Analysis of factors associated with disease outcomes in hospitalized patients with 2019 novel coronavirus disease / 中华医学杂志(英文版)

Background@#Since early December 2019, the 2019 novel coronavirus disease (COVID-19) has caused pneumonia epidemic in Wuhan, Hubei province of China. This study aims to investigate the factors affecting the progression of pneumonia in COVID-19 patients. Associated results will be used to evaluate the prognosis and to find the optimal treatment regimens for COVID-19 pneumonia.@*Methods@#Patients tested positive for the COVID-19 based on nucleic acid detection were included in this study. Patients were admitted to three tertiary hospitals in Wuhan between December 30, 2019, and January 15, 2020. Individual data, laboratory indices, imaging characteristics, and clinical data were collected, and statistical analysis was performed. Based on clinical typing results, the patients were divided into a progression group or an improvement/stabilization group. Continuous variables were analyzed using independent samples t-test or Mann-Whitney U test. Categorical variables were analyzed using chi-squared test or Fisher’s exact test. Logistic regression analysis was performed to explore the risk factors for disease progression.@*Results@#Seventy-eight patients with COVID-19-induced pneumonia met the inclusion criteria and were included in this study. Efficacy evaluation at 2 weeks after hospitalization indicated that 11 patients (14.1%) had deteriorated, and 67 patients (85.9%) had improved/stabilized. The patients in the progression group were significantly older than those in the disease improvement/stabilization group (66 [51, 70] years vs. 37 [32, 41] years, U =4.932, P =0.001). The progression group had a significantly higher proportion of patients with a history of smoking than the improvement/stabilization group (27.3% vs. 3.0%, χ2=9.291, P =0.018). For all the 78 patients, fever was the most common initial symptom, and the maximum body temperature at admission was significantly higher in the progression group than in the improvement/stabilization group (38.2 [37.8, 38.6]℃ vs. 37.5 [37.0, 38.4]℃, U=2.057, P =0.027). Moreover, the proportion of patients with respiratory failure (54.5% vs. 20.9%, χ2=5.611, P=0.028) and respiratory rate (34 [18, 48] breaths/min vs. 24 [16, 60] breaths/min, U=4.030, P=0.004) were significantly higher in the progression group than in the improvement/stabilization group. C-reactive protein was significantly elevated in the progression group compared to the improvement/stabilization group (38.9 [14.3, 64.8] mg/L vs. 10.6 [1.9, 33.1] mg/L, U=1.315, P=0.024). Albumin was significantly lower in the progression group than in the improvement/stabilization group (36.62±6.60 g/L vs. 41.27±4.55 g/L, U =2.843, P =0.006). Patients in the progression group were more likely to receive high-level respiratory support than in the improvement/stabilization group (χ2=16.01, P=0.001). Multivariate logistic analysis indicated that age (OR, 8.546; 95% CI: 1.628-44.864; P = 0.011), history of smoking (OR, 14.285; 95% CI: 1.577-25.000; P = 0.018), maximum body temperature at admission (OR, 8.999; 95% CI: 1.036-78.147, P = 0.046), respiratory failure (OR, 8.772, 95% CI: 1.942-40.000; P = 0.016), albumin (OR, 7.353, 95% CI: 1.098-50.000; P = 0.003) and C-reactive protein (OR, 10.530; 95% CI: 1.224-34.701, P = 0.028) were risk factors for disease progression.@*Conclusions@#Several factors that led to the progression of COVID-19 pneumonia were identified, including age, history of smoking, maximum body temperature on admission, respiratory failure, albumin, C-reactive protein. These results can be used to further enhance the ability of management of COVID-19 pneumonia.

Clinical characteristics of novel coronavirus cases in tertiary hospitals in Hubei Province / 中华医学杂志(英文版)

Background@#A novel coronavirus (2019-nCoV) causing an outbreak of pneumonia in Wuhan, Hubei province of China was isolated in January 2020. This study aims to investigate its epidemiological history, and analyzed the clinical characteristics, treatment regimens and prognosis of patients infected with 2019-nCoV during this outbreak.@*Methods@#Clinical data from 137 2019-nCoV-infected patients admitted to the respiratory departments of nine tertiary hospitals in Hubei province from December 30, 2019 to January 24, 2020 were collected, including general status, clinical manifestations, laboratory test results, imaging characteristics, and treatment regimens.@*Results@#None of the 137 patients (61 males, 76 females, aged 20-83 years, mean age 55 ± 16 years) had a definite history of exposure to Huanan Seafood Wholesale Market. Major initial symptoms included fever (112/137, 81.8%), coughing (66/137, 48.2%), and muscle pain or fatigue (44/137, 32.1%), with other, less typical initial symptoms observed at low frequency, including heart palpitations, diarrhea, and headache. Nearly 80% of the patients had normal or decreased white blood cell counts, and 72.3% (99/137) had lymphocytopenia. Lung involvement was present in all cases, with most chest computed tomography scans showing lesions in multiple lung lobes, some of which were dense; ground-glass opacity co-existed with consolidation shadows or cord-like shadows. Given the lack of effective drugs, treatment focused on symptomatic and respiratory support. Immunoglobulin G was delivered to some critically ill patients according to their condition. Systemic corticosteroid treatment did not show significant benefits. Notably, early respiratory support facilitated disease recovery and improved prognosis. The risk of death was primarily associated with age, underlying chronic diseases, and median interval from the appearance of initial symptoms to dyspnea.@*Conclusions@#The majority of patients with 2019-nCoV coronavirus pneumonia present with fever as the first symptom, and most of them still showed typical manifestations of viral pneumonia on chest imaging. Middle-aged and elderly patients with underlying comorbidities are susceptible to respiratory failure and may have a poorer prognosis.

