Altitude Cardiomyopathy Is Associated With Impaired Stress Electrocardiogram and Increased Circulating Inflammation Makers.

Many sea-level residents suffer from acute mountain sickness (AMS) when first visiting altitudes above 4,000 m. Exercise tolerance also decreases as altitude increases. We observed exercise capacity at sea level and under a simulated hypobaric hypoxia condition (SHHC) to explore whether the response to exercise intensity represented by physiological variables could predict AMS development in young men. Eighty young men from a military academy underwent a standard treadmill exercise test (TET) and biochemical blood test at sea level, SHHC, and 4,000-m altitude, sequentially, between December 2015 and March 2016. Exercise-related variables and 12-lead electrocardiogram parameters were obtained. Exercise intensity and AMS development were investigated. After exposure to high altitude, the count of white blood cells, alkaline phosphatase and serum albumin were increased (P < 0.05). There were no significant differences in exercise time and metabolic equivalents (METs) between SHHC and high-altitude exposures (7.05 ± 1.02 vs. 7.22 ± 0.96 min, P = 0.235; 9.62 ± 1.11 vs. 9.38 ± 1.12, P = 0.126, respectively). However, these variables were relatively higher at sea level (8.03 ± 0.24 min, P < 0.01; 10.05 ± 0.31, P < 0.01, respectively). Thus, subjects displayed an equivalent exercise tolerance upon acute exposure to high altitude and to SHHC. The trends of cardiovascular hemodynamics during exercise under the three different conditions were similar. However, both systolic blood pressure and the rate-pressure product at every TET stage were higher at high altitude and under the SHHC than at sea level. After acute exposure to high altitude, 19 (23.8%) subjects developed AMS. Multivariate logistic regression analysis showed that METs under the SHHC {odds ratio (OR) 0.355 per unit increment [95% confidence intervals (CI) 0.159-0.793], P = 0.011}, diastolic blood pressure (DBP) at rest under SHHC [OR 0.893 per mmHg (95%CI 0.805-0.991), P = 0.030], and recovery DBP 3 min after exercise at sea level [OR 1.179 per mmHg (95%CI 1.043-1.333), P = 0.008] were independently associated with AMS. The predictive model had an area under the receiver operating characteristic curve of 0.886 (95%CI 0.803-0.969, P < 0.001). Thus, young men have similar exercise tolerance in acute exposure to high altitude and to SHHC. Moreover, AMS can be predicted with superior accuracy using characteristics easily obtainable with TET.

Early Warning of Acute Altitude Sickness by Physiological Variables and Noninvasive Cardiovascular Indicators.

Objective To examine if the variations at sea level would be able to predict subsequent susceptibility to acute altitude sickness in subjects upon a rapid ascent to high altitude. Methods One hundred and six Han nationality male individuals were recruited to this research. Dynamic electrocardiogram, treadmill exercise test, echocardiography, routine blood examination and biochemical analysis were performed when subjects at sea level and entering the plateau respectively. Then multiple regression analysis was performed to construct a multiple linear regression equation using the Lake Louise Score as dependent variable to predict the risk factors at sea level related to acute mountain sickness (AMS). Results Approximately 49.05% of the individuals developed AMS. The tricuspid annular plane systolic excursion (22.0±2.66 vs. 23.2±3.19 mm, t=1.998, P=0.048) was significantly lower in the AMS group at sea level, while count of eosinophil [(0.264±0.393)×109/L vs. (0.126±0.084)×109/L, t=-2.040, P=0.045], percentage of differences exceeding 50 ms between adjacent normal number of intervals (PNN50, 9.66%±5.40% vs. 6.98%±5.66%, t=-2.229, P=0.028) and heart rate variability triangle index (57.1±16.1 vs. 50.6±12.7, t=-2.271, P=0.025) were significantly higher. After acute exposure to high altitude, C-reactive protein (0.098±0.103 vs. 0.062±0.045 g/L, t=-2.132, P=0.037), aspartate aminotransferase (19.7±6.72 vs. 17.3±3.95 U/L, t=-2.231, P=0.028) and creatinine (85.1±12.9 vs. 77.7±11.2 mmol/L, t=-3.162, P=0.002) were significantly higher in the AMS group, while alkaline phosphatase (71.7±18.2 vs. 80.6±20.2 U/L, t=2.389, P=0.019), standard deviation of normal-to-normal RR intervals (126.5±35.9 vs. 143.3±36.4 ms, t=2.320, P=0.022), ejection time (276.9±50.8 vs. 313.8±48.9 ms, t=3.641, P=0.001) and heart rate variability triangle index (37.1±12.9 vs. 41.9±11.1, t=2.020, P=0.047) were significantly lower. Using the Lake Louise Score as the dependent variable, prediction equation were established to estimate AMS: Lake Louise Score=3.783+0.281×eosinophil-0.219×alkaline phosphatase+0.032×PNN50. Conclusions We elucidated the differences of physiological variables as well as noninvasive cardiovascular indicators for subjects after high altitude exposure compared with those at sea level. We also created an acute high altitude reaction early warning equation based on the physiological variables and noninvasive cardiovascular indicators at sea level.

