Mucosal recombinant BCG vaccine induces lung-resident memory macrophages and enhances trained immunity via mTORC2/HK1-mediated metabolic rewiring.

Bacillus Calmette-Guérin (BCG) vaccination induces a type of immune memory known as "trained immunity", characterized by the immunometabolic and epigenetic changes in innate immune cells. However, the molecular mechanism underlying the strategies for inducing and/or boosting trained immunity in alveolar macrophages remains unknown. Here, we found that mucosal vaccination with the recombinant strain rBCGPPE27 significantly augmented the trained immune response in mice, facilitating a superior protective response against Mycobacterium tuberculosis and non-related bacterial reinfection in mice when compared to BCG. Mucosal immunization with rBCGPPE27 enhanced innate cytokine production by alveolar macrophages associated with promoted glycolytic metabolism, typical of trained immunity. Deficiency of the mammalian target of rapamycin complex 2 and hexokinase 1 abolished the immunometabolic and epigenetic rewiring in mouse alveolar macrophages after mucosal rBCGPPE27 vaccination. Most noteworthy, utilizing rBCGPPE27's higher-up trained effects: The single mucosal immunization with rBCGPPE27-adjuvanted coronavirus disease (CoV-2) vaccine raised the rapid development of virus-specific immunoglobulin G antibodies, boosted pseudovirus neutralizing antibodies, and augmented T helper type 1-biased cytokine release by vaccine-specific T cells, compared to BCG/CoV-2 vaccine. These findings revealed that mucosal recombinant BCG vaccine induces lung-resident memory macrophages and enhances trained immunity via reprogramming mTORC2- and HK-1-mediated aerobic glycolysis, providing new vaccine strategies for improving tuberculosis (TB) or coronavirus variant vaccinations, and targeting innate immunity via mucosal surfaces.

Association of cumulative monocyte to high-density lipoprotein ratio with the risk of type 2 diabetes: a prospective cohort study.

BACKGROUND: Recent studies have established that monocyte-derived inflammation plays a central role in the pathogenesis of type 2 diabetes mellitus (T2DM). It is unclear whether chronic metabolic inflammation, reflected by the cumulative monocyte to high-density lipoprotein ratio (CumMHR), predisposes the general population to T2DM. METHODS: This study included 40,813 participants without diabetes from a real-life, community-based cohort (the Kailuan Study) attending a 2-year cycle of health survey since 2006. Cumulative exposure was obtained from 2006/2007 to 2010/2011. Follow-up started at 2010/2011 and through 2020. Multivariable-adjusted Cox regression models were used to calculate the CumMHR-associated risk of incident T2DM. RESULTS: Over a median follow-up period of 7.98 (IQR: 5.74-8.87) years, 4,848 T2DM cases occurred. The CumMHR was positively associated with the risk of incident T2DM after adjusting for age, sex, smoking, drinking habits, physical activities, BMI, triglyceride-glycemia index, log(leukocyte count), log(hsCRP), blood pressure, renal function, and medication uses with adjusted HRs of 1.0 (ref.), 1.18 (1.05‒1.25), 1.17 (1.07‒1.27), 1.38 (1.26‒1.50), respectively, in CumMHR Quartiles 1, 2, 3 and 4. When follow-up ended at 2014/2015, the short-term (4‒year) adjusted T2DM risks in CumMHR Quartiles 2, 3, and 4 were 1.14 (1.01‒1.29), 1.17 (1.04‒1.32), 1.40 (1.25‒1.58), respectively, relative to Quartile 1. A significant interaction between CumMHR and cumulative high-sensitivity C-reactive protein (CumCRP) was observed (P-interaction: 0.0109). The diabetic risk in the highest quartile of CumMHR was higher (1.53 [1.28‒1.84]) when CumCRP < 1 mg/L, attenuated with increasing CumCRP levels (1 ~ 10 mg/L) and disappeared in CumCRP ≥ 10 mg/L. Hypertension, overweight, or smoking habits further modified the CumMHR-associated diabetic risk. CONCLUSIONS: Cumulative MHR may be a promising supplement to hsCRP for more comprehensively assessing the influence of metabolic inflammation on T2DM susceptibility. For primary prevention, targeting high CumMHR, especially in cases at low risk of diabetes defined by traditional risk factors, may further help reduce the diabetic risk.

