Sleep deprivation alters pubertal timing in humans and rats: the role of the gut microbiome.

STUDY OBJECTIVES: Evidence implied that sleeping duration is associated with the timing of puberty and that sleep deprivation triggers early pubertal onset in adolescents. Sleep deprivation can affect metabolic changes and gut microbiota composition. This study investigated the effects of sleep deprivation on pubertal onset and gut microbiota composition in animal models and a human cohort. METHODS: This study comprised 459 boys and 959 girls from the Taiwan Pubertal Longitudinal Study. Sleep duration was evaluated using the self-report Pittsburgh Sleep Quality Index questionnaire. Early sexual maturation was defined by pediatric endocrinologist assessments. Mediation analyses were done to examine the association between sleep parameters, obesity, and early sexual maturation. Besides, Sprague Dawley juvenile rats were exposed to 4 weeks of chronic sleep deprivation. Vaginal opening (VO) and preputial separation (PS) were observed every morning to determine pubertal onset in female and male rats. RESULTS: The sleep-deprived juvenile rats in the sleep-deprived-female (SDF) and sleep-deprived-male (SDM) groups experienced delayed VO (mean VO days: 33 days in control; 35 days in SDF; p-value < 0.05) and PS (mean PS days: 42 days in control; 45 days in SDM; p-value < 0.05), respectively. Relative to their non-sleep-deprived counterparts, the sleep-deprived juvenile rats exhibited lower body weight and body fat percentage. Significant differences in relative bacterial abundance at genus levels and decreased fecal short-chain-fatty-acid levels were identified in both the SDF and SDM groups. In the human cohort, insufficient sleep increased the risk of early sexual maturation, particularly in girls (OR, 1.44; 95% CI: 1.09 to 1.89; p-value < 0.01). Insufficient sleep also indirectly affected early sexual maturation in girls, with obesity serving as the mediator. CONCLUSIONS: Overall, sleep deprivation altered the timing of puberty in both animal and human models but in different directions. In the rat model, sleep deprivation delayed the pubertal onset in juvenile rats through gut dysbiosis and metabolic changes, leading to a low body weight and body fat percentage. In the human model, sleep deprivation led to fat accumulation, causing obesity in girls, which increased the risk of early puberty.

Associations of central precocious puberty with blood pressure trajectories: prospective cohort study.

BACKGROUND: Sex differences in blood pressure (BP) appear during childhood and adolescence, but the role of central precocious puberty (CPP) remains unclear. In this study, we aimed to examine the association of CPP with the risk of early hypertension and BP trajectories in girls and boys. METHODS: We analyzed trajectories of BP before and after puberty in girls aged 6-13 years (n = 305) and boys aged 10-15 years (n = 153) in the Taiwan Pubertal Longitudinal Study. The timing of puberty onset was defined as the month at which the children reached Tanner stage 2. We examined the association of CPP with the risk of early hypertension and BP trajectories before and after puberty onset. RESULTS: Among boys, CPP was found to be associated with early hypertension (odds ratio, 7.45 [95% CI, 1.15-48.06]), whereas no such association was observed among girls. Boys with CPP had higher systolic BP than did those with normal puberty onset before puberty onset (mean difference, 6.51 [95% CI, 0.58-12.43]) and after puberty onset (mean difference, 8.92 [95% CI, 8.58-15.26]). CONCLUSION: A large proportion of the higher systolic BP observed in boys with CPP compared with in those with normal puberty onset is accrued after puberty. IMPACT: We examined the sex-specific association of central precocious puberty with blood pressure trajectories to better understand whether central precocious puberty was associated with early hypertension. Central precocious puberty was associated with differences in systolic blood pressure trajectories, especially after puberty onset in boys. For boys only, central precocious puberty was associated with early hypertension. A large proportion of the higher systolic blood pressure observed in boys with central precocious puberty compared with in those with normal puberty onset was accrued after puberty. Interventions targeting central precocious puberty are likely to influence systolic blood pressure in early adulthood.