Clinical characteristics of novel coronavirus cases in tertiary hospitals in Hubei Province / 中华医学杂志(英文版)

BACKGROUND@#The 2019 novel coronavirus (2019-nCoV) causing an outbreak of pneumonia in Wuhan, Hubei province of China was isolated in January 2020. This study aims to investigate its epidemiologic history, and analyze the clinical characteristics, treatment regimens, and prognosis of patients infected with 2019-nCoV during this outbreak.@*METHODS@#Clinical data from 137 2019-nCoV-infected patients admitted to the respiratory departments of nine tertiary hospitals in Hubei province from December 30, 2019 to January 24, 2020 were retrospectively collected, including general status, clinical manifestations, laboratory test results, imaging characteristics, and treatment regimens.@*RESULTS@#None of the 137 patients (61 males, 76 females, aged 20-83 years, median age 57 years) had a definite history of exposure to Huanan Seafood Wholesale Market. Major initial symptoms included fever (112/137, 81.8%), coughing (66/137, 48.2%), and muscle pain or fatigue (44/137, 32.1%), with other, less typical initial symptoms observed at low frequency, including heart palpitations, diarrhea, and headache. Nearly 80% of the patients had normal or decreased white blood cell counts, and 72.3% (99/137) had lymphocytopenia. Lung involvement was present in all cases, with most chest computed tomography scans showing lesions in multiple lung lobes, some of which were dense; ground-glass opacity co-existed with consolidation shadows or cord-like shadows. Given the lack of effective drugs, treatment focused on symptomatic and respiratory support. Immunoglobulin G was delivered to some critically ill patients according to their conditions. Systemic corticosteroid treatment did not show significant benefits. Notably, early respiratory support facilitated disease recovery and improved prognosis. The risk of death was primarily associated with age, underlying chronic diseases, and median interval from the appearance of initial symptoms to dyspnea.@*CONCLUSIONS@#The majority of patients with 2019-nCoV pneumonia present with fever as the first symptom, and most of them still showed typical manifestations of viral pneumonia on chest imaging. Middle-aged and elderly patients with underlying comorbidities are susceptible to respiratory failure and may have a poorer prognosis.

Analysis of factors associated with disease outcomes in hospitalized patients with 2019 novel coronavirus disease / 中华医学杂志(英文版)

BACKGROUND@#Since early December 2019, the 2019 novel coronavirus disease (COVID-19) has caused pneumonia epidemic in Wuhan, Hubei province of China. This study aimed to investigate the factors affecting the progression of pneumonia in COVID-19 patients. Associated results will be used to evaluate the prognosis and to find the optimal treatment regimens for COVID-19 pneumonia.@*METHODS@#Patients tested positive for the COVID-19 based on nucleic acid detection were included in this study. Patients were admitted to 3 tertiary hospitals in Wuhan between December 30, 2019, and January 15, 2020. Individual data, laboratory indices, imaging characteristics, and clinical data were collected, and statistical analysis was performed. Based on clinical typing results, the patients were divided into a progression group or an improvement/stabilization group. Continuous variables were analyzed using independent samples t-test or Mann-Whitney U test. Categorical variables were analyzed using Chi-squared test or Fisher's exact test. Logistic regression analysis was performed to explore the risk factors for disease progression.@*RESULTS@#Seventy-eight patients with COVID-19-induced pneumonia met the inclusion criteria and were included in this study. Efficacy evaluation at 2 weeks after hospitalization indicated that 11 patients (14.1%) had deteriorated, and 67 patients (85.9%) had improved/stabilized. The patients in the progression group were significantly older than those in the disease improvement/stabilization group (66 [51, 70] vs. 37 [32, 41] years, U = 4.932, P = 0.001). The progression group had a significantly higher proportion of patients with a history of smoking than the improvement/stabilization group (27.3% vs. 3.0%, χ = 9.291, P = 0.018). For all the 78 patients, fever was the most common initial symptom, and the maximum body temperature at admission was significantly higher in the progression group than in the improvement/stabilization group (38.2 [37.8, 38.6] vs. 37.5 [37.0, 38.4]°C, U = 2.057, P = 0.027). Moreover, the proportion of patients with respiratory failure (54.5% vs. 20.9%, χ = 5.611, P = 0.028) and respiratory rate (34 [18, 48] vs. 24 [16, 60] breaths/min, U = 4.030, P = 0.004) were significantly higher in the progression group than in the improvement/stabilization group. C-reactive protein was significantly elevated in the progression group compared to the improvement/stabilization group (38.9 [14.3, 64.8] vs. 10.6 [1.9, 33.1] mg/L, U = 1.315, P = 0.024). Albumin was significantly lower in the progression group than in the improvement/stabilization group (36.62 ± 6.60 vs. 41.27 ± 4.55 g/L, U = 2.843, P = 0.006). Patients in the progression group were more likely to receive high-level respiratory support than in the improvement/stabilization group (χ = 16.01, P = 0.001). Multivariate logistic analysis indicated that age (odds ratio [OR], 8.546; 95% confidence interval [CI]: 1.628-44.864; P = 0.011), history of smoking (OR, 14.285; 95% CI: 1.577-25.000; P = 0.018), maximum body temperature at admission (OR, 8.999; 95% CI: 1.036-78.147, P = 0.046), respiratory failure (OR, 8.772, 95% CI: 1.942-40.000; P = 0.016), albumin (OR, 7.353, 95% CI: 1.098-50.000; P = 0.003), and C-reactive protein (OR, 10.530; 95% CI: 1.224-34.701, P = 0.028) were risk factors for disease progression.@*CONCLUSIONS@#Several factors that led to the progression of COVID-19 pneumonia were identified, including age, history of smoking, maximum body temperature at admission, respiratory failure, albumin, and C-reactive protein. These results can be used to further enhance the ability of management of COVID-19 pneumonia.