Crystallographic insights into diamond-shaped 7M martensite in Ni-Mn-Ga ferromagnetic shape-memory alloys.

For Heusler-type Ni-Mn-Ga ferromagnetic shape-memory alloys, the configuration of the martensite variants is a decisive factor in achieving a large magnetic shape-memory effect through field-induced variant reorientation. Based upon the spatially resolved electron backscatter diffraction technique, the microstructural evolution associated with the martensitic transformation from austenite to seven-layered modulated (7M) martensite was investigated on a polycrystalline Ni53Mn22Ga25 alloy. It was clearly shown that grain interior nucleation led to the formation of diamond-shaped 7M martensite within the parent austenite matrix. This diamond microstructure underwent further growth through an isotropic expansion with the coordinated outward movement of four side habit planes, followed by an anisotropic elongation with the forward extension of a type-I twin pair. A two-step growth model is proposed to describe the specific morphology and crystallography of 7M martensite. In addition, the habit planes were revealed to possess a stepped structure, with the {1 0 1}A plane as the terrace and the {0 1 0}A plane as the step. The characteristic combination of martensite variants and the underlying mechanism of self-accommodation in the martensitic transformation have been analysed in terms of the minimum total transformation strain, where the deformation gradient matrix was constructed according to the experimentally determined orientation relationship between the two phases. The present results may deepen the understanding of special martensite microstructures during the martensitic transformation in ferromagnetic shape-memory alloys.

Physiological Variables Associated with the Development of Acute Mountain Sickness.

Objective To identify the physiological variables associated with the development of acute mountain sickness (AMS).Methods Eighty four young Chinese men residing at low altitude were taken to an altitude of 4000 m within 40 hours. At sea level and at high altitude, we measured the heart rate, blood pressure, and peripheral oxygen saturation (SpO2) respectively. We also collect blood samples from each participants before and after the altitude elevation. The blood routine and biochemical examinations were performed for all blood samples. The revised Lake Louise Criteria was adopted to diagnose AMS after the subjects arrived at the target high altitude. The association between the presence of AMS and subjects' physiological variables were analysed statistically.Results Of 84 participants, 34 (40.5%) developed AMS. Compared with non AMS group, in the AMS group, the percentage of neutrophils was significantly higher (64.5%±11.2% vs. 58.1%±8.8%, P =0.014), while the level of SpO2 was significantly lower (79.4%±5.4% vs. 82.7%±5.6, P=0.008). Binary logistic regression analyses emphasized the association of neutrophils (OR: 1.06, 95% CI: 1.01-1.12, P=0.034) and SpO2 level (OR: 0.87, 95% CI : 0.79-0.95, P=0.004) with the development of AMS.Conclusion The ability to sustain SpO2 after altitude elevation and the increase of neutrophils were associated with the development of AMS in young males.

Clinical, Laboratory and Imaging Features of High Altitude Pulmonary Edema in Tibetan Plateau.