How do maternal emotion and sleep conditions affect infant sleep: a prospective cohort study.

BACKGROUND: Recent studies suggest that the incidence of infant sleep disorder is related to maternal emotional and sleep conditions, but how they influence each other is not fully understood. METHODS: A total of 513 pairs of parents and infants were enrolled in this prospective cohort study. Maternal emotional and sleep conditions were assessed using a self-rating depression scale, self-rating anxiety scale, and Pittsburgh Sleep Quality Index at the third trimester and within 3 months after delivery. Infant sleep was assessed by the Brief Screening Questionnaire for Infant Sleep Problems within 3 months after birth. Expression of the glucocorticoid receptor (GR), melatonin receptors (MR), exchange proteins directly activated by cAMP (EPAC) receptors, and dopamine receptor (DR) in the placenta was detected by immunohistochemistry. Methylation of the promoter regions for the GR (NR3C1 and NR3C2), MR (MTNR1A and MTNR1B), EPAC (RASGRF1 and RASGRF2), and DR (DRD1 and DRD2) genes was assessed by next generation sequencing-based bisulfite sequencing PCR. RESULTS: The incidence of sleep disorders in infants 0-3 months of age in this cohort was 40.5%. Risk factors for infant sleep disorder were low education level of the father, depression of father, maternal postpartum depression, postpartum anxiety, postpartum sleep disorder, and maternal sleep disorder extend from the third trimester to postpartum. There was no difference in expression of placental DR, GR, MR, and EPAC between mothers whose infants were with and without sleep disorders. Methylation of MTNR1B was higher and expression of MR was lower in the placenta of mothers with sleep disorder in the third trimester than in mothers without sleep disorder. Level of NR3C2 methylation was lower and GR expression was higher in the placenta of mothers with sleep disorder extend from the third trimester to postpartum than in mothers without sleep disorder. CONCLUSION: Maternal sleep disorders in the third trimester could lead to decreased MR expression by up-regulating MTNR1B methylation, and then resulting in elevated cortisol and increased GR expression by down-regulating NR3C2 methylation, which could increase the incidence of maternal postpartum sleep disorders, finally, the maternal postpartum sleep disorder could result in the high incidence of infant sleep disorder.

Promoter methylation changes in the placenta involved in the relationship between prenatal depression and small for gestational age.

BACKGROUND: Recent studies suggest that the incidence of small for gestational age (SGA) birth related to maternal depression, but the mechanism is unclear. The aim of this study was to explore the changes of promoter methylation in the placenta which may be involved in the relationship between prenatal depression and SGA. METHODS: Three hundred forty-five pregnant women were enrolled in this prospective cohort study. Perinatal emotion and sleep quality in the second and third trimesters were assessed using self-rating depression scale, self-rating anxiety scale, and Pittsburgh sleep quality index. According to the exposure (depressed emotion of mother) and outcome (SGA), the placentas were divided into four groups. Methylation of the promoter regions of the placental CRH, HSD11ß2, SLA16A10, DIO3, and MTNR1B genes was determined using next generation sequencing based on bisulfite sequencing PCR. RESULTS: There were 97 (28.1%) and 95 (27.5%) pregnant women who had depression in the second trimester and third trimester, respectively. Thirty-five pregnant women had an SGA birth. The incidence of SGA births in this prospective cohort was 10.1%. The risk factors of SGA birth were low BMI of pregnancy women (RR = 0.71, 95%CI = 0.54 ~ 0.92), hypertensive disorder complicating pregnancy (HDCP, RR = 4.7, 95%CI = 1.18 ~ 18.72), and maternal depression in the second trimester (RR = 3.71, 95%CI = 1.31 ~ 12.16). We found that the CRH and HSD11ß2 methylation levels were higher in the depression group than those in the non-depression group. Methylation levels of DIO3 were higher in SGA group than that in the non-SGA group. Higher methylation levels of CRH correlated with higher methylation levels of DIO3 in the placenta. CONCLUSIONS: Maternal depression in the second trimester may lead to the changes of methylation levels in the promoter region of CRH and HSD11ß2 gene, while the changes of methylation of DIO3 in subsequent could related to SGA. This study suggests that maternal depressed emotion during pregnancy may result in SGA due to the epigenetic changes of placenta.