Clinical characteristics of fatal and recovered cases of coronavirus disease 2019 in Wuhan, China: a retrospective study / 中华医学杂志(英文版)

BACKGROUND@#The 2019 novel coronavirus has caused the outbreak of the acute respiratory disease in Wuhan, Hubei Province of China since December 2019. This study was performed to analyze the clinical characteristics of patients who succumbed to and who recovered from 2019 novel coronavirus disease (COVID-19).@*METHODS@#Clinical data were collected from two tertiary hospitals in Wuhan. A retrospective investigation was conducted to analyze the clinical characteristics of fatal cases of COVID-19 (death group) and we compare them with recovered patients (recovered group). Continuous variables were analyzed using the Mann-Whitney U test. Categorical variables were analyzed by χ test or Fisher exact test as appropriate.@*RESULTS@#Our study enrolled 109 COVID-19 patients who died during hospitalization and 116 recovered patients. The median age of the death group was older than the recovered group (69 [62, 74] vs. 40 [33, 57] years, Z = 9.738, P < 0.001). More patients in the death group had underlying diseases (72.5% vs. 41.4%, χ = 22.105, P < 0.001). Patients in the death group had a significantly longer time of illness onset to hospitalization (10.0 [6.5, 12.0] vs. 7.0 [5.0, 10.0] days, Z = 3.216, P = 0.001). On admission, the proportions of patients with symptoms of dyspnea (70.6% vs. 19.0%, χ = 60.905, P < 0.001) and expectoration (32.1% vs. 12.1%, χ = 13.250, P < 0.001) were significantly higher in the death group. The blood oxygen saturation was significantly lower in the death group (85 [77, 91]% vs. 97 [95, 98]%, Z = 10.625, P < 0.001). The white blood cell (WBC) in death group was significantly higher on admission (7.23 [4.87, 11.17] vs. 4.52 [3.62, 5.88] ×10/L, Z = 7.618, P < 0.001). Patients in the death group exhibited significantly lower lymphocyte count (0.63 [0.40, 0.79] vs. 1.00 [0.72, 1.27] ×10/L, Z = 8.037, P < 0.001) and lymphocyte percentage (7.10 [4.45, 12.73]% vs. 23.50 [15.27, 31.25]%, Z = 10.315, P < 0.001) on admission, and the lymphocyte percentage continued to decrease during hospitalization (7.10 [4.45, 12.73]% vs. 2.91 [1.79, 6.13]%, Z = 5.242, P < 0.001). Alanine transaminase (22.00 [15.00, 34.00] vs. 18.70 [13.00, 30.38] U/L, Z = 2.592, P = 0.010), aspartate transaminase (34.00 [27.00, 47.00] vs. 22.00 [17.65, 31.75] U/L, Z = 7.308, P < 0.001), and creatinine levels (89.00 [72.00, 133.50] vs. 65.00 [54.60, 78.75] μmol/L, Z = 6.478, P < 0.001) were significantly higher in the death group than those in the recovered group. C-reactive protein (CRP) levels were also significantly higher in the death group on admission (109.25 [35.00, 170.28] vs. 3.22 [1.04, 21.80] mg/L, Z = 10.206, P < 0.001) and showed no significant improvement after treatment (109.25 [35.00, 170.28] vs. 81.60 [27.23, 179.08] mg/L, Z = 1.219, P = 0.233). The patients in the death group had more complications such as acute respiratory distress syndrome (ARDS) (89.9% vs. 8.6%, χ = 148.105, P < 0.001), acute cardiac injury (59.6% vs. 0.9%, χ = 93.222, P < 0.001), acute kidney injury (18.3% vs. 0%, χ = 23.257, P < 0.001), shock (11.9% vs. 0%, χ = 14.618, P < 0.001), and disseminated intravascular coagulation (DIC) (6.4% vs. 0%, χ = 7.655, P = 0.006).@*CONCLUSIONS@#Compared to the recovered group, more patients in the death group exhibited characteristics of advanced age, pre-existing comorbidities, dyspnea, oxygen saturation decrease, increased WBC count, decreased lymphocytes, and elevated CRP levels. More patients in the death group had complications such as ARDS, acute cardiac injury, acute kidney injury, shock, and DIC.

Atorvastatin Attenuates Myocardial Hypertrophy Induced by Chronic Intermittent Hypoxia In Vitro Partly through miR-31/PKCε Pathway / 华中科技大学学报（医学）（英德文版）

Atorvastatin is proven to ameliorate cardiac hypertrophy induced by chronic intermittent hypoxia (CIH).However,little is known about the mechanism by which atorvastatin modulates CIH-induced cardiac hypertrophy,and whether specific hypertrophyrelated microRNAs are involved in the modulation.MiR-31 plays key roles in the development of cardiac hypertrophy induced by ischemia/hypoxia.This study examined whether miR-31 was involved in the protective role of atorvastatin against CIH-induced myocardial hypertrophy.H9c2 cells were subjected to 8-h intermittent hypoxia per day in the presence or absence of atorvastatin for 5 days.The size of cardiomyocytes,and the expression of caspase 3 and miR-31 were determined by Western blotting and RT-PCR,respectively.MiR-31 mimic or Ro 31-8220,a specific inhibitor of protein kinase C epsilon (PKCε),was used to determine the role of miR-31 in the anti-hypertrophic effect of atorvastatin on cardiomyocytes.PKCε in the cardiomyocytes with miR-31 upregulation or downregulation was detected using RT-PCR and Western blotting.The results showed that CIH induced obvious enlargement of cardiomyocytes,which was paralleled with increased atrial natriuretic peptide (ANP),brain natriuretic peptide (BNP),and slow/beta cardiac myosin heavy-chain (MYH7) mRNA levels.All these changes were reversed by the treatment with atorvastatin.Meanwhile,miR-31 was increased by CIH in vitro.Of note,the atorvastatin pretreatment significantly increased the mRNA and protein expression of PKCε and decreased that of miR-31.Moreover,overexpression of miR-31 abolished the anti-hypertrophic effect of atorvastatin on cardiomyocytes.Upregulation and downregulation of miR-31 respectively decreased and increased the mRNA and protein expression of PKCε.These results suggest that atorvastatin provides the cardioprotective effects against CIH probably via up-regulating PKCε and down-regulating miR-31.

