Chronobiological Patterns of Aneurysmal Subarachnoid Hemorrhage in Central China.

Background: Aneurysmal subarachnoid hemorrhage (aSAH) is an acute and sometimes fatal cerebrovascular disease. The chronobiological patterns of aSAH are still unclear worldwide. This 15-year time-series study aims to clarify the chronobiological patterns including seasonal, monthly, weekly, and circadian distributions of aSAH. Methods: We retrospectively analyzed the medical records of aSAH patients in central China. To investigate seasonal and weekly distributions, we used the χ2 goodness-of-fit test to analyze the uniformity of the onset time. To explore monthly and circadian distributions, we established Fourier models to show the rhythmicity in chronobiological patterns. Subgroup analyses were conducted to assess the impact of age, gender, hypertension statuses, and aneurysmal characteristics (number, size, and location) on the chronobiological patterns of aSAH. Results: A total of 1469 patients with aSAH were recruited in the study. The seasonal and monthly distribution exhibited significantly higher incidence in winter and January/December and lower incidence in summer and July. The weekly distribution of aSAH onset showed no significant uneven variation. The circadian distribution of aSAH exhibited a significant pattern (p = 0.0145), with a morning peak around 8:00, and a late afternoon peak at 16:00-20.00. The circadian rhythmicity varied in subgroups of different ages, genders, and aneurysmal locations. Conclusion: The occurrence of aSAH exhibits significant circannual and circadian patterns among the Chinese population. Patients with aSAH of different ages, genders, and aneurysmal locations would present different chronobiological patterns.

Outcomes of intramural hematoma involving the ascending aorta and extending into the descending thoracic aorta.

OBJECTIVE: The optimal treatment of intramural hematoma (IMH) involving the ascending aorta remains controversial. This study aimed to analyze the results of the management of patients with acute IMH involving the ascending aorta and extending into the descending thoracic aorta, to compare outcomes of descending thoracic endovascular aortic repair (TEVAR) with that of medical therapy (MT), and to assess the risk factors associated with adverse aortic events. METHODS: We retrospectively analyzed all patients diagnosed with acute IMH involving the ascending aorta and extending into the descending thoracic aorta from January 2012 to December 2019. The primary end points during follow-up were aortic disease-related death and adverse aorta-related events that required surgical or endovascular treatment, such as aortic rupture, the progression of aortic disease, or endoleak. RESULTS: We identified a total of 135 patients with acute IMH involving the ascending aorta and extending into the descending thoracic aorta, of whom 104 underwent descending TEVAR (group 1) and 31 were managed with MT (group 2). Freedom from adverse aorta-related events at 1, 3, and 5 years was significantly higher for patients who underwent descending TEVAR compared with those managed with MT (89.2%, 88.2%, and 84.0% vs 74.2%, 74.2%, and 74.2%, respectively; P = .026). The 1-, 3-, and 5-year survival rates for patients in the descending TEVAR group was 100%, 100%, and 100%, respectively, which was significantly higher than the survival of the MT group: 93.5%, 93.5%, and 81.9%, respectively (P = .002). On a univariate analysis among patients receiving MT, those who suffered adverse aorta-related events showed a higher prevalence of renal insufficiency (55.6% vs 9.1%; P = .003). In MT patients, multivariate analysis showed that renal insufficiency was the only independent risk factor associated with adverse aorta-related events (hazard ratio, 8.691; 95% confidence interval, 2.056-36.737; P = .003). CONCLUSIONS: Based on our study, compared with MT, descending TEVAR might be the more favorable treatment for patients with IMH involving the ascending aorta and extending into the descending thoracic aorta. Patients with renal insufficiency are more likely to experience adverse aorta-related events, which implies the need for subsequent intervention or an increased risk of mortality. The risk factor would be helpful for clinical decision-making.

Association of Daily Mean Temperature and Temperature Variability With Onset Risks of Acute Aortic Dissection.