Effects of Nonnutritive Sweeteners on Body Composition Changes during Pubertal Growth.

The effects of consuming specific types of nonnutritive sweeteners (NNSs) on adiposity changes in children have remained inconsistent. In this study, we aimed to investigate the effects of the intake of different kinds of NNSs on long-term adiposity changes during pubertal growth. Furthermore, we examined the above relationships among different sexes, pubertal stages, and levels of obesity. A total of 1893 6-15-year-old adults were recruited and followed-up every 3 months. The NNS-FFQ (Food Frequency Questionnaire) was conducted and urine samples were collected to investigate the effects of the selected sweeteners, which included acesulfame potassium, aspartame, sucralose, glycyrrhizin, steviol glycosides, and sorbitol. Multivariate linear mixed-effects models were used to examine the relationship between NNS intake and body composition. The consumption of aspartame, sucralose, glycyrrhizin, stevioside, and sorbitol was associated with decreased fat mass and increased fat-free mass. In the highest tertile group, the effects of NNS consumption on fat mass corresponded to values of -1.21 (95% CI: -2.04 to -0.38) for aspartame, -0.62 (95% CI: -1.42 to 0.19) for sucralose, -1.26 (95% CI: -2.05 to -0.47) for glycyrrhizin, -0.90 (95% CI: -2.28 to 0.48) for stevioside, and -0.87 (95% CI: -1.67 to -0.08) for sorbitol, while the effects on fat-free mass corresponded to values of 1.20 (95% CI: 0.36 to -0.38) for aspartame, 0.62 (95% CI: -0.19 to 1.43) for sucralose, 1.27 (95% CI: 0.48 to 2.06) for glycyrrhizin, 0.85 (95% CI: -0.53 to 2.23) for stevioside, and 0.87 (95% CI: 0.08 to 1.67) for sorbitol. Particularly, aspartame and sorbitol revealed a dose-responsiveness effect. The above finding was more prominent among girls than boys. Moreover, fat mass was significantly reduced in normal-weight children who consumed a moderate amount of aspartame and a large amount of glycyrrhizin and sorbitol compared with obese children. In conclusion, the NNS-specific and sex-specific effects of long-term NNS consumption revealed associations of decreasing fat mass and increasing fat-free mass for children undergoing pubertal growth.

Hypertension as a Novel Link for Shared Heritability in Age at Menarche and Cardiometabolic Traits.

CONTEXT: Extremely early age at menarche, also called precocious puberty, has been associated with various cardiometabolic traits, but their shared heritability remains unclear. OBJECTIVES: This work aimed to identify new shared genetic variants and their pathways for age at menarche and cardiometabolic traits and to investigate the influence of central precocious puberty on childhood cardiometabolic traits. METHODS: Using the conjunction false discovery rate method, this study analyzed genome-wide association study data from the menarche-cardiometabolic traits among 59 655 females of Taiwanese ancestry and systemically investigated pleiotropy between age at menarche and cardiometabolic traits. To support the novel hypertension link, we used the Taiwan Puberty Longitudinal Study (TPLS) to investigate the influence of precocious puberty on childhood cardiometabolic traits. RESULTS: We discovered 27 novel loci, with an overlap between age at menarche and cardiometabolic traits, including body fat and blood pressure. Among the novel genes discovered, SEC16B, CSK, CYP1A1, FTO, and USB1 are within a protein interaction network with known cardiometabolic genes, including traits for obesity and hypertension. These loci were confirmed through demonstration of significant changes in the methylation or expression levels of neighboring genes. Moreover, the TPLS provided evidence regarding a 2-fold higher risk of early-onset hypertension that occurred in girls with central precocious puberty. CONCLUSION: Our study highlights the usefulness of cross-trait analyses for identifying shared etiology between age at menarche and cardiometabolic traits, especially early-onset hypertension. The menarche-related loci may contribute to early-onset hypertension through endocrinological pathways.