Atorvastatin Attenuates Myocardial Hypertrophy Induced by Chronic Intermittent Hypoxia In Vitro Partly through miR-31/PKCε Pathway / 华中科技大学学报（医学）（英德文版）

Atorvastatin is proven to ameliorate cardiac hypertrophy induced by chronic intermittent hypoxia (CIH).However,little is known about the mechanism by which atorvastatin modulates CIH-induced cardiac hypertrophy,and whether specific hypertrophyrelated microRNAs are involved in the modulation.MiR-31 plays key roles in the development of cardiac hypertrophy induced by ischemia/hypoxia.This study examined whether miR-31 was involved in the protective role of atorvastatin against CIH-induced myocardial hypertrophy.H9c2 cells were subjected to 8-h intermittent hypoxia per day in the presence or absence of atorvastatin for 5 days.The size of cardiomyocytes,and the expression of caspase 3 and miR-31 were determined by Western blotting and RT-PCR,respectively.MiR-31 mimic or Ro 31-8220,a specific inhibitor of protein kinase C epsilon (PKCε),was used to determine the role of miR-31 in the anti-hypertrophic effect of atorvastatin on cardiomyocytes.PKCε in the cardiomyocytes with miR-31 upregulation or downregulation was detected using RT-PCR and Western blotting.The results showed that CIH induced obvious enlargement of cardiomyocytes,which was paralleled with increased atrial natriuretic peptide (ANP),brain natriuretic peptide (BNP),and slow/beta cardiac myosin heavy-chain (MYH7) mRNA levels.All these changes were reversed by the treatment with atorvastatin.Meanwhile,miR-31 was increased by CIH in vitro.Of note,the atorvastatin pretreatment significantly increased the mRNA and protein expression of PKCε and decreased that of miR-31.Moreover,overexpression of miR-31 abolished the anti-hypertrophic effect of atorvastatin on cardiomyocytes.Upregulation and downregulation of miR-31 respectively decreased and increased the mRNA and protein expression of PKCε.These results suggest that atorvastatin provides the cardioprotective effects against CIH probably via up-regulating PKCε and down-regulating miR-31.

Altered Wnt Signaling Pathway in Cognitive Impairment Caused by Chronic Intermittent Hypoxia: Focus on Glycogen Synthase Kinase-3β and β-catenin / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Cognitive impairment is a severe complication caused by obstructive sleep apnea (OSA). The mechanisms of causation are still unclear. The Wnt/β-catenin signaling pathway is involved in cognition, and abnormalities in it are implicated in neurological disorders. Here, we explored the Wnt/β-catenin signaling pathway abnormalities caused by chronic intermittent hypoxia (CIH), the most characteristic pathophysiological component of OSA.</p><p><b>METHODS</b>We divided 32 4-week-old male C57/BL mice into four groups of eight each: a CIH + normal saline (NS) group, CIH + LiCl group, sham CIH + NS group, and a sham CIH + LiCl group. The spatial learning performance of each group was assessed by using the Morris water maze (MWM). Protein expressions of glycogen synthase kinase-3β (GSK-3β) and β-catenin in the hippocampus were examined using the Western blotting test. EdU labeling and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling staining methods were used, respectively, to determine the proliferation and apoptosis of neurons in the hippocampal dentate gyrus region.</p><p><b>RESULTS</b>Mice exposed to CIH showed impaired spatial learning performance in the MWM, including increased mean escape latencies to reach the target platform, decreased mean times passing through the target platform and mean duration in the target quadrant. The GSK-3β activity increased, and expression of β-catenin decreased significantly in the hippocampus of the CIH-exposed mice. Besides, CIH significantly increased hippocampal neuronal apoptosis, with an elevated apoptosis index. Meanwhile, LiCl decreased the activity of GSK-3β and increased the expression of β-catenin and partially reversed the spatial memory deficits in MWM and the apoptosis caused by CIH.</p><p><b>CONCLUSIONS</b>Wnt/β-catenin signaling pathway abnormalities possibly play an important role in the development of cognitive deficits among mice exposed to CIH and that LiCl might attenuate CIH-induced cognitive impairment via Wnt/β-catenin signaling pathway.</p>