Clinical characterization of NTCP deficiency in paediatric patients : A case-control study based on SLC10A1 genotyping analysis.

Na+ -taurocholate cotransporting polypeptide deficiency (NTCPD) is a newly described disorder arising from biallelic mutations of the SLC10A1 gene. As a result of a lack of compelling evidence from case-control studies, its genotypic and phenotypic features remain open for in-depth investigation. This study aimed to explore the genotypic and clinical phenotypic characteristics of paediatric patients with NTCPD. The SLC10A1 genotypes of all NTCPD patients were confirmed by screening for the prevalent variant c.800C>T and Sanger sequencing when necessary. The clinical presentations and laboratory changes were collected, reviewed and analysed, and then qualitatively and quantitatively compared with the relevant controls. A total of 113 paediatric NTCPD patients were diagnosed while c.374dupG and c.682_683delCT were detected as two novel pathogenic mutations. Hypercholanemia was observed in 99.12% of the patients. Indirect hyperbilirubinemia in affected neonates exhibited higher positive rates in comparison to controls. Moreover, transient cholestatic jaundice, elevated liver enzymes and 25-hydroxyvitamin D (Vit D) deficiency during early infancy were more commonly observed in patients than in controls. All NTCPD patients exhibited favourable clinical outcomes as a result of symptomatic and supportive treatment. The findings enriched the SLC10A1 mutation spectrum and provided comprehensive insights into the phenotypic characteristics of NTCPD. NTCPD should be considered and SLC10A1 gene should be analysed in patients with above age-dependent clinical features. Furthermore, over investigation and intervention should be avoided in the management of NTCPD patients.

Hypertonic saline or mannitol for treating elevated intracranial pressure in traumatic brain injury: a meta-analysis of randomized controlled trials.

Hyperosmolar therapy is regarded as the mainstay for treatment of elevated intracranial pressure (ICP) in traumatic brain injury (TBI). This still has been disputed as application of hypertonic saline (HS) or mannitol for treating patients with severe TBI. Thus, this meta-analysis was performed to further compare the advantages and disadvantages of mannitol with HS for treating elevated ICP after TBI. We conducted a systematic search on PubMed, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), Wan Fang Data, VIP Data, SinoMed, and China National Knowledge Infrastructure (CNKI) databases. Studies were included or not based on the quality assessment by the Jadad scale and selection criteria. Twelve RCTs with 438 patients were enrolled for the meta-analysis. The comparison of HS and mannitol indicated that they were close in field of improving function outcome (RR = 1.17, 95% CI 0.89 to 1.54, p = 0.258) and reducing intracranial pressure (MD = - 0.16, 95% CI: - 0.59 to 0.27, p = 0.473) and mortality (RR = 0.78, 95% CI 0.53 to 1.16, p = 0.216). The pooled relative risk of successful ICP control was 1.06 (95% CI: 1.00 to 1.13, p = 0.044), demonstrating that HS was more effective than mannitol in ICP management. Both serum sodium (WMD = 5.30, 95% CI: 4.37 to 6.22, p < 0.001) and osmolality (WMD = 3.03, 95% CI: 0.18 to 5.88, p = 0.037) were increased after injection of hypertonic saline. The results do not lend a specific recommendation to select hypertonic saline or mannitol as a first-line for the patients with elevated ICP caused by TBI. However, for the refractory intracranial hypertension, hypertonic saline seems to be preferred.