Objective To analyze characteristics of high altitude pulmonary edema (HAPE) in Chinese patients.Methods We performed a retrospective study of 98 patients with HAPE. We reviewed the medical records and summarized the clinical, laboratory and imaging characteristics of these cases, and compared the results on admission with those determined before discharge.Results Forty-eight (49.0%) patients developed HAPE at the altitude of 2800 m to 3000 m. Ninty-five (96.9%) patients were man. Moist rales were audible from the both lungs, and moist rales over the right lung were clearer than those over the left lung in fourteen patients. The white blood cells [(12.83±5.55) versus (8.95±3.23) ×10 9/L, P=0.001)] as well as neutrophil counts [(11.34±3.81) versus (7.49±2.83)×10 9/L, P=0.001)] were higher, whereas the counts of other subsets of white blood cells were lower on admission than those after recovery (all P<0.05). Serum levels of alkaline phosphatase (115.8±37.6 versus 85.7±32.4 mmol/L, P=0.020), cholinesterase (7226.2±1631.8 versus 6285.3±1693.3 mmol/L, P=0.040), creatinine (85.2±17.1 versus75.1±12.8 mmol/L, P=0.021), uric acid (401.9±114.2 versus 326.0±154.3 mmol/L, P=0.041), and uric glucose (7.20±1.10 versus 5.51±1.11 mmol/L, P=0.001) were higher, but carbondioxide combining power (CO2CP, 26.7±4.4 versus 28.9±4.5 mmol/L, P=0.042) and serous calcium (2.32±0.13 versus 2.41±0.10 mmol/L, P=0.006) were lower on admission. Arterial blood gas results showed hypoxemia and respiratory alkalosis on admission. Conclusions In the present research, men were more susceptible to HAPE than women, and in the process of HAPE, the lesions of the right lung were more serious than those of the left lung. Some indicators of routine blood test and blood biochemistry of HAPE patients changed.

[Effects of pioglitazone on TGFbeta1 expression in ischemia/reperfusion injury myocardium of rats].

OBJECTIVE: To investigate the effects of pioglitazone on transforming growth factor beta1 (TGFbeta1) expression in ischemia/reperfusion injury myocardium of rats. METHODS: Thirty SD rats were randomly divided into five groups (n = 6): ischemia/reperfusion group, pioglitazone 5 mg/(kg x d) group, pioglitazone 10 mg/(kg x d) group, pioglitazone 20 mg/(kg x d) group and pioglitazone 20 mg/(kg x d) + peroxisome proliferator-activated receptor gamma (PPARgamma) specific antagonist GW9662 group. Left anterior descending coronary artery of rats were ligated for 30 min and reperfused for 120 min to establish the model of ischemia/reperfusion in vivo. RT-PCR was performed to detect the expression of TGFbeta1 mRNA. Western blot was performed to detect the expression of TGFbeta1 protein. RESULTS: Myocardial apoptosis was significantly suppressed by pioglitazone. Pioglitazone upregulated TGFPbeta1 expression both in mRNA and protein level. GW9662 reversed the inhibition of myocardial apoptosis and the upregulation of TGFbeta1 expression by pioglitazone. CONCLUSION: Pioglitazone can inhibit the myocardial apoptosis induced by ischemia/reperfusion. Pioglitazone may protect the myocardium from ischemia/reperfusion via upregulation of TGFbeta1. This protection may be mediated by PPARgamma.

Mutational analysis of KCNJ11 in Chinese elderly essential hypertensive patients.

OBJECTIVE: To compare the distribution of KCNJ11 polymorphisms between elderly Chinese population with and without hypertension. METHODS: We examined the mutation of KCNJ11 gene by directly sequencing. Data for the present study were obtained from 250 hypertensive subjects (60 to 83 years old) as well as 250 normotensive subjects (60 to 86 years old). RESULTS: We found nine different mutations in KCNJ11, including six novel mutations (I131M, L147I, L147V, L147L, Q235H, G245C). None of the novel mutations were found in the normotensive subjects, and all the residues were conserved in other species. These sequence variants in Chinese population indicate the diversity of the human library and the complexity of hypertension. CONCLUSIONS: The consistent finding of our present study provided a basis for the development of new strategies to diagnosis and treat hypertension in the elderly.

[Mitochondrial tRNAMet mutation in Chinese Han essential hypertensive individuals].