P2X7 Receptor Antagonism Attenuates the Intermittent Hypoxia-induced Spatial Deficits in a Murine Model of Sleep Apnea Via Inhibiting Neuroinflammation and Oxidative Stress / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>The mechanism of the neural injury caused by chronic intermittent hypoxia (CIH) that characterizes obstructive sleep apnea syndrome (OSAS) is not clearly known. The purpose of this study was to investigate whether P2X7 receptor (P2X7R) is responsible for the CIH-induced neural injury and the possible pathway it involves.</p><p><b>METHODS</b>Eight-week-old male C57BL/6 mice were used. For each exposure time point, eight mice divided in room air (RA) and IH group were assigned to the study of P2X7R expression. Whereas in the 21 days-Brilliant Blue G (BBG, a selective P2X7R antagonist) study, 48 mice were randomly divided into CIH group, BBG-treated CIH group, RA group and BBG-treated RA group. The hippocampus P2X7R expression was determined by Western blotting and real-time polymerase chain reaction (PCR). The spatial learning was analyzed by Morris water maze. The nuclear factor kappa B (NFκB) and NADPH oxidase 2 (NOX2) expressions were analyzed by Western blotting. The expressions of tumor necrosis factor α, interleukin 1β (IL-β), IL-18, and IL-6 were measured by real-time PCR. The malondialdehyde and superoxide dismutase levels were detected by colorimetric method. Cell damage was evaluated by Hematoxylin and Eosin staining and Terminal Transferase dUTP Nick-end Labeling method.</p><p><b>RESULTS</b>The P2X7R mRNA was elevated and sustained after 3-day IH exposure and the P2X7R protein was elevated and sustained after 7-day IH exposure. In the BBG study, the CIH mice showed severer neuronal cell damage and poorer performance in the behavior test. The increased NFκB and NOX2 expressions along with the inflammation injury and oxidative stress were also observed in the CIH group. BBG alleviated CIH-induced neural injury and consequent functional deficits.</p><p><b>CONCLUSIONS</b>The P2X7R antagonism attenuates the CIH-induced neuroinflammation, oxidative stress, and spatial deficits, demonstrating that the P2X7R is an important therapeutic target in the cognition deficits accompanied OSAS.</p>

Effects of Continuous Positive Airway Pressure on Cognitive Deficits in Middle-aged Patients with Obstructive Sleep Apnea Syndrome: A Meta-analysis of Randomized Controlled Trials / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Current views on continuous positive airway pressure (CPAP) treatment to improve the cognitive deficits of patients with obstructive sleep apnea syndrome (OSAS) are controversial, so we performed a meta-analysis.</p><p><b>METHODS</b>A comprehensive literature search was undertaken in PubMed, CINAHL, Medline, PsycInfo, EMBASE, Cochrane Library, CNKI, WanFang, VIP, and CBMdisc for studies published from June 1971 to July 2014. The outcome measures included neuropsychological tests of the 7 cognitive domains detailed below.</p><p><b>RESULTS</b>After screening the titles and abstracts and thoroughly reading the full text, we obtained 13 studies with little risk of bias that incorporated 1744 middle-aged obese participants with mild to severe OSAS. The studies were published from 1994 to 2012. Treatment durations varied from 1 to 24 weeks. The effect sizes of attention, vigilance, processing speed, working memory, memory, verbal fluency, and visuoconstructive skills domains were -0.10 (P = 0.24), -0.12 (P = 0.04), -0.08 (P = 0.16), 0.00 (P = 0.95), -0.04 (P = 0.30), -0.06 (P = 0.34), and -0.01 (P = 0.92), respectively.</p><p><b>CONCLUSIONS</b>Cognition partially improved in patients with OSAS after CPAP treatment. The only domain with significant improvement was vigilance. Rigorous randomized controlled trials need to be performed to obtain clear results.</p>

Regulatory effects of AT₁R-TRAF6-MAPKs signaling on proliferation of intermittent hypoxia-induced human umbilical vein endothelial cells / 华中科技大学学报（医学）（英德文版）

Endothelial dysfunction induced by intermittent hypoxia (IH) participates in obstructive sleep apnea syndrome (OSAS)-associated cardiovascular disorders. Myeloid differentiation primary response 88 (MyD88) and tumor necrosis factor receptor-associated factor 6 (TRAF6) regulate numerous downstream adaptors like mitogen-activated protein kinases (MAPKs) and the subsequent oxidative stress and inflammatory responses. This study aimed to characterize the role of MyD88/TRAF6 in IH-treated cell function and its associated signaling. Human umbilical vein endothelial cells (HUVECs) were randomly exposed to IH or normoxia for 0, 2, 4 and 6 h. Western blotting was used to detect the expression pattern of target gene proteins [angiotensin 1 receptor (AT1R), p-ERK1/2, p-p38MAPK, MyD88 and TRAF6], and the relationships among these target genes down-regulated by the corresponding inhibitors were studied. Finally, the influence of these target genes on proliferation of HUVECs was also assessed by EdU analysis. Protein levels of AT1R, TRAF6 and p-ERK1/2 were increased after IH exposure, with a slight rise in MyD88 and a dynamic change in p-p38MAPK. The down-regulation of TRAF6 by siRNA reduced ERK1/2 phosphorylation during IH without any effects on AT1R. Blockade of AT1R with valsartan decreased TRAF6 and p-ERK1/2 protein expression after IH exposure. ERK1/2 inhibition with PD98059 suppressed only AT1R expression. IH promoted HUVECs proliferation, which was significantly suppressed by the inhibition of TRAF6, AT1R and ERK1/2. The findings demonstrate that TRAF6 regulates the proliferation of HUVECs exposed to short-term IH by modulating cell signaling involving ERK1/2 downstream of AT1R. Targeting the AT1R-TRAF6-p-ERK1/2 signaling pathway might be helpful in restoring endothelial function.