Mechanisms of neuroprotection from hypoxia-ischemia (HI) brain injury by up-regulation of cytoglobin (CYGB) in a neonatal rat model.

This study was designed to investigate the expression profile of CYGB, its potential neuroprotective function, and underlying molecular mechanisms using a model of neonatal hypoxia-ischemia (HI) brain injury. Cygb mRNA and protein expression were evaluated within the first 36 h after the HI model was induced using RT-PCR and Western blotting. Cygb mRNA expression was increased at 18 h in a time-dependent manner, and its level of protein expression increased progressively in 24 h. To verify the neuroprotective effect of CYGB, a gene transfection technique was employed. Cygb cDNA and shRNA delivery adenovirus systems were established (Cygb-cDNA-ADV and Cygb-shRNA-ADV, respectively) and injected into the brains of 3-day-old rats 4 days before they were induced with HI treatment. Rats from different groups were euthanized 24 h post-HI, and brain samples were harvested. 2,3,5-Triphenyltetrazolium chloride, TUNEL, and Nissl staining indicated that an up-regulation of CYGB resulted in reduced acute brain injury. The superoxide dismutase level was found to be dependent on expression of CYGB. The Morris water maze test in 28-day-old rats demonstrated that CYGB expression was associated with improvement of long term cognitive impairment. Studies also demonstrated that CYGB can up-regulate mRNA and protein levels of VEGF and increase both the density and diameter of the microvessels but inhibits activation of caspase-2 and -3. Thus, this is the first in vivo study focusing on the neuroprotective role of CYGB. The reduction of neonatal HI injury by CYGB may be due in part to antioxidant and antiapoptotic mechanisms and by promoting angiogenesis.

Pre-gestational stress alters stress-response of pubertal offspring rat in sexually dimorphic and hemispherically asymmetric manner.

BACKGROUND: There is increasing evidence that maternal stress may have long-term effects on brain development in the offspring. In this study, we examined whether pre-gestational stress might affect offspring rats on the medial prefrontal cortical (mPFC) dopaminergic activity in response to acute stress in puberty and if so, whether such effects exhibited hemispheric asymmetry or sexual dimorphism. RESULTS: We used behavioral tests to assess the model of chronic unpredictable stress (CUS). We found that the activity in the open field test and sucrose intake test were lower for maternal rats in the CUS group than those in the control group. Offspring rats in the CUS group floated more and swam or climbed less as compared to the offsprings in the control group in the forced swimming test. The floating time was longer and swimming or climbing time was shorter in the female offspring rats than those in the males. Serum corticosterone and corticotrophin-releasing hormone levels were significantly higher for CUS maternal rats and their offsprings than the respective controls. The ratio of dihydroxy-phenyl acetic acid (DOPAC) to dopamine (DA), DA transporter (DAT), norepinephrine transporter (NET) were lower in the mPFC of offspring rats in the CUS group than the control group. Levels of catechol-O-methyltransferase (COMT) in the left mPFC of female offspring rats and in the right mPFC of both female and male offspring rats were lower in the CUS group than those in the controls, but there was no difference in the left mPFC of male offspring between the CUS and control groups. DOPAC, the ratio of DOPAC to DA, NET and COMT were lower in the right mPFC than in the left mPFC of offspring rats in the CUS group. The ratio of DOPAC to DA in the right mPFC was lower in the female offspring rats than male offspring rats in the CUS group. The NET and COMT levels in both left and right mPFC were lower in the female offspring rats than those of the male offsprings in the CUS group. CONCLUSION: Our data provide evidence that the effect of pre-gestational stress on the mPFC dopaminergic activity in response to acute stress exhibited hemispheric asymmetry and sexual dimorphism in the pubertal offspring rats.

The expression of cytoglobin as a prognostic factor in gliomas: a retrospective analysis of 88 patients.