The objective of the present study was to explore the relationship between mitochondrial tRNAMet mutation and development of essential hypertension in Chinese Han individuals. A total of 990 patients with essential hypertension were involved. The general data (sex, age, body mass index, onset age, and family history) and information on routine blood test, blood biochemical examination, and color Doppler echocardiography of these patients were collected. All subjects under-went venous blood drawing for seperating white blood cells and DNA extraction. Then, mitochondrial tRNAMet was amplified and sequenced after purification. The patients who carried the tRNAMet mutation were taken as the indicative cases and the controls were the patients with essential hypertension who did not carry the mutation. We performed a comparative analysis on the routine blood test, blood biochemical examination, color Doppler echocardiography, and other data between the indicative cases and control cases. Among the 990 essential hypertensive patients, there were 8 who carried the tRNAMet mutation, and 6 mutation sites were confirmed, including A4401G, C4410A, U4418C, A4435G, U4454C, and C4456U. Compared with the control cases, the indicative cases developed essential hypertension at earlier ages. The average levels of high density of lipoprotein cholesterol, left ventricular end diastolic diameter, stroke volume, and cardiac index were higher in the indicative cases than in the controls. While the average levels of hemoglobin and left ventricular ejection fraction were lower in the indicative cases than in the control cases. Among the 8 indicative cases, 5 had maternally inherited hyper-tension; one had paternally inherited hypertension; and two denied any family history of hypertension. These results indicated that the mitochondrial tRNAMet mutations might induce the changes in structure and function, which was involved in the progress of the essential hypertension by disturbing the blood metabolism, the steady-state of the blood cells, and the cardiac structure and function.

[Cathepsin B promoted the apoptosis of vascular smooth muscle cells as induced by tumor necrosis factor-α].

OBJECTIVE: To establish the cathepsin B over-expression group and cathepsin B gene-silencing group so as to investigate whether cathepsin B was capable of promoting the apoptosis of VSMC (vascular smooth muscle cell) induced by TNF-α/act D. METHODS: Human aortic smooth muscle cell (HA-VSMC) was transfected with pcDNA3.1-cathepsin B and pSilencer2.1-cathepsin B plasmids by lipofection to establish the over-expression and gene-silencing groups. Through TNF-α induced apoptosis, the cell viability was observed by MTT assay, morphological observation and assays of apoptotic proteins as indicators of apoptosis. RESULTS: The cathepsin B over-expression and gene-silencing group were successfully established. MTT assay showed no significant difference between the transfected cell and blank control. After the intervention of TNF-α, the HA-VSMC viability decreased significantly. As compared with control group, the over-expression group significantly decreased (9.98% ± 1.04% vs 14.60% ± 1.34%). As compared with the over-expression group, the E64d and CA-074ME groups (18.23% ± 1.05%, 17.40% ± 1.03%) increased significantly while the silent group (21.30% ± 2.37%) significantly increased. The analysis of acridine orange/ethidium bromide staining showed similar results. Western blot showed the Bcl-2 protein were significantly higher in the silent group than that in the control group. And the over-expression group was significantly lower than the control group. The E64d and CA-074ME groups were significantly higher than that in the over-expression group. But the Bax protein level had no significant difference among all groups. CONCLUSION: The over-expression of cathepsin B promotes TNF-α-induced VSMC apoptosis while Cathepsin B gene silencing and the addition of cathepsin inhibitor in over-expression group inhibit the TNF-α induced VSMC apoptosis.

Dexamethasone enhances cell resistance to chemotherapy by increasing adhesion to extracellular matrix in human ovarian cancer cells.

Glucocorticoids (GCs) are widely used as co-medication in the therapy of solid malignant tumors to relieve some of the side effects of chemotherapeutic drugs. However, recent studies have shown that GCs could render cancer cells more resistant to cytotoxic drug-induced apoptosis, but the mechanism is largely unknown. In the present study, we found that the treatment of human ovarian cancer cell lines HO-8910 and SKOV3 with synthetic GCs dexamethasone (Dex) significantly increased their adhesion to extracellular matrix (ECM) and their resistance to apoptosis induced by cytotoxic drugs cisplatin and paclitaxel. Dex also increased the protein levels of adhesion molecules integrins beta1, alpha 4, and alpha 5 in HO-8910 cells. The neutralizing antibody against integrin beta1 prevented Dex-induced adhesion and significantly abrogated the protective effect of Dex toward cytotoxic agents. We further found that transforming growth factor-beta1 (TGF-beta1) alone not only increased cell adhesion and cell survival of HO-8910 cells in the presence of cisplatin, but also had synergistic pro-adhesion and pro-survival effects with Dex. Moreover, TGF-beta1-neutralizing antibody that could block TGF-beta1-induced cell adhesion and apoptosis resistance markedly abrogated the synergistic pro-adhesion and pro-survival effects of Dex and TGF-beta1. Finally, we further demonstrated that Dex could up-regulate the expression of TGF-beta receptor type II and enhance the responsiveness of cells to TGF-beta1. In conclusion, our results indicate that increased adhesion to ECM through the enhancement of integrin beta1 signaling and TGF-beta1 signaling plays an important role in chemoresistance induced by GCs in ovarian cancer cells.

