Amino acids downregulate SIRT4 to detoxify ammonia through the urea cycle.

Ammonia production via glutamate dehydrogenase is inhibited by SIRT4, a sirtuin that displays both amidase and non-amidase activities. The processes underlying the regulation of ammonia removal by amino acids remain unclear. Here, we report that SIRT4 acts as a decarbamylase that responds to amino acid sufficiency and regulates ammonia removal. Amino acids promote lysine 307 carbamylation (OTCCP-K307) of ornithine transcarbamylase (OTC), which activates OTC and the urea cycle. Proteomic and interactome screening identified OTC as a substrate of SIRT4. SIRT4 decarbamylates OTCCP-K307 and inactivates OTC in an NAD+-dependent manner. SIRT4 expression was transcriptionally upregulated by the amino acid insufficiency-activated GCN2-eIF2α-ATF4 axis. SIRT4 knockout in cultured cells caused higher OTCCP-K307 levels, activated OTC, elevated urea cycle intermediates and urea production via amino acid catabolism. Sirt4 ablation decreased male mouse blood ammonia levels and ameliorated CCl4-induced hepatic encephalopathy phenotypes. We reveal that SIRT4 safeguards cellular ammonia toxicity during amino acid catabolism.

Gestational weight gain outside the 2009 Institute of Medicine recommendations: novel psychological and behavioural factors associated with inadequate or excess weight gain in a prospective cohort study.

BACKGROUND: Previous studies have noted traditional physical, demographic, and obstetrical predictors of inadequate or excess gestational weight gain, but the roles of psychological and behavioral factors are not well established. Few interventions targeting traditional factors of gestational weight gain have been successful, necessitating exploration of new domains. The objective of this study was to identify novel psychological and behavioral factors, along with physical, demographic, and obstetrical factors, associated with gestational weight gain that is discordant with the 2009 Institute of Medicine guidelines (inadequate or excess gain). METHODS: We recruited English-speaking women with a live singleton fetus at 8 to 20 weeks of gestation who received antenatal care from 12 obstetrical, family medicine, and midwifery clinics. A questionnaire was used to collect information related to demographic, physical, obstetrical, psychological, and behavioural factors anticipated to be related to weight gain. The association between these factors and total gestational weight gain, classified as inadequate, appropriate, and excess, was examined using stepwise multinomial logistic regression. RESULTS: Our study population comprised 970 women whose baseline data were obtained at a mean of 14.8 weeks of gestation ±3.4 weeks (standard deviation). Inadequate gestational weight gain was associated with obesity, planned gestational weight gain (below the guidelines or not reported), anxiety, and eating sensibly when with others but overeating when alone, while protective factors were frequent pregnancy-related food cravings and preferring an overweight or obese body size image. Excess gestational weight gain was associated with pre-pregnancy overweight or obese body mass index, planned gestational weight gain (above guidelines), frequent eating in front of a screen, and eating sensibly when with others but overeating when alone, while a protective factor was being underweight pre-pregnancy. CONCLUSIONS: In addition to commonly studied predictors, this study identified psychological and behavioral factors associated with inadequate or excess gestational weight gain. Factors common to both inadequate and excessive gestational weight gain were also identified, emphasizing the multidimensional nature of the contributors to guideline-discordant weight gain.

Psychological or educational eHealth interventions on depression, anxiety or stress following preterm birth: a systematic review.

Objective: To determine the efficacy and characteristics of psychological or educational eHealth interventions on reducing symptoms of mental illness in parents of preterm or low birthweight infants. Background: Many parents suffer psychological disorders after preterm birth. Computer or mobile application-based interventions are a promising alternative. Methods: We searched seven electronic databases up to January 2020 and included randomised and quasi-randomised controlled trials assessing psychological or educational eHealth interventions in parents of infants born very preterm <32 weeks or with very low birthweight <1500g (primary question), or preterm <37 weeks or with low birthweight <2500g (secondary question). Primary outcomes were measures of depression, anxiety, acute stress disorder or post-traumatic stress disorder. Secondary outcomes included other indicators of mental health, quality of life and intervention characteristics. We had planned random-effects meta-analysis in our protocol (CRD42018105731). Results: Of 9768 records, no study reported our primary outcomes. Three studies showed potential benefits for parental self-efficacy, discharge preparedness, parental satisfaction and family satisfaction with the neonatal intensive care unit. Conclusions: We found scarce evidence on the efficacy of psychological or educational eHealth interventions on reducing mental illness in parents of preterm or low birthweight infants, highlighting the need for more research.