Background The association between ambient temperature and cardiovascular diseases has been well established, but evidence of temporal changes in the risk of acute aortic dissection (AAD) onset is lacking. Methods and Results We conducted an 8-year time-series study based on data from 2120 patients diagnosed with AAD at Tongji Hospital (Wuhan, China). Daily meteorological parameters were measured in the study area. Spearman's rank correlation analysis was applied to measure the associations between daily meteorological data and air pollution indicators. A distributed lag nonlinear model following quasi-Poisson regression was used to express the nonlinear exposure-response relationships and lag effects of daily mean temperature and temperature variability on the occurrence of AAD. Considering a 25-day lag effect, lower or higher temperatures with reference to 25°C did not alter the onset risk of AAD. The lag effect of daily mean temperature on the incidence of AAD is statistically significant within 2 days, and the impact of daily mean temperature on the risk is most influential on the day. The exposure-response curve between daily mean temperature and onset risks of AAD at lag 0 showed that the extremely cold temperature (2.5th percentile, 0.5°C) significantly increased the AAD risk for the total (relative risk, 1.733; 95% CI, 1.130-2.658) and type A dissection (relative risk, 3.951; 95% CI, 1.657-9.418). Temperature variability within 1 week did not affect the onset risks of AAD for the total. Conclusions We confirmed that extremely cold temperatures significantly increased the AAD risk, which could contribute to early prevention and timely diagnosis of the disease.

The Role of Aspirin in the Management of Intracranial Aneurysms: A Systematic Review and Meta-Analyses.

Objective: To evaluate the association between aspirin use and the risks of unruptured intracranial aneurysm (UIA) growth and aneurysmal subarachnoid hemorrhage (aSAH). Methods: We searched PubMed and Scopus from inception to 1 September 2020. Studies evaluating the associations between aspirin prescription and the risk of UIA growth or the risk of aSAH were included. The study only included patients with intracranial aneurysms. We assessed the quality of included studies using the Newcastle-Ottawa scale. Random-effects meta-analysis was conducted to pool the estimates of effect size quantitatively. Sensitivity analyses using the leave-one-out strategy were performed to identify any potential source of heterogeneity. Results: After a review of 2,226 citations, five cohort studies, two case-control studies, and one nested case-control study involving 8,898 participants were included. Pooled analyses showed that aspirin use, regardless of frequency and duration, was associated with a statistically significantly lower risk of UIA growth (OR 0.25, 95% CI 0.11-0.54; I 2 = 0.0%, p = 0.604) and aSAH (OR, 0.37, 95% CI, 0.23-0.58; I 2 = 79.3%, p = 0.001) in patients presented with intracranial aneurysms. The results did not significantly change in sensitivity analyses. Conclusions: Summarizing available evidence in the literature, our findings indicate that aspirin use, regardless of frequency and duration, was associated with a statistically significantly lower risk of UIA growth and aSAH in patients with UIA. Well-designed and large-scale clinical trials are needed to help define the role of aspirin as a protective pharmaceutical for UIAs.

Risk of aortic aneurysm in patients with psoriasis: A systematic review and meta-analysis of cohort studies.

BACKGROUND: The association between psoriasis and the risk of aortic aneurysm is still unclear. HYPOTHESIS: Patients with psoriasis have a higher risk of aortic aneurysm than healthy individuals. METHODS: PubMed, Embase, and Scopus from inception to 20 July 2019 were searched. We included cohort studies if they reported estimate effects on the risk of aortic aneurysm in patient with psoriasis. We used Newcastle-Ottawa Scale to evaluate methodology quality of eligible studies. Random-effect meta-analyses were used to estimate the overall risk. Subgroup analyses were conducted for analysis of influencing factors. RESULTS: After a view of 2207 citations, we included three large cohort studies enrolling 5 706 525 participants in this systematic review. Psoriasis patients have an increased risk of development of aortic aneurysm (hazard ratio [HR]: 1.30, 95%confidence intervals [CI], 1.10-1.55, I2 = 53.1%). The risk is not statistically different between patients with severe psoriasis (HR, 1.51, 95%CI, 1.04-2.19, I2 = 40.2%) and patients with mild psoriasis (HR, 1.24, 95%CI, 1.08-1.42, I2 = 24.1%). The risk was not statistically increased in female patients (HR, 1.55, 95%CI, 0.65-3.72), patients ≥50 years old (HR, 4.05, 95%CI, 0.69-23.75, I2 = 97.3%), and patients with diabetes (HR, 0.97, 95%CI, 0.83-1.14). CONCLUSIONS: Current evidence from observational studies suggests that psoriasis increases the risk of aortic aneurysm, and screening of aortic aneurysm might be considered among psoriasis patients.