BACKGROUND: Evidence suggests that cytoglobin (Cygb) may function as a tumor suppressor gene. METHODS: We immunohistochemically evaluated the expression of Cygb, phosphatidylinositol-3 kinase (PI-3K), phosphorylated (p)-Akt, Interleukin-6 (IL-6), tumor necrosis factor-α (TNFα) and vascular endothelial growth factor (VEGF) in 88 patients with 41 high-grade gliomas and 47 low-grade gliomas. Intratumoral microvessel density (IMD) was also determined and associated with clinicopathological factors. RESULTS: Low expression of Cygb was significantly associated with the higher histological grading and tumor recurrence. A significant negative correlation emerged between Cygb expression and PI3K, p-Akt, IL-6, TNFα or VEGF expression. Cygb expression was negatively correlated with IMD. There was a positive correlation between PI3K, p-Akt, IL-6, TNFα and VEGF expression with IMD.High histologic grade, tumor recurrence, decreased Cygb expression, increased PI3K expression, increased p-Akt expression and increased VEGF expression correlated with patients' overall survival in univariate analysis. However, only histological grading and Cygb expression exhibited a relationship with survival of patients as independent prognostic factors of glioma by multivariate analysis. CONCLUSIONS: Cygb loss may contribute to tumor recurrence and a worse prognosis in gliomas. Cygb may serve as an independent predictive factor for prognosis of glioma patients.

Pre-gestational stress reduces the ratio of 5-HIAA to 5-HT and the expression of 5-HT1A receptor and serotonin transporter in the brain of foetal rat.

BACKGROUND: Many studies have found that stress before or during pregnancy is linked to an increased incidence of behavioural disorders in offspring. However, few studies have investigated hypothalamic-pituitary-adrenal (HPA) axis activity and the serotonergic system as a consequence of pregestational stress. In the present study, we investigated the effect of pre-gestational stress on HPA axis activity in maternal rats and their foetuses and examined whether changes in HPA axis activity of maternal rats produced functional changes in the serotonergic system in the brain of foetuses. RESULTS: We used the behavioural tests to assess the model of chronic unpredictable stress (CUS) in maternal rats. We found the activity in the open field and sucrose consumption was lower for rats with CUS than for the controls. Body weight but not brain weight was higher for control foetuses than those from the CUS group. Serum corticosterone and corticotrophin-releasing hormone levels were significantly higher for mothers with CUS before pregnancy and their foetuses than for the controls. Levels of 5-hydroxytryptamine (5-HT) were higher in the hippocampus and hypothalamus of foetuses in the CUS group than in the controls, and 5-hydroxyindoleacetic acid (5-HIAA) levels were lower in the hippocampus in foetuses in the CUS group than in the control group. Levels of 5-HIAA in the hypothalamus did not differ between foetuses in the CUS group and in the control group. The ratio of 5-HIAA to 5-HT was significantly lower for foetuses in the CUS group than in the control group. Levels of 5-HT1A receptor were significantly lower in the foetal hippocampus in the CUS group than in the control group, with no significant difference in the hypothalamus. The levels of serotonin transporter (SERT) were lower in both the foetal hippocampus and foetal hypothalamus in the CUS group than in the control group. CONCLUSIONS: Our data demonstrate that pre-gestational stress alters HPA axis activity in maternal rats and their foetuses, which is associated with functional changes in 5-HT activity (5-HT, 5-HIAA and ratio of 5-HIAA to 5-HT), as well as the levels of the 5-HT1A receptor and SERT in the hippocampus and hypothalamus of foetuses.

Healthy individuals vs patients with bipolar or unipolar depression in gray matter volume.