Sinularin Induces Oxidative Stress-Mediated Apoptosis and Mitochondrial Dysfunction, and Inhibits Angiogenesis in Glioblastoma Cells.

Glioblastoma multiforme (GBM) is a cancer of largely unknown cause that leads to a 5-year survival rate of approximately 7% in the United States. Current treatment strategies are not effective, indicating a strong need for the development of novel therapies. In this study, the outcomes of sinularin, a marine-derived product, were evaluated against GBM. Our cellular studies using GBM cells revealed that sinularin induces cell death. The measured half maximal inhibitory concentrations (IC50) values ranged from 30 to 6 µM at 24-72 h. Cell death was induced via the generation of ROS leading to mitochondria-mediated apoptosis. This was evidenced by annexin V/propidium iodine staining and an upregulation of cleaved forms of the pro-apoptotic proteins caspase 9, 3, and PARP, and supported by CellROXTM Green, MitoSOXTM Red, and CM-H2DCFDA staining methods. In addition, we observed a downregulation of the antioxidant enzymes SOD1/2 and thioredoxin. Upon treatment with sinularin at the ~IC50 concentration, mitochondrial respiration capacities were significantly reduced, as shown by measuring the oxygen consumption rates and enzymatic complexes of oxidative phosphorylation. Intriguingly, sinularin significantly inhibited indicators of angiogenesis such as vessel tube formation, cell migration, and cell mobility in human umbilical vein endothelial cells or the fusion cell line EA.Hy926. Lastly, in a transgenic zebrafish model, intersegmental vessel formation was also significantly inhibited by sinularin treatment. These findings indicate that sinularin exerts anti-brain cancer properties that include apoptosis induction but also antiangiogenesis.

Early strategy of scepter XC balloon angioplasty and simultaneous Nimodipine infusion for vasospasm following ruptured aneurysm.

BACKGROUND: Cerebral vasospasm still results in high morbidity and mortality rates in patients after aneurysmal subarachnoid hemorrhage (SAH). The aim of this study was to establish a protocol for the management of vasospasm and demonstrate our experience of angioplasty using the Scepter XC balloon catheter. METHODS: In this retrospective study, a computed tomography angiography and perfusion image was arranged if early symptoms occurred or on the 7th day following aneurysmal SAH. In patients with clear consciousness, balloon angioplasties were performed for symptomatic vasospasms, which were not improved within 6-12 h after maximal medical treatments. In unconscious patients, balloon angioplasties were performed for all patients with angiographic vasospasms. RESULTS: Fifty patients underwent Scepter XC balloon angioplasty among 396 consecutive patients who accepted endovascular or surgical treatments for ruptured aneurysms. All angioplasty procedures were successful without complications. 100% angiographic improvement and 94% clinical improvement were reached immediately after the angioplasties. A favorable functional outcome (modified Rankin Score of ≤2) could be achieved in 82% of patients. Even in patients with poor clinical grading (Hunt-Hess grade 4-5), a clinical improvement rate of 87.5% and favorable outcome rate was 70.8% could be achieved. CONCLUSION: Balloon angioplasty with Scepter XC balloon catheter is safe and effective for post-SAH vasospasm. This device's extra-compliant characteristics could considerably improve the quality of angioplasty procedures. For all patients, even those with poor neurological status, early treatment with combined protocol of nimodipine and angioplasty can have good clinical outcomes.

Factors Associated With Prolonged Mechanical Ventilation and Reventilation in Acute Cervical Spinal Cord Injury Patients.

