toxicants that are metabolized by UGT1A1.Support or Funding InformationSupported by National Institutes of Health grants GM126074 and ES010337

Preferential Perinatal Development of Skin-Homing NK1.1+ Innate Lymphoid Cells for Regulation of Cutaneous Microbiota Colonization.

SummaryProper immune cell development at early ontogenic stages is critical for life-long health. How resident immune cells are established in barrier tissues at neonatal stages to provide early protection is an important but still poorly understood question. We herein report that a developmentally programmed preferential generation of skin-homing group 1 innate lymphoid cells (ILC1s) at perinatal stages helps regulate early skin microbiota colonization. We found that a population of skin-homing NK1.1+ ILC1s was preferentially generated in the perinatal thymi of mice. Unique thymic environments and progenitor cells are responsible for the preferential generation of skin-homing NK1.1+ ILC1s at perinatal stages. In the skin, NK1.1+ ILC1s regulate proper microbiota colonization and control the opportunistic pathogen Pseudomonas aeruginosa in neonatal mice. These findings provide insight into the development and function of tissue-specific immune cells at neonatal stages, a critical temporal window for establishment of local tissue immune homeostasis.

The Influence of Perinatal Stress and Antidepressants on Different Types of Adaptive Behavior and Cognitive Abilities of Prepubertal Female Rats

We investigated the influence of repeated peripheral inflammatory nociceptive stimulation of neonate female rats born to mothers exposed during pregnancy to chronic stress and the effect of an antidepressant drug fluoxetine, a selective serotonin (5-HT) reuptake inhibitor, and an anxiolytic drug buspirone, a 5-HT1A receptor agonist, on adaptive behavior and cognitive abilities of the offspring during the prepubertal period. The data on the effect of maternal stress exposure during the critical perinatal period of individual development on adaptive behavior and spatial learning abilities of the offspring provide support for the hypothesis on the possible beneficial effect of moderate stressful events experienced at an early age on stress tolerance in subsequent ontogenesis. The corrective effect of the above drugs on adaptive behavior and cognitive abilities of the prenatally stressed prepubertal female offspring exposed to repeated peripheral inflammatory pain at the neonatal stage is characterized.

Resveratrol Mitigates Sevoflurane-Induced Neurotoxicity by the SIRT1-Dependent Regulation of BDNF Expression in Developing Mice.

Various lines of evidence suggest that neonatal exposure to general anesthetics, especially repeatedly, results in neuropathological brain changes and long-term cognitive impairment. Although progress has been made in experimental models, the exact mechanism of GA-induced neurotoxicity in the developing brain remains to be clarified. Sirtuin 1 (SIRT1) plays an important role in synaptic plasticity and cognitive performance, and its abnormal reduction is associated with cognitive dysfunction in neurodegenerative diseases. However, the role of SIRT1 in GA-induced neurotoxicity is unclear to date. In this study, we found that the protein level of SIRT1 was inhibited in the hippocampi of developing mice exposed to sevoflurane. Furthermore, the SIRT1 inhibition in hippocampi was associated with brain-derived neurotrophic factor (BDNF) downregulation modulated by methyl-cytosine-phosphate-guanine–binding protein 2 (MeCP2) and cAMP response element-binding protein (CREB). Pretreatment of neonatal mice with resveratrol nearly reversed the reduction in hippocampal SIRT1 expression, which increased the expression of BDNF in developing mice exposed to sevoflurane. Moreover, changes in the levels of CREB and MeCP2, which were considered to interact with BDNF promoter IV, were also rescued by resveratrol. Furthermore, resveratrol improved the cognitive performance in the Morris water maze test of the adult mice with exposure to sevoflurane in the neonatal stage, without changing motor function in the open field test. Taken together, our findings suggested that SIRT1 deficiency regulated BDNF signaling via regulation of the epigenetic activity of MeCP2 and CREB, and resveratrol might be a promising agent for mitigating sevoflurane-induced neurotoxicity in developing mice.

Tuberculosis: a challenge in newborn care and how to deal with it. Update document

Tuberculosis in the neonatal stage has a high morbidity and mortality, is difficult to diagnose and involves the mother-child binomial and their environment. The particular characteristics of the immune system in pregnant women and the newborn, impact the clinical presentation of this disease. Its diagnosis is complex and the establishment of treatment must be timely and cannot be postponed. Relevant aspects for the diagnosis and management of the newborn exposes to the tuberculosis are covered.

Negligible senescence in naked mole rats may be a consequence of well-maintained splicing regulation

Naked mole-rats (NMRs) have amongst the longest lifespans relative to body size of any known, non-volant mammalian species. They also display an enhanced stress resistance phenotype, negligible senescence and very rarely are they burdened with chronic age-related diseases. Alternative splicing (AS) dysregulation is emerging as a potential driver of senescence and ageing. We hypothesised that the expression of splicing factors, important regulators of patterns of AS, may differ in NMRs when compared to other species with relatively shorter lifespans. We designed assays specific to NMR splicing regulatory factors and also to a panel of pre-selected brain-expressed genes known to demonstrate senescence-related alterations in AS in other species, and measured age-related changes in the transcript expression levels of these using embryonic and neonatal developmental stages through to extreme old age in NMR brain samples. We also compared splicing factor expression in both young mouse and NMR spleen and brain samples. Both NMR tissues showed approximately double the expression levels observed in tissues from similarly sized mice. Furthermore, contrary to observations in other species, following a brief period of labile expression in early life stages, adult NMR splicing factors and patterns of AS for functionally relevant brain genes remained remarkably stable for at least two decades. These findings are consistent with a model whereby the conservation of splicing regulation and stable patterns of AS may contribute to better molecular stress responses and the avoidance of senescence in NMRs, contributing to their exceptional lifespan and prolonged healthspan.