BACKGROUND: Previous studies using voxel-based morphometry (VBM) revealed changes in gray matter volume (GMV) of patients with depression, but the differences between patients with bipolar disorder (BD) and unipolar depression (UD) are less known. AIM: To analyze the whole-brain GMV data of patients with untreated UD and BD compared with healthy controls. METHODS: Fourteen patients with BD and 20 with UD were recruited from the Mental Health Center of Shantou University between August 2014 and July 2015, and 20 non-depressive controls were recruited. After routine three-plane positioning, axial T2WI scanning was performed. The connecting line between the anterior and posterior commissures was used as the scanning baseline. The scanning range extended from the cranial apex to the foramen magnum. Categorical data are presented as frequencies and were analyzed using the Fisher exact test. RESULTS: There were no significant intergroup differences in gender, age, or years of education. Disease course, age at the first episode, and Hamilton depression rating scale scores were similar between patients with UD and those with BD. Compared with the non-depressive controls, patients with BD showed smaller GMVs in the right inferior temporal gyrus, left middle temporal gyrus, right middle occipital gyrus, and right superior parietal gyrus and larger GMVs in the midbrain, left superior frontal gyrus, and right cerebellum. In contrast, UD patients showed smaller GMVs than the controls in the right fusiform gyrus, left inferior occipital gyrus, left paracentral lobule, right superior and inferior temporal gyri, and the right posterior lobe of the cerebellum, and larger GMVs than the controls in the left posterior central gyrus and left middle frontal gyrus. There was no difference in GMV between patients with BD and UD. CONCLUSION: Using VBM, the present study revealed that patients with UD and BD have different patterns of changes in GMV when compared with healthy controls.

Chronic unpredictable stress before pregnancy reduce the expression of brain-derived neurotrophic factor and N-methyl-D-aspartate receptor in hippocampus of offspring rats associated with impairment of memory.

To investigate the effect of stress before pregnancy on memory function and serum corticosterone (COR) levels, as well as the expression of brain-derived neurotrophic factor (BDNF), N-methyl-D-aspartate (NMDA) 2A (NR2A) and 2B (NR2B) receptors in the hippocampus of the offspring rats when they were 2 months postnatally. Adult female Sprague-Dawley (SD) rats were divided randomly into two groups: control group (n = 8) and chronic unpredictable stress (CUS) group (n = 12). All rats were tested in the open field test and sucrose intake test before and after CUS. The memory function of their offspring were tested in the Morris water maze. Serum COR levels were determined by using a standard radioimmunoassay kit. The expression of BDNF, NR2A and NR2B in the hippocampus of the offspring rats were studied by immunoreactivity quantitative analysis and real-time RT-PCR. (1) Following CUS, reduced open field test activity and decreased sucrose consumption were observed relative to controls. (2) The Morris water maze task demonstrated increased escape latency in the offspring rats of CUS group relative to controls (P < 0.01). No-platform probe testing showed reduced crossings for offspring of CUS relative to controls (P < 0.05). (3) CUS induced a significant increase in serum COR levels of the offspring rats (P < 0.01), but no difference was observed in the body or brain weight between the offspring of the two groups. (4) Immunoreactivity quantitative analysis shows that BDNF and NR2B in the offspring of CUS group was decreased in the CA3 and DG regions of the hippocampus compared to the control group offspring, but NR2A levels were not altered between the offspring of the two groups. (5) Real-time RT-PCR demonstrated that BDNF and NR2B mRNAs were significantly decreased in the offspring of the CUS group compared with the control group (P < 0.01). No significant difference in the levels of NR2A mRNA was detected between offspring of CUS and offspring of control groups. In our study, pregestational stress can increase serum corticosterone levels and reduce the expression of BDNF and NR2B in the hippocampus of offspring. These alterations are associated with impairment of memory in the adult offspring. These data suggest that, stress before pregnancy might have a profound influence on brain development of offspring, that may persist into and be manifested in adulthood.

Relationship of Serum Uric Acid to Hematoma Volume and Prognosis in Patients with Acute Supratentorial Intracerebral Hemorrhage.