MINI: In this study, respiratory function at the time of extubation can be useful optimal clinical guidelines for weaning and extubation attempts in patients with acute cervical spinal cord injury. Serum thiobarbituric acid-reactive substances level at admission can be a useful predictor for severity in acute cervical patients with spinal cord injury. STUDY DESIGN: Patients who had suffered from acute blunt cervical spinal cord injury (SCI) and admitted our hospital within 24 hours after injury were included in the study. OBJECTIVE: We compared the respiratory function and serum reactive oxidative stress (ROS) after acute cervical SCI, and tried to find out the valuable predictors of weaning in patients with acute cervical SCI. SUMMARY OF BACKGROUND DATA: Ventilation impairment is a major complication of acute cervical SCI. Evidence of oxygen radical formation in secondary injury from animal SCI models demonstrates an immediate postinjury increase in ROS production after SCI. We hypothesize that the serum ROS is associated with the severity of patients with acute cervical SCI. METHODS: Thirty-eight adult patients who had acute cervical SCI and 58 healthy volunteers were enrolled. Respiratory function at admission, at the time of extubation and at 48 hours after extubation, serum oxidative stress, Injury Severity Score and Japanese Orthopaedic Association score at admission were compared. RESULTS: The most notable predictor of mechanical ventilation more than 48 hours was serum thiobarbituric acid-reactive substances (TBARS) level at admission (P = 0.027), and the cut-off value of serum TBARS level was 731.7 µmol/L (sensitivity 87.5% and specificity 78.9%). For the reventilation ≤5 days, the notable predictors were respiratory function at the time of extubation (maximal inspiratory pressure, P = 0.040; maximal expiratory pressure, P = 0.020; and tidal volume, P = 0.036) and serum TBARS level at admission (P = 0.013), the cut-off value of serum TBARS level at admission was 762.3 µmol/L (sensitivity 100% and specificity 90.0%). CONCLUSION: In this study, respiratory function (maximal inspiratory pressure, maximal expiratory pressure, and tidal volume) at the time of extubation can be useful optimal clinical guidelines for weaning and extubation attempts in patients with acute cervical SCI. Serum TBARS level at admission can be a useful predictor for severity in acute cervical SCI patients. LEVEL OF EVIDENCE: 3.

Patients who had suffered from acute blunt cervical spinal cord injury (SCI) and admitted our hospital within 24 hours after injury were included in the study. We compared the respiratory function and serum reactive oxidative stress (ROS) after acute cervical SCI, and tried to find out the valuable predictors of weaning in patients with acute cervical SCI. Ventilation impairment is a major complication of acute cervical SCI. Evidence of oxygen radical formation in secondary injury from animal SCI models demonstrates an immediate postinjury increase in ROS production after SCI. We hypothesize that the serum ROS is associated with the severity of patients with acute cervical SCI. Thirty-eight adult patients who had acute cervical SCI and 58 healthy volunteers were enrolled. Respiratory function at admission, at the time of extubation and at 48 hours after extubation, serum oxidative stress, Injury Severity Score and Japanese Orthopaedic Association score at admission were compared. The most notable predictor of mechanical ventilation more than 48 hours was serum thiobarbituric acid-reactive substances (TBARS) level at admission (P = 0.027), and the cut-off value of serum TBARS level was 731.7 µmol/L (sensitivity 87.5% and specificity 78.9%). For the reventilation ≤5 days, the notable predictors were respiratory function at the time of extubation (maximal inspiratory pressure, P = 0.040; maximal expiratory pressure, P = 0.020; and tidal volume, P = 0.036) and serum TBARS level at admission (P = 0.013), the cut-off value of serum TBARS level at admission was 762.3 µmol/L (sensitivity 100% and specificity 90.0%). In this study, respiratory function (maximal inspiratory pressure, maximal expiratory pressure, and tidal volume) at the time of extubation can be useful optimal clinical guidelines for weaning and extubation attempts in patients with acute cervical SCI. Serum TBARS level at admission can be a useful predictor for severity in acute cervical SCI patients. Level of Evidence: 3.

Serial plasma DNA levels as predictors of outcome in patients with acute traumatic cervical spinal cord injury.