Education interventions in Chinese cardiac patients on health behaviours, disease-related knowledge, and health outcomes: A systematic review and meta-analysis.

OBJECTIVE: This systematic review and meta-analysis aimed to summarize and synthesize the available evidence in adult Chinese cardiac patients to determine the effect of education interventions on health behaviours, disease-related knowledge, self-efficacy, depressive symptoms, anxiety symptoms, health-related quality of life, morbidity, and mortality. METHODS: Seven databases were searched from database inception until January 2020 for randomized controlled trials. Characteristics of education interventions were described and random-effects meta-analysis was performed where feasible. RESULTS: Overall, 18 randomized controlled trials were included in this systematic review and suggested that education interventions are effective in improving patients' physical activity, dietary habits, medication behaviour, disease-related knowledge, and health-related quality of life. Meta-analysis of two studies demonstrated benefit on physical activity (standardized mean difference [SMD] 1.27, 95% confidence interval [CI] 1.06-1.48; participants = 422; I2 = 0%), dietary habits (SMD 0.76, 95%CI 0.44-1.08; participants = 422; I2 = 61%), and medication behaviour (mean difference [MD] 0.31, 95%CI 0.17-0.46; participants = 422; I2 = 28%). CONCLUSION: This study supports the benefits of education interventions for adult Chinese cardiac patients on health behaviours, disease-related knowledge, and health-related quality of life. Future studies should characterize their education interventions in detail to facilitate reproducibility and comparison. PRACTICE IMPLICATIONS: This study identified the need for studies on the outcome of alcohol consumption and in Chinese immigrant populations.

Vaginal birth vs caesarean section for extremely preterm vertex infants: a systematic review and meta-analyses.

PURPOSE: To synthesize evidence of mode of birth in extremely preterm vertex infants. METHODS: We searched MEDLINE, EMBASE, CINAHL, Cochrane CENTRAL, Web of Science, and ClinicalTrials.gov (January 1995-July 2019). We included studies comparing outcomes by vaginal birth or caesarean section in vertex infants born < 28 weeks or with birthweight < 1500 g. Two reviewers independently performed all steps. Primary outcomes were death and/or severe brain injury. We synthesised the data using random-effects meta-analyses (PROSPERO CRD42017074145). RESULTS: We included 14 studies with 129,475 infants. In vertex singletons < 28 weeks, caesarean section was associated with reduced adjusted odds of death (aOR 0.62, 95% confidence interval [CI] 0.39-0.99, 3 studies, 10,331 infants). For severe brain injury or a composite of death or severe brain injury, adjusted data were lacking. In infants with very low birth weight overall (< 1500 g) we found no significant benefit for our primary outcomes (e.g., death, aOR 0.77, 0.55-1.07, 2 studies, 105,439 infants), although there were some benefits associated with caesarean section in smaller weight subgroups (e.g., death aOR 500-700 g: 0.53, 0.49-0.57 [1 study, 5989 infants] and 1000-1250 g: 0.78, 0.65-0.93 [1 study, 14,906 infants]), but not larger weights (1250-1500 g: 1.38, 1.15-1.65 [1 study, 17,715 infants]). CONCLUSION: Caesarean section was associated with a significant decrease in the adjusted odds of death in extremely preterm vertex infants < 28 weeks. Smaller birth weight subgroups supported these results. The absence of randomized trials warrants judicious interpretation of these results, which are the currently available highest level of evidence. This study will inform further research.

Alteration of microRNA-4474/4717 expression and CREB-binding protein in human colorectal cancer tissues infected with Fusobacterium nucleatum.