Clinical characteristics of hereditary multiple exostoses: A retrospective study of mainland chinese cases in recent 23 years / 华中科技大学学报（医学）（英德文版）

Hereditary multiple exostoses (HME) are an autosomal dominant skeletal disease with wide variations in clinical manifestations among different ethnic groups. This study investigated the epidemiology, clinical presentations, pathogenetic features and treatment strategies of HME in mainland China. We searched and reviewed the related cases published since 1990 by searching electronic databases, namely SinoMed database, Wanfang database, CNKI, Web of Science and PubMed as well as Google search engines. A total of 1051 cases of HME (male-to-female ratio 1.5:1) were investigated and the diagnosis was made in 83% before the age of 10 years. Approximately 96% patients had a family history. Long bones, ribs, scapula and pelvis were the frequently affected sites. Most patients were asymptomatic with multiple palpable masses. Common complications included angular deformities, impingement on neighbouring tissues and impaired articular function. Chondrosarcomas transformation occurred in 2% Chinese cases. Among the cases examined, about 18% had mutations in EXT1 and 28% in EXT2. Frameshift, nonsense and missense mutations represented the majority of HME-causing mutations. Diagnosis of HME was made based on the clinical presentations and radiological documentations. Most patients needed no treatment. Surgical treatment was often directed to remove symptomatic exostoses, particularly those of suspected malignancy degeneration, and correction of skeletal deformities. This study shows some variance from current literature regarding other ethnic populations and may provide valuable baseline assessment of the natural history of HME in mainland China.

Clinical characteristics of hereditary multiple exostoses: a retrospective study of mainland chinese cases in recent 23 years / 华中科技大学学报（医学）（英德文版）

Hereditary multiple exostoses (HME) are an autosomal dominant skeletal disease with wide variations in clinical manifestations among different ethnic groups. This study investigated the epidemiology, clinical presentations, pathogenetic features and treatment strategies of HME in mainland China. We searched and reviewed the related cases published since 1990 by searching electronic databases, namely SinoMed database, Wanfang database, CNKI, Web of Science and PubMed as well as Google search engines. A total of 1051 cases of HME (male-to-female ratio 1.5:1) were investigated and the diagnosis was made in 83% before the age of 10 years. Approximately 96% patients had a family history. Long bones, ribs, scapula and pelvis were the frequently affected sites. Most patients were asymptomatic with multiple palpable masses. Common complications included angular deformities, impingement on neighbouring tissues and impaired articular function. Chondrosarcomas transformation occurred in 2% Chinese cases. Among the cases examined, about 18% had mutations in EXT1 and 28% in EXT2. Frameshift, nonsense and missense mutations represented the majority of HME-causing mutations. Diagnosis of HME was made based on the clinical presentations and radiological documentations. Most patients needed no treatment. Surgical treatment was often directed to remove symptomatic exostoses, particularly those of suspected malignancy degeneration, and correction of skeletal deformities. This study shows some variance from current literature regarding other ethnic populations and may provide valuable baseline assessment of the natural history of HME in mainland China.

Effect of NADPH oxidase inhibitor apocynin on the expression of hypoxia-induced factor-1α and endothelin-1 in rat carotid body exposed to chronic intermittent hypoxia / 华中科技大学学报（医学）（英德文版）

The effects of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor apocynin on the enhanced hypoxia induced factor-1α (HIF-1α) and endothelin-1 (ET-1) expression, elevated systolic blood pressure under chronic intermittent hypoxia (CIH) condition and its action mechanism were investigated. Thirty healthy 8-week old Sprague-Dawley (SD) male rats were randomly divided into three groups (n=10 each): sham group, CIH group, and apocynin-treated CIH group. Tail artery systolic blood pressure was measured by tail-cuff method. Real-time fluorescence quantitative polymerase chain reaction (PCR) was used to detect the mRNA expression of HIF-1α and ET-1 in the carotid body, and the HIF-1α protein expression was examined by using Western blotting. The levels of malondialdehyde (MDA) and superoxide dismutase (SOD) were determined by using colorimetric method. In addition, the plasma ET-1 and HIF-1α levels were measured by using enzyme-linked immunosorbent assay. It was found that CIH exposure was associated with increased MDA levels, and apocynin-treated CIH animals showed reduction in MDA levels. Apocynin treatment prevented CIH-induced hypertension as well as CIH-induced decrease in SOD. The increases of HIF-1α and ET-1 mRNA along with HIF-1α protein expression in the carotid body, and elevated circulating HIF-1α and ET-1 levels were observed in CIH-exposed animals. Treatment with apocynin significantly decreased the ET-1 mRNA, HIF-1α protein expression and circulating HIF-1α level in CIH-exposed animals, and there was no statistically significant difference in the HIF-1α mRNA expression between CIH group and apocynin-treated group. These results indicated that apocynin alleviated CIH-induced hypertension by inhibiting NADPH oxidase, further leading to the reduced vasoconstrictor ET-1 level and oxidative stress. HIF-1α/ET-1 system signal pathway may interact with CIH-induced NADPH oxidase-dependent oxidative stress. Inhibition of NADPH oxidase activity may hopefully serve as a useful strategy for prevention and treatment of obstructive sleep apnea hypopnea syndrome-induced hypertension.