BACKGROUND: Acute traumatic cervical spinal cord injury (SCI) is a leading cause of disability in adolescents and young adults worldwide. Evidence from previous studies suggests that circulating cell-free DNA is associated with severity following acute injury. The present study determined whether plasma DNA levels in acute cervical SCI are predictive of outcome. METHODS: In present study, serial plasma nuclear DNA (nDNA) and mitochondrial DNA (mtDNA) levels were obtained from 44 patients with acute traumatic cervical SCI at five time points from day 1 to day 180 post-injury. Control blood samples were obtained from 66 volunteers. RESULTS: Data showed a significant increase in plasma nDNA and mtDNA concentrations at admission in SCI patients compared to the control group. Plasma nDNA levels at admission, but not plasma mtDNA levels, were significantly associated with the Japanese Orthopaedic Association (JOA) score and Injury Severity Score in patients with acute traumatic cervical SCI. In patients with non-excellent outcomes, plasma nDNA increased significantly at days 1, 14 and 30 post-injury. Furthermore, its level at day 14 was independently associated with outcome. Higher plasma nDNA levels at the chosen cutoff point (> 45.6 ng/ml) predicted poorer outcome with a sensitivity of 78.9% and a specificity of 78.4%. CONCLUSIONS: These results indicate JOA score performance and plasma nDNA levels reflect the severity of spinal cord injury. Therefore, the plasma nDNA assays can be considered as potential neuropathological markers in patients with acute traumatic cervical SCI.

Predictive factors of neurologic deterioration in patients with spontaneous cerebellar hemorrhage: a retrospective analysis.

BACKGROUND: Cerebellar hemorrhage is a potentially life-threatening condition and neurologic deterioration during hospitalization could lead to severe disability and poor outcome. Finds out the factors influencing neurologic deterioration during hospitalization is essential for clinical decision-making. METHODS: One hundred fifty-five consecutive patients who suffered a first spontaneous cerebellar hemorrhage (SCH) were evaluated in this 10-year retrospective study. This study aimed to identify potential clinical, radiological and clinical scales risk factors for neurologic deterioration during hospitalization and outcome at discharge. RESULTS: Neurologic deterioration during hospitalization developed in 17.4% (27/155) of the patient cohort. Obliteration of basal cistern (p≦0.001) and hydrocephalus (p≦0.001) on initial brain computed tomography (CT), median Glasgow Coma Scale (GCS) score at presentation (p≦0.001) and median intracerebral hemorrhage (ICH) score (P≦0.001) on admission were significant factors associated with neurologic deterioration. Stepwise logistic regression analysis showed that patients with obliteration of basal cistern on initial brain CT scan had an odds ratio (OR) of 9.17 (p = 0.002; 95% confidence interval (CI): 0.026 to 0.455) adjusted risk of neurologic deterioration compared with those without obliteration of basal cistern. An increase of 1 point in the ICH score on admission would increase the neurologic deterioration rate by 83.2% (p = 0.010; 95% CI: 1.153 to 2.912). The ROC curves showed that the AUC for ICH score on presentation was 0.719 (p = 0.000; 95% CI: 0.613-0.826) and the cutoff value was 2.5 (sensitivity 80.5% and specificity 73.7%). CONCLUSION: Patients had obliteration of basal cistern on initial brain CT and ICH score greater or equal to 3 at admission implies a greater danger of neurologic deterioration during hospitalization. Cautious clinical assessments and repeated brain images study are mandatory for those high-risk patients to prevent neurologic deterioration during hospitalization.

Risk Factors for Ventriculoperitoneal Shunt Dependency in Patients with Spontaneous Cerebellar Hemorrhage.