BACKGROUND: Oxidative stress and inflammation play important roles in the neuronal injury caused by intracerebral hemorrhage (ICH). Uric acid (UA), an important natural antioxidant, might reduce the neuronal injury caused by ICH. Delineating the relationship between UA and ICH will enhance our understanding of antioxidative mechanisms in recovery from ICH. METHODS: We conducted a retrospective study of 325 patients with acute supratentorial ICH to investigate the relationship between serum UA levels and hematoma volumes and prognosis. A hematoma volume of ≥30 mL was defined as a large hematoma. An unfavorable outcome was defined as a modified Rankin scale score of 4-6 on day 30. RESULTS: The serum UA level was significantly lower in the patients with a large hematoma volume (median, 306 µmol/L; 25th to 75th percentile, 243-411 µmol/L) than in those with a small hematoma volume (median, 357 µmol/L; 25th to 75th percentile, 271-442 µmol/L; P = 0.012). Similarly, the unfavorable outcome group had had lower serum UA levels (median, 309 vs. 363 µmol/L; P = 0.009) compared with the favorable outcome group. The results of the multivariate logistic analysis indicated that a lower serum UA level was associated with a larger hematoma volume (odds ratio, 0.996; P = 0.006) and an unfavorable outcome (odds ratio, 0.997; P = 0.030). CONCLUSIONS: The results from the present study have indicated that in patients with acute supratentorial ICH, a low serum UA level might indicate that the patient has a large hematoma volume and might be a risk factor for a poor day 30 functional prognosis.

Are they necessary? Preventive therapies for post-stroke depression: A meta-analysis of RCTs.

To explore the necessity and feasibility of early anti-depressive therapies in acute stroke patients, we conducted a meta-analysis of currently available randomized control studies (RCTs). Literature search in six databases was done with keywords of cerebrovascular accident, depression and prevention. Only RCTs that met the inclusion criteria were enrolled for further analysis. Twelve eligible studies were included in this meta-analysis. Prophylactic anti-depressive therapies following acute stroke were shown to reduce the incidence of depression in the patients (RR = =0.33, 95% CI: 0.25 to 0.43, p < 0.001), improve symptoms of depression (WMD: 5.73, 95% CI: 4.18 to 7.29, p < 0.001), improve motor function (WMD: 12.56, 95%CI: 9.07 to 16.04, p < 0.001) and neurological function (WMD: 1.13, 95%CI: 0.57 to 1.69, p < 0.001). However, anti-depressive therapies showed no effects on mortality (RR = 1.63, 95%CI: 0.55 to 4.85, p = 0.377) and adverse events incidence (RR = 0.93, 95%CI: 0.53 to 1.64, p = 0.806). Anti-depressive therapies following acute stroke is effective thus deserves to be advocated.

Development and validation of a nomogram for predicting late-onset sepsis in preterm infants on the basis of thyroid function and other risk factors: Mixed retrospective and prospective cohort study.

Preterm birth and infection are common causes of neonatal death. In this study, we aimed to develop a nomogram for assessing the individual prior probability of late-onset sepsis on the basis of risk factors in preterm infants. This study is a mixed retrospective and prospective cohort study conducted in three centers. Data from January 2014 to December 2017 was used for the development cohort, and data from January 2018 to December 2018 was used for the validation cohort. In the development cohort, we identified the predicting variables of late-onset sepsis in preterm infants, from which a nomogram was obtained. Then we built nomograms, for with and without thyroid function, to predict late-onset sepsis. The nomogram was validated in the validation cohort concerning discrimination and calibration. A total of 1256 and 452 preterm infants were included in the development and validation cohort, respectively. We found thyroid hypofunction in preterm infants could increase the incidence of late-onset infection. The prediction model incorporated thyroid function, birth weight, use of endotracheal intubation, and duration of umbilical venous catheters was validated and developed as a nomogram for predicting late-onset sepsis in preterm infants. Nomogram in this study may contribute to clinical assessment and treatment decisions.

PKA-mediated phosphorylation of CREB and NMDA receptor 2B in the hippocampus of offspring rats is involved in transmission of mental disorders across a generation.