[Testosterone therapy improves cardiac function of male rats with right heart failure].

OBJECTIVE: Clinical studies have shown decreased levels of sexual hormones, particularly testosterone deficiency, in men with chronic heart failure (CHF). The authors aimed to investigate the effect of testosterone on cardiac function and the possible mechanism of androgen protecting the heart in male rats. METHODS: Forty-three male SD rats were randomly divided into 3 groups: right heart failure (RHF, n = 15), physiologic testosterone treatment (TT, n = 15) and control (n = 13). The RHF group was given intraperitoneal injection of monocrotaline at 60 mg/kg to make RHF models; the TT group was injected with testosterone at 5 mg/kg 3 days after monocrotaline administration; and the control group received equal volume of saline. The CD34+ cells in the peripheral blood of each rat were counted by flow cytometry. The levels of serum testosterone and tumor necrosis factor alpha (TNF-alpha) were measured by chemiluminescence immunoassay and enzyme linked immunosorbent assay, respectively. The hearts, lungs and livers of all the surviving rats were excised at 6 weeks for pathological and immunohistochemical examinations. RESULTS: The level of serum testosterone was gradually decreased, while that of TNF-alpha obviously increased in the RHF group. After testosterone treatment, the TT group showed a remarkable improvement of cardiac performance and a significant decrease in the level of serum TNF-alpha as compared with the RHF group. Statistically significant differences were observed neither in the CD34+ cell count in the peripheral blood nor in the CD34+ expression of the myocardial cells between the TT and RHF groups. CONCLUSION: Physiological supplementation of testosterone can improve the cardiac function of RHF male rats, probably through its inhibition of TNF-alpha rather than by autologous mobilization of bone marrow stem cells.

Up-regulation of RhoB by glucocorticoids and its effects on the cell proliferation and NF-kappaB transcriptional activity.

Although there is ample evidence that glucocorticoids (GCs) have an antiproliferative effect on many cell types, the molecular mechanism remains elusive. We reported in our previous study that Dex treatment led to cell growth arrest in a human ovarian cancer cell HO-8910. RhoB, as a member of Rho GTPases, have been implicated to be a negative regulator of cell proliferation. In this study, we provided novel evidence that Dex induced the expressions of small GTPase RhoB mRNA and protein, but not RhoA and RhoC mRNA in a dose- and time-dependent fashion via glucocorticoid receptor (GR). Over-expression of RhoB increased while inhibition of RhoB expression by RNA interference reversed Dex-induced growth arrest, indicating that RhoB signaling is involved in Dex-induced proliferation inhibition. We also presented the novel observation that over-expression or activation of RhoB signaling elevated the basal transcriptional activity of the transcription factor NF-kappaB in HO-8910 cells. Furthermore, elevating RhoB signaling enhanced the inhibitory effect of Dex on NF-kappaB activity, while attenuating RhoB signaling almost abrogated Dex suppression of NF-kappaB signaling, indicating that RhoB pathway is involved in the regulation of NF-kappaB activity and is essential for Dex transcriptional repression on NF-kappaB signaling in HO-8910 cells.

Effects of pharmacological concentrations of estrogens on growth of 3AO human ovarian cancer cells.