Effect of NADPH oxidase inhibitor apocynin on the expression of hypoxia-induced factor-1α and endothelin-1 in rat carotid body exposed to chronic intermittent hypoxia / 华中科技大学学报（医学）（英德文版）

The effects of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor apocynin on the enhanced hypoxia induced factor-1α (HIF-1α) and endothelin-1 (ET-1) expression, elevated systolic blood pressure under chronic intermittent hypoxia (CIH) condition and its action mechanism were investigated. Thirty healthy 8-week old Sprague-Dawley (SD) male rats were randomly divided into three groups (n=10 each): sham group, CIH group, and apocynin-treated CIH group. Tail artery systolic blood pressure was measured by tail-cuff method. Real-time fluorescence quantitative polymerase chain reaction (PCR) was used to detect the mRNA expression of HIF-1α and ET-1 in the carotid body, and the HIF-1α protein expression was examined by using Western blotting. The levels of malondialdehyde (MDA) and superoxide dismutase (SOD) were determined by using colorimetric method. In addition, the plasma ET-1 and HIF-1α levels were measured by using enzyme-linked immunosorbent assay. It was found that CIH exposure was associated with increased MDA levels, and apocynin-treated CIH animals showed reduction in MDA levels. Apocynin treatment prevented CIH-induced hypertension as well as CIH-induced decrease in SOD. The increases of HIF-1α and ET-1 mRNA along with HIF-1α protein expression in the carotid body, and elevated circulating HIF-1α and ET-1 levels were observed in CIH-exposed animals. Treatment with apocynin significantly decreased the ET-1 mRNA, HIF-1α protein expression and circulating HIF-1α level in CIH-exposed animals, and there was no statistically significant difference in the HIF-1α mRNA expression between CIH group and apocynin-treated group. These results indicated that apocynin alleviated CIH-induced hypertension by inhibiting NADPH oxidase, further leading to the reduced vasoconstrictor ET-1 level and oxidative stress. HIF-1α/ET-1 system signal pathway may interact with CIH-induced NADPH oxidase-dependent oxidative stress. Inhibition of NADPH oxidase activity may hopefully serve as a useful strategy for prevention and treatment of obstructive sleep apnea hypopnea syndrome-induced hypertension.

Role of endoplasmic reticular stress in aortic endothelial apoptosis induced by intermittent/persistent hypoxia / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Accumulated evidence shows that hypoxia can induce endothelial apoptosis, however the mechanism is still unknown. We hypothesized whether intermittent or persistent hypoxia could induce endoplasmic reticular stress, leading to endothelial apoptosis.</p><p><b>METHODS</b>Twenty-four 8-week male Sprague Dawley (SD) rats were divided into three groups: normoxia (NC) group, intermittent hypoxia (IH) group and persistent hypoxia (PH) group. TUNEL staining was performed to detect aortic arch endotheliar apoptosis, and immunohistochemistry for BIP, CHOP and caspase12 to test protein expression; human umbilical vein endothelial cells (HUVECs) of the line ECV304 were cultured (with or without taurodeoxycholic acid (TUDCA) 10 mmol/L, 100 mmol/L) and divided into four groups: NC group (20.8% O2 for 4 hours), PH1 group (5% O2 for 4 hours), PH2 group (5% O2 for 12 hours) and IH group (20.8% O2 and 5% O2 alternatively for 8 hours). Annexin V-fluorescein-isothiocyanate/propidium iodide flow cytometry was used to assess apoptosis in each group. The expressions of GRP78, CHOP and caspase12 were detected by real-time quantitative reverse-transcription PCR. Result Intermittent and persistent hypoxia could increase the rate of endothelium apoptosis and the expressions of GRP78, CHOP and caspase12 compared with the control, induction by intermittent hypoxia was slightly higher than persistent hypoxia. In the HUVEC experiment, TUDCA significantly reduced apoptosis and the expressions of GRP78, CHOP and caspase12.</p><p><b>CONCLUSION</b>Hypoxia, especially intermittent, can induce endothelial cell apoptosis possibly through endoplasmic reticulum stress pathway, which can be attenuated by taurodeoxycholic acid.</p>

ERK signaling mediates enhanced angiotensin II-induced rat aortic constriction following chronic intermittent hypoxia / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Obstructive sleep apnea (OSA) has been recognized as an independent risk factor for systemic hypertension. The study investigated the functional consequences of chronic intermittent hypoxia (CIH) on aortic constriction induced by angiotensin II (Ang II) and the possible signaling involving ERK1/2 and contractile proteins such as myosin light chain kinase (MLCK), myosin phosphatase targeting subunit (MYPT1) and myosin light chain (MLC).</p><p><b>METHODS</b>Male Wistar rats were randomly divided into CIH group and normoxia group and exposed to either CIH procedure or air-air cycles. Phosphorylation of ERK1/2, MYPT1 and MLC was assessed by Western blotting following constrictor studies in the presence or absence of PD98059 (10 µmol/L).</p><p><b>RESULTS</b>CIH-exposure resulted in more body weight gain and elevated blood pressure, which could be attenuated by pretreatment with PD98059. Endothelium-removed aortic rings from CIH rats exhibited higher constrictor sensitivity to Ang II (Emax: (138.56 ± 5.78)% versus (98.45±5.31)% of KCl; pD2: 7.98 ± 0.14 versus 8.14 ± 0.05, respectively). CIH procedure exerted complex effects on ERK expressions (total ERK1/2 decreased whereas the ratio of phosphorylated to total ERK1/2 increased). CIH aortas had higher MLCK mRNA and basal phosphorylation of MYPT1 and MLC. In parallel to greater increases in phosphorylation of ERK1/2, MYPT1 and MLC, Ang II-induced aortic constriction was significantly enhanced in CIH rats, which was largely reversed by PD98059. However vascular constriction of normoxia rats remained unchanged despite similar but smaller changing tendency of proteins phosphorylation.</p><p><b>CONCLUSION</b>These data suggest that CIH exposure results in aortic hyperresponsiveness to Ang II, presumably owing to more activated ERK1/2 signaling pathway.</p>