Chronobiological patterns of acute aortic dissection in central China.

BACKGROUND: Acute aortic dissection (AAD) is a life-threatening emergency with poor clinical outcomes. Understanding the chronological patterns of AAD onset would be helpful for identifying the triggers of AAD and preventing this catastrophic event. METHODS: We collected data from 2048 patients diagnosed with AAD at Tongji Hospital (Wuhan, China) from 2011 to 2018. The χ2 test was used to determine whether a specific period had significantly different seasonal/weekly distributions from other periods. Fourier models were used to analyse the rhythmicity in monthly/circadian distribution. RESULTS: The mean age was 53.4±10.9 years, and 1161 patients (56.7%) were under 55 years. One thousand six hundred fifty-seven patients (80.9%) were male, and 935 cases (45.7%) were type A dissections. The proportions of patients with comorbid hypertension/diabetes were 60.3% (1234 cases) and 1.8% (36 cases), respectively. A peak was identified in colder periods (winter/December) and a trough in warmer periods (summer/June). No significant variation was observed in weekly distribution. Fourier analysis showed a statistically significant circadian variation (p<0.001) with a nocturnal trough in 2:00-3:00, a morning peak in 9:00-10:00, and an afternoon peak in 16:00-17:00. Subgroup analyses identified circadian rhythmicity in all subgroups except for the female group and younger group (younger than 55 years). CONCLUSION: Our results confirmed that the onset of AAD exhibits significant seasonal, monthly and circadian patterns. Patients with AAD with different Stanford-type dissections, sexes, ages and hypertension statuses could present different circadian variations. These findings may provide novel perspectives for identifying the triggers of AAD and better preventing this catastrophic event.

Prevalence of Intracranial Aneurysm in Patients with Aortopathy: A Systematic Review with Meta-Analyses.

BACKGROUND AND PURPOSE: Patients with aortic disease might have an increased risk of intracranial aneurysm (IA). We conducted this research to assess the prevalence of IA in patients with aortopathy, considering the impact of gender, age, and cardiovascular risk factors. METHODS: We searched PubMed and Scopus from inception to August 2019 for epidemiological studies reporting the prevalence of IA in patients with aortopathy. Random-effect meta-analyses were performed to calculate the overall prevalence, and the effect of risk factors on the prevalence was also evaluated. Anatomical location of IAs in patients suffered from distinct aortic disease was extracted and further analyzed. RESULTS: Thirteen cross-sectional studies involving 4,041 participants were included in this systematic review. We reported an estimated prevalence of 12% (95% confidence interval [CI], 9% to 14%) of IA in patients with aortopathy. The pooled prevalence of IA in patients with bicuspid aortic valve, coarctation of the aorta, aortic aneurysm, and aortic dissection was 8% (95% CI, 6% to 10%), 10% (95% CI, 7% to 14%), 12% (95% CI, 9% to 15%), and 23% (95% CI, 12% to 34%), respectively. Gender (female) and smoking are risk factors related to an increased risk of IA. The anatomical distribution of IAs was heterogeneously between participants with different aortic disease. CONCLUSIONS: According to current epidemiological evidence, the prevalence of IA in patients with aortic disease is quadrupled compared to that in the general population, which suggests that an early IA screening should be considered among patients with aortic disease for timely diagnosis and treatment of IA.