During the past two decades, the knowledge of the molecular mechanism by which estrogens exert various functions in different tissues and organs has evolved rapidly. Recent reports demonstrated that estrogen could decrease the cell growth in several types of cancer cells, including ovarian cancer cells. Though experiments explored the possible mechanism of the inhibitory effect, the exact mechanism is responsible for the effect, which remains unclear. The ovary is the main source of the estrogen, estrogen receptor is expressed in several ovarian cell types, including ovarian surface epithelium, the tissue of origin of approximately 90% of the ovarian cancers. It was of great interest to analyze the effects of 17beta-estradiol (E2) on apoptosis of ovarian cancer cells, and the identification of E2-regulated specific genes involved in epithelial proliferation apoptosis, thus may be a clue for understanding the progression of ovarian cancer and for the design of new target therapies. To elucidate the mechanism involved, effects of pharmacological concentrations of estrogen were studied in human ovarian cancer cell line 3AO cells. Inhibition of cellular growth of 3AO cells was seen with E2 at concentrations higher than 0.1 micromol/L. The estrogen receptor inhibitor ICI 182780 cannot block the inhibitory effect of E2. It was surprising to find that ICI 182780 itself can inhibit the growth of 3AO cells, and had a collaborative effect with E2. The decreased cell growth induced by E2 was shown to be apoptosis as analyzed by flow cytometry. ERbeta was detected in the 3AO ovarian cancer cell line but not ERalpha. The expression of ERbeta was weak, which may partially explain why high but not low dose of E2 needed to induce the apoptosis of 3AO cells. We also observed that membrane impermeable E2, E2-BSA have lost growth inhibitory on 3AO cells, which excluded the membrane effect of E2 as previously reported by many investigators. The p38 kinase inhibitor, SB203580 were partially protected 3AO cells against growth inhibition by E2, while inhibitor of JNK, SP600125 enhanced cell death induced by E2. These results showed that MAPK is implicated in cellular processes involving apoptosis.

[Mechanism of inhibiting proliferation of human ovarian cancer cells of the line HO-8910 by dexamethasone: the role of RhoB signaling pathway].

OBJECTIVE: To observe the effect of dexamethasone (Dex) on the proliferation of human ovarian cancer cells of the line HO-8910, and explore the role of RhoB signaling pathway in this process. METHODS: Human ovarian cancer cells of the line HO-8910he were cultured in culture fluids with or without different concentrations of Dex. The cell growth levels in anchor-dependent and anchor-independent manner were detected by MTT and soft agar assay. Another HO-8910 cells were inoculated in gel with different concentrations of Dex. HO-8910 was transfected with the eukaryotic expression plasmid RhoB-wt, blank plasmids pcDNA3 and RhoB-RNAi, and then the mRNA expression of RhoB, a small GTPase gene, was examined by semi-quantitative RT-PCR. and the protein expressions of RhoB, p-Akt, and p21(cip1/waf1) and p27, both cyclin kinase inhibitors (CDIs), were detected by Western blotting. HO-8910 cells were co-transfected with the reporter gene p21-luc containing p21 promoter and marker reporter gene pRL-tk-luc, then treated with Dex for 24 h. Western blotting was used to detect the transcription of p21(cip1/waf1) gene. RESULTS: The RhoB mRNA expression was significantly increased 2 hours after the treatment of 100 nM Dex, and peaked 4 hours later as high as 2.5 times that of the control group. Western blotting showed that the RhoB protein expression increased along the increase of the Des concentration. The protein expression of RhoB in the HO-8910 cells transfected with RhoB-wt was 2.02 times that in the HO-8910 cells transfected with blank plasmid, and the protein expression of RhoB in the HO-8910 cells transfected with RhoB-RNAi was 36% of that of the blank plasmid group (P < 0.01). The HO-8910 cell proliferation of the RhoB-RNA1 group was not significantly different from that of the control group, however, the proliferation of the HO-8910 cell treated by 100 nM Dex for 6 days was significantly inhibited with an inhibition rate of 13% (P < 0.01). Western blotting showed that Dex down-regulated the p-Akt protein expression. Dex time and dose-dependently up-regulated the protein expression of p21(cip1/waf1) and p27. The HO-8910 cells co-transfected with p21-luc and pRL-tk-luc and then treated with Dex for 24 h showed an higher p21-luc activity, 1.72 times that of the control group (P < 0.05). CONCLUSION: The mechanism of inhibiting the proliferation by Dex in ovarian cancer cells may involve the depression of PI3K/p-Akt, and then up-regulation of RhoB and its downstream signal molecules p21(cip1/waf1) and p27 proteins.