Colorectal cancer (CRC) is a common and highly lethal form of cancer. Although the etiologic role of Fusobacterium nucleatum (F. nucleatum) in the development of CRC has been elucidated, the specific tumor molecules involved in the progression of CRC induced by F. nucleatum have not been identified. This study investigated several miRNAs and genes involved in the progression of F. nucleatum-induced CRC by Affymetrix miRNA microarray technology and GeneChip Human Transcriptome Array 2.0. The results suggest that miR-4474 and miR-4717 are up-regulated in CRC tissues in response to F. nucleatum infection, compared with the control group (paracancerous tissues), while other genes associated with signaling pathways in cancer, including CREB-binding protein (CREBBP), STAT1, PRKACB, CAMK2B, JUN, TP53 and EWSR1, were dysregulated. Bioinformatic analysis identified CREBBP as the primary aberrantly expressed gene in F. nucleatum-induced CRC. Consistent with the microarray analysis results, real-time RT-PCR analysis demonstrated that the expression of miR-4474/4717 was upregulated while that of CREBBP mRNA was downregulated in CRC patients infected with F. nucleatum. Additionally, CREBBP was identified as a novel target of miR-4474/4717. The results of this study suggest that miR-4474 and miR-4717 are involved in the progression of F. nucleatum-induced CRC by posttranscriptionally regulating the target gene CREBBP.

What Interventions Are Being Used to Prevent Preterm Birth and When?

OBJECTIVE: This study sought to determine the proportions of women at risk of preterm birth who received progesterone, elective and rescue cerclage, or pessary to prevent preterm birth, by using medical records. The authors also sought to determine whether these proportions differed among primary-, secondary-, and tertiary-level centres. METHODS: The authors conducted a retrospective cohort study and extracted data from consecutive medical charts of women with an estimated date of confinement over 3 months in primary-, secondary-, and tertiary-level centres in Southern Ontario. The study identified women with a previous spontaneous preterm birth or a short cervix and determined whether they were offered and whether they received a preventive intervention for preterm birth. Descriptive statistics and Fisher exact tests were calculated. RESULTS: The authors reviewed 1024 consecutive charts at primary, secondary, and tertiary centres and identified 31 women with a previous spontaneous preterm birth or a short cervix. Of these women, less than one half (42%) received progesterone or cerclage for prevention of preterm birth, and none received pessary. One in four women (26%) were not referred to an obstetrician or maternal-fetal medicine specialist in time for an intervention, and among those referred before 24 weeks of gestation, an intervention was offered to 57% of the women. CONCLUSION: Less than half of women at risk of spontaneous preterm birth received progesterone, cerclage, or pessary, attesting to the importance of improving knowledge translation methods to encourage timely referral and use of progesterone for the prevention of preterm birth.

Glucose deprivation induces chemoresistance in colorectal cancer cells by increasing ATF4 expression.

AIM: To investigate the role of activating transcription factor 4 (ATF4) in glucose deprivation (GD) induced colorectal cancer (CRC) drug resistance and the mechanism involved. METHODS: Chemosensitivity and apoptosis were measured under the GD condition. Inhibition of ATF4 using short hairpin RNA in CRC cells under the GD condition and in ATF4-overexpressing CRC cells was performed to identify the role of ATF4 in the GD induced chemoresistance. Quantitative real-time RT-PCR and Western blot were used to detect the mRNA and protein expression of drug resistance gene 1 (MDR1), respectively. RESULTS: GD protected CRC cells from drug-induced apoptosis (oxaliplatin and 5-fluorouracil) and induced the expression of ATF4, a key gene of the unfolded protein response. Depletion of ATF4 in CRC cells under the GD condition can induce apoptosis and drug re-sensitization. Similarly, inhibition of ATF4 in the ATF4-overexpressing CRC cells reintroduced therapeutic sensitivity and apoptosis. In addition, increased MDR1 expression was observed in GD-treated CRC cells. CONCLUSION: These data indicate that GD promotes chemoresistance in CRC cells through up-regulating ATF4 expression.

Tiny cystine stones in the gallbladder of a patient with cholecystolithiasis complicating acute cholecystitis: a case report.

Cystine stones, the main component of which is cystine, are very common urinary calculi, but are rare in the gall bladder. In animals, there has been only one report of cystine gallstones in tree shrews, and to our knowledge, this is the first report of cystine gallstones in humans.