Impact of metformin on the risk and treatment outcomes of tuberculosis in diabetics: a systematic review.

BACKGROUND: Tuberculosis (TB) remains one of the infectious diseases with a leading cause of death among adults worldwide. Metformin, a first-line medication for the treatment of type 2 diabetes, may have potential for treating TB. The aims of the present systematic review were to evaluate the impact of metformin prescription on the risk of tuberculosis diseases, the risk of latent TB infection (LTBI) and treatment outcomes of tuberculosis among patients with diabetic mellitus. METHODS: Databases were searched through March 2019. Observational studies reporting the effect of metformin prescription on the risk and treatment outcomes of TB were included in the systematic review. We qualitatively analyzed results of included studies, and then pooled estimate effects with 95% confidence intervals (CIs) of different outcome using random-effect meta-analyses. RESULTS: This systematic review included 6980 cases from 12 observational studies. The meta-analysis suggested that metformin prescription could decrease the risk of TB among diabetics (pooled odds ratio [OR], 0.38; 95%CI, 0.21 to 0.66). Metformin prescription was not related to a lower risk of LTBI (OR, 0.73; 95%CI, 0.30 to 1.79) in patients with diabetes. Metformin medication during the anti-tuberculosis treatment is significantly associated with a smaller TB mortality (OR, 0.47; 95%CI, 0.27 to 0.83), and a higher probability of sputum culture conversion at 2 months of TB disease (OR, 2.72; 95%CI, 1.11 to 6.69) among patients with diabetes. The relapse of TB was not statistically reduced by metformin prescription (OR, 0.55; 95%CI, 0.04 to 8.25) in diabetics. CONCLUSIONS: According to current observational evidence, metformin prescription significantly reduced the risk of TB in patients with diabetes mellitus. Treatment outcomes of TB disease could also be improved by the metformin medication among diabetics.

Berberine Ameliorates High Glucose-Induced Cardiomyocyte Injury via AMPK Signaling Activation to Stimulate Mitochondrial Biogenesis and Restore Autophagic Flux.

Background: Type II diabetes (T2D)-induced cardiomyocyte hypertrophy is closely linked to the impairment of mitochondrial function. Berberine has been shown to be a promising effect for hypoglycemia in T2D models. High glucose-induced cardiomyocyte hypertrophy in vitro has been reported. The present study investigated the protective effect and the underlying mechanism of berberine on high glucose-induced H9C2 cell line. Methods: High glucose-induced H9C2 cell line was used to mimic the hyperglycemia resulting in cardiomyocyte hypertrophy. Berberine was used to rescue in this model and explore the mechanism in it. Confocal microscopy, immunofluorescence, RT-PCR, and western blot analysis were performed to evaluate the protective effects of berberine in high glucose-induced H9C2 cell line. Results: Berberine dramatically alleviated hypertrophy of H9C2 cell line and significantly ameliorated mitochondrial function by rectifying the imbalance of fusion and fission in mitochondrial dynamics. Furthermore, berberine further promoted mitogenesis and cleared the damaged mitochondria via mitophagy. In addition, berberine also restored autophagic flux in high glucose-induced cardiomyocyte injury via AMPK signaling pathway activation. Conclusion: Berberine ameliorates high glucose-induced cardiomyocyte injury via AMPK signaling pathway activation to stimulate mitochondrial biogenesis and restore autophagicflux in H9C2 cell line.

Berberine Alleviates Tau Hyperphosphorylation and Axonopathy-Associated with Diabetic Encephalopathy via Restoring PI3K/Akt/GSK3ß Pathway.