BACKGROUND: Hydrocephalus is a common complication after spontaneous cerebellar hemorrhage (CH). This study focused on predicting ventriculoperitorneal (VP) shunt dependency in patients with spontaneous CH. METHODS: Ninety-nine patients with spontaneous CH were evaluated in this retrospective study. A comparison between patients with and those without VP shunt dependency during hospitalization was made. RESULTS: VP shunt-dependent hydrocephalus developed in 19.2% of the patients (19 of 99). Comparison of neuroimaging findings on admission between the 2 patient groups identified large hematoma dimension (P < 0.001), large hematoma volume (P = 0.001), fourth ventricular degradation (P < 0.001), development of hydrocephalus (P < 0.001), and obliteration of the basal cisterns (P < 0.001) as significant risk factors for VP shunt-dependent hydrocephalus. Stepwise logistic regression analysis identified hydrocephalus on admission and maximum hematoma diameter on admission as independent risk factors for VP shunt dependency (P = 0.006 and 0.020, respectively). The adjusted risk of VP shunt dependency for patients with hydrocephalus on admission had an odds ratio of 37.04. Furthermore, an increase of 1 mm in the blood clot diameter on admission would increase the VP shunt dependency rate by 11.9%. The cutoff value of blood clot diameter on presentation was 36.15 mm (sensitivity, 84.2%; specificity, 85.0%). CONCLUSIONS: A patient with hydrocephalus on admission and a hematoma of larger size and dimension at the time of initial imaging is at elevated risk for VP shunt dependency. Repeat neuroimaging studies and careful clinical assessment are mandatory for high-risk patients to determine the presence of post-CH hydrocephalus.

Application of Surgical Apgar Score in intracranial meningioma surgery.

Surgical resection is the main therapeutic option for intracranial meningiomas, but it is not without significant morbidities. The Surgical Apgar Score (SAS), assessed by intraoperative blood pressure, heart rate, and blood loss, was developed for prognostic prediction in general and vascular surgery. We aimed to examine whether the application of SAS in patients undergoing craniotomy for meningioma resection can predict postoperative major complications. We retrospectively enrolled 99 patients that had undergone intracranial meningioma surgery. The patients were subdivided into 2 groups based on whether major complications were present (N = 34) or not (N = 65). We recognized the intergroup differences in SAS and clinical variables. The incidence of 30-day major complications in patients after operation was 34.3%. The lengths of ICU and hospital stay for the morbid cases were prolonged significantly (p = 0.009, p < 0.001, respectively). In the multivariate logistic regression model, SAS was an independent predicting factor of major complications following surgery for intracranial meningiomas (odds ratio, 95% confidence interval = 0.57, 0.38-0.87; p = 0.009), and thus a decrease of one mean SAS increased the rate of major complications by 43%. In conclusions, SAS is an independent predictor of major complications in patients undergoing intracranial meningioma surgery, and provides acceptable risk discrimination. Since this scoring system is relatively simple, objective, and practical, we suggest that SAS be included as an indicator in the guidance for the level of care after craniotomy for meningioma resection.

Surgical apgar score in patients undergoing lumbar fusion for degenerative spine diseases.

OBJECTIVE: Lumbar fusion is a procedure broadly performed for degenerative diseases of spines, but it is not without significant morbidities. Surgical Apgar Score (SAS), based on intraoperative blood loss, blood pressure, and heart rate, was developed for prognostic prediction in general and vascular operations. We aimed to examine whether the application of SAS in patients undergoing fusion procedures for degeneration of lumbar spines predicts in-hospital major complications. METHODS: One hundred and ninety-nine patients that underwent lumbar fusion operation for spine degeneration were enrolled in this retrospective study. Based on whether major complications were present (N=16) or not (N=183), the patients were subdivided. We identified the intergroup differences in SAS and clinical parameters. RESULTS: The incidence of in-hospital major complications was 8%. The duration of hospital stay for the morbid patents was significantly prolonged (p=0.04). In the analysis of multivariable logistic regression, SAS was an independent predicting factor of the complications after lumbar fusion for degenerative spine diseases [p=0.001; odds ratio (95% confidence interval)=0.35 (0.19-0.64)]. Lower scores were accompanied with higher rates of major complications, and the area was 0.872 under the receiver operating characteristic curve. CONCLUSION: SAS is an independent predicting factor of major complications in patients after fusion surgery for degenerative diseases of lumbar spines, and provides good risk discrimination. Since the scoring system is relatively simple, objective, and practical, we suggest that SAS be included as an indicator in the guidance for level of care after lumbar fusion surgery.