Ang II type 1 receptor expression in rat aorta exposed to chronic intermittent hypoxia: effects of p38MAPK and ERK1/2 signaling / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Obstructive sleep apnea is a frequent medical condition consisting of repetitive sleep-related episodes of upper air ways obstruction and can lead to hypertension. Ang II type 1 receptor (AT1R) played important roles in hypertension since it binds with Ang II, controlling salt-water and blood pressure homeostasis. This study explores rat aorta AT1R expression during intermittent hypoxia (IH) and the signaling pathways involved.</p><p><b>METHODS</b>A rat model and a cell model used a BioSpherix-OxyCycler A84 system and a ProOx C21 system respectively. The arterial blood pressure was recorded by a Nihon Kohden Polygraph System. Immunohistochemic was used to focus and analyze the expression of AT1R in rat aorta. Real-time PCR and Western blotting were used to explore the signaling pathways that participated in AT1R expression.</p><p><b>RESULTS</b>In this study, we found that chronic intermittent hypoxia (CIH) induced AT1R transcription which increased the blood pressure in rat aorta compared to normoxia and to sustained hypoxia. The AT1R protein expression in the aorta was similar to the real-time PCR results. We explored the signaling mechanisms involved in the AT1R induction in both rat aorta and the aortic endothelial cells by real-time PCR and Western blotting. Compared to normoxia, CIH increased ERK1 mRNA transcription but not ERK2 or p38MAPK in the aorta; whereas sustained hypoxia (SH) upregulated ERK2 but not ERK1 or p38MAPK mRNA. In cells, IH induced AT1R expression with ERK1/2 phosphorylation but reduced p38MAPKs phosphorylation, whereas SH induced only ERK1/2 phosphorylation. The ERK1/2 inhibitor PD98059 attenuated the IHinduced AT1R increase but the p38MAPK inhibitor SB203580 did not.</p><p><b>CONCLUSIONS</b>Our results indicate that CIH induced the elevation of rat blood pressure and aorta AT1R expression. Moreover, AT1R expression in IH and sustained hypoxia might be regulated by different signal transduction pathways, highlighting a novel regulatory function through ERK1/2 signaling in IH.</p>

Thioredoxin and impaired spatial learning and memory in the rats exposed to intermittent hypoxia / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Obstructive sleep apnea (OSA) can cause cognitive dysfunction and may be a reversible cause of cognitive loss in patients with Alzheimer's disease (AD). Chronic exposure to intermittent hypoxia (IH), such as encountered in OSA, is marked by neurodegenerative changes in rat brain. We investigated the change of thioredoxin (Trx), spatial learning and memory in rats exposed to chronic intermittent hypoxia (CIH).</p><p><b>METHODS</b>Forty healthy male Sprague-Dawley (SD) rats were randomly divided into four groups of ten each: a CIH+normal saline (CIH+NS group), a N-acetylcystein-treated CIH (CIH+NAC) group, a sham CIH group (sham CIH+NS), and a sham NAC-treated sham CIH (CIH+NAC) group. Spatial learning and memory in each group was assessed with the Morris water maze. Real-time PCR and Western blotting were used to examine mRNA and protein expression of Trx in the hippocampus tissue. The terminal deoxynucleotidyl transferase-mediated dUTP-nick end-labeling (TUNEL) method was used to detect the apoptotic cells of the hippocampus CA1 region.</p><p><b>RESULTS</b>CIH-rats showed impaired spatial learning and memory in the Morris water maze, including longer mean latencies for the target platform, reduced numbers of passes over the previous target platform and a smaller percentage of time spent in the target quadrant. Trx mRNA and protein levels were significantly decreased in the CIH-hippocampus, meanwhile, an elevated apoptotic index revealed apoptosis of hippocampal neurons of rats exposed to CIH. The rats, which acted better in the Morris water maze, showed higher levels of the Trx mRNA and protein in the hippocampus; apoptotic index of the neurons in the hippocampus of each group was negatively correlated with the Trx mRNA and protein levels.</p><p><b>CONCLUSION</b>The Trx deficit likely plays an important role in the impaired spatial learning and memory in the rats exposed to CIH and may work through the apoptosis of neurons in the hippocampus.</p>

Elevated nocturnal and morning blood pressure in patients with obstructive sleep apnea syndrome / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>The nocturnal nondipping and elevated morning blood pressure (BP) in patients with obstructive sleep apnea syndrome (OSAS) have not yet been well investigated in Chinese patients. This study aimed to describe the BP profile, and to elucidate the relationships between daytime BP and nighttime BP, and between evening BP and morning BP in patients with OSAS.</p><p><b>METHODS</b>Twenty teaching hospital sleep centers in China were organized by the Chinese Medical Association to participate in this study and 2297 patients were recruited between January 2004 and April 2006. BP assessments were made at four time points (daytime, evening, nighttime and morning) and polysomnography (PSG) was performed and subjects were classified into four groups by their apnea-hypopnea index (AHI): control, n = 213 with AHI < 5; mild, n = 420 with AHI ≥ 5 and < 15; moderate, n = 460 with AHI ≥ 15 and < 30; and severe, n = 1204 with AHI ≥ 30. SPSS 11.5 software package was used for statistical analysis and figure drawing.</p><p><b>RESULTS</b>All the average daytime, nighttime, evening and morning BPs were positively correlated with AHI and negatively correlated with nadir nocturnal oxygen saturation. The ratios of nighttime/daytime and morning/evening average BP were positively correlated with AHI. The ratio of nighttime/daytime systolic BP became a "reversed BP dipping" pattern until the classification reached severe, while the ratio of nighttime/daytime diastolic BP became reversed at moderate. Similarly, the ratio of morning/evening diastolic BP becomes reversed even at mild.</p><p><b>CONCLUSIONS</b>OSAS may result in higher BP levels at all four time points. The ratios of nighttime/daytime and morning/evening BP increase with increased AHI. The increasing of diastolic BP, which is inclined to rise more quickly, is not parallel with increasing systolic BP.</p>