BACKGROUND: Axonopathy is closely linked to the development of diabetic encephalopathy induced by type II diabetes (T2D). Berberine has been shown to cross the blood-brain barrier and holds promising effect for neuronal damage in diabetes. OBJECTIVE: The present study investigated the protective effect and the underlying mechanism of berberine on neuronal axonopathy in both in vitro and in vivo models. METHODS: High glucose/high fat diet and streptozotocin injection-induced T2D rat model was used. Berberine was administered p.o. to T2D rat model for 10 weeks. Morris water maze test, in vivo neuronal tracing, immunohistochemistry, and western blot analysis were performed to evaluate the protective effects of berberine in T2D-induced diabetic encephalopathy rats. Primary cultured neurons were used to further explore the underlying mechanisms in vitro. RESULTS: Berberine dramatically reduced blood glucose and serum insulin levels and alleviated insulin resistance. Berberine significantly attenuated memory impairment, axonopathy, and tau hyperphosphorylation, and also restored PI3K/Akt/GSK3ß signaling pathway in T2D rats. In vitro, berberine induced an increase in the phosphorylation of PI3K/Akt as well as GSK3ß in high glucose-treated primary neurons. Furthermore, berberine-induced PI3K/Akt activation also resulted in the dephosphorylation of tau protein, which could improve axonal transport impairment in high glucose-treated primary neurons. Pretreated neurons with LY294002, an inhibitor of PI3K, partially blocked berberine-inhibited tau phosphorylation and berberine-activated PI3K/Akt signaling pathway. CONCLUSIONS: Berberine exerts the protective effect against cognitive deficits by improving tau hyperphosphorylation and the axonal damage through restoring PI3K/Akt/GSK3ß signaling pathway.

Melatonin Mitigates Kainic Acid-Induced Neuronal Tau Hyperphosphorylation and Memory Deficits through Alleviating ER Stress.

Kainic acid (KA) exposure causes neuronal degeneration featured by Alzheimer-like tau hyperphosphorylation and memory deficits. Melatonin (Mel) is known to protect hippocampal neurons against KA-induced damage. However, the underlying mechanisms remain elusive. In the current study, we investigated the protective effect of melatonin on KA-induced tau hyperphosphorylation by focusing on endoplasmic reticulum (ER) stress-mediated signaling pathways. By using primary hippocampal neurons and mouse brain, we showed that KA treatment specifically induced ER stress and activated GSK-3ß and CDK5, two major kinases responsible for tau phosphorylation. Inhibition of ER stress efficiently inactivated GSK-3ß and CDK5. Mechanistically, we found that KA-induced ER stress significantly activated calpain, a calcium-dependent protease. Inhibition of ER stress or calpain leads to the reduction in KA-induced GSK-3ß and CDK5 activities and tau phosphorylation. Moreover, GSK-3ß or CDK5 inhibition failed to downregulate ER stress efficiently, suggesting that ER stress functions upstream of GSK-3ß or CDK5. Notably, our results revealed that melatonin acts against KA-induced neuronal degeneration and tau hyperphosphorylation via easing ER stress, further highlighting the protective role of melatonin in the KA-induced neuronal defects.

Melatonin Mediates Protective Effects against Kainic Acid-Induced Neuronal Death through Safeguarding ER Stress and Mitochondrial Disturbance.

Kainic acid (KA)-induced neuronal death is linked to mitochondrial dysfunction and ER stress. Melatonin is known to protect hippocampal neurons from KA-induced apoptosis, but the exact mechanisms underlying melatonin protective effects against neuronal mitochondria disorder and ER stress remain uncertain. In this study, we investigated the sheltering roles of melatonin during KA-induced apoptosis by focusing on mitochondrial dysfunction and ER stress mediated signal pathways. KA causes mitochondrial dynamic disorder and dysfunction through calpain activation, leading to neuronal apoptosis. Ca2+ chelator BAPTA-AM and calpain inhibitor calpeptin can significantly restore mitochondrial morphology and function. ER stress can also be induced by KA treatment. ER stress inhibitor 4-phenylbutyric acid (PBA) attenuates ER stress-mediated apoptosis and mitochondrial disorder. It is worth noting that calpain activation was also inhibited under PBA administration. Thus, we concluded that melatonin effectively inhibits KA-induced calpain upregulation/activation and mitochondrial deterioration by alleviating Ca2+ overload and ER stress.