This study is aimed at the mechanism of transmission of mental disorders across a generation. We used 10 different stressors to establish an animal model of chronic unpredictable stress (CUS) before pregnancy. Forced swimming test (FST) and open field test (OFT) were used to analyze the behavior of 30-day-old adolescent offspring rats born to stress mothers. Magnetic resonance spectroscopy was used to measure glutamate, gamma-aminobutyric acid (GABA), and glutamine. Phosphate-activated glutaminase (PAG), glutamate decarboxylase (GAD), GABA-transaminase (GABA-T), protein kinase A (PKA), cAMP response element-binding protein (CREB), and N-methyl-D-aspartate (NMDA) receptor 2B (NR2B) were detected by western blot. Adolescent offspring rats in the CUS group exhibited depressive-like behavior in the FST and anxious behavior in the OFT. GAD was increased and GABA-T was decreased, which resulted in an increase in GABA levels and decrease of the glutamate/GABA ratio in the hippocampus of CUS offspring rats. Disruption of the glutamate/GABA-glutamine cycle was related to decrease PKA-mediated phosphorylation of CREB and NR2B in the hippocampus. These findings highlight the importance of mental health of females before pregnancy and suggest that CUS before pregnancy reduces p-CREB and p-NR2B in the offspring hippocampus, which could be responsible for behavioral disorders in the adolescent offspring.

Exposure of mother rats to chronic unpredictable stress before pregnancy alters the metabolism of gamma-aminobutyric acid and glutamate in the right hippocampus of offspring in early adolescence in a sexually dimorphic manner.

There is increasing evidence that mothers' exposure to stress before or during pregnancy is linked to an incidence of psychiatric disorders in offspring. However, a few studies have estimated the role of sex in the detrimental effects of pre-gestational stress on the offspring rats at early adolescence. Sex differences regarding the metabolism of gamma-aminobutyric acid and glutamate in the right hippocampus were investigated by MRS when the offspring rats reached 30 days. Additionally, the impact of pre-gestational stress exposed on an additional short-term acute stressor, such as forced swim, was examined in the male and female offspring rats. Our findings showed female offspring rats were more vulnerable to stressful conditions for either pre-gestational stress or acute stress in early adolescence, and had decreased GABA/Cr+PCr and Glu/Cr+PCr in the right hippocampus. Interestingly, in response to forced swim, male offspring rats whose mothers were exposed to pre-gestational stress were more affected by the short-term acute stressor and this was manifested by change of Glu/GABA and Glu/Gln in the right hippocampus. These data indicated that although female offspring rats were more vulnerable to pre-gestational stress from their mothers than males, in response to an additional acute stressor they showed better response. Therefore, both sexually dimorphic manner and combination of stressful procedures should be carefully considered in the study of stress-related psychiatric disorders in early adolescence.

Impact of perinatal systemic hypoxic-ischemic injury on the brain of male offspring rats: an improved model of neonatal hypoxic-ischemic encephalopathy in early preterm newborns.

In this study, we attempted to design a model using Sprague-Dawley rats to better reproduce perinatal systemic hypoxic-ischemic encephalopathy (HIE) in early preterm newborns. On day 21 of gestation, the uterus of pregnant rats were exposed and the blood supply to the fetuses of neonatal HIE groups were thoroughly abscised by hemostatic clamp for 5, 10 or 15 min. Thereafter, fetuses were moved from the uterus and manually stimulated to initiate breathing in an incubator at 37 °C for 1 hr in air. We showed that survival rates of offspring rats were decreased with longer hypoxic time. TUNEL staining showed that apoptotic cells were significant increased in the brains of offspring rats from the 10 min and 15 min HIE groups as compared to the offspring rats in the control group at postnatal day (PND) 1, but there was no statistical difference between the offspring rats in the 5 min HIE and control groups. The perinatal hypoxic treatment resulted in decreased neurons and increased cleaved caspase-3 protein levels in the offspring rats from all HIE groups at PND 1. Platform crossing times and the percentage of the time spent in the target quadrant of Morris Water Maze test were significantly reduced in the offspring rats of all HIE groups at PND 30, which were associated with decreased brain-derived neurotrophic factor levels and neuronal cells in the hippocampus of offspring rats at PND 35. These data demonstrated that perinatal ischemic injury led to the death of neuronal cells and long-lasting impairment of memory. This model reproduced hypoxic ischemic encephalopathy in early preterm newborns and may be appropriate for investigating therapeutic interventions.