The Role of MMP-9 in Regulating Degradation of the Splenic Microvascular Basement Membrane Induced by High Altitude Hypoxia / Rol de la MMP-9 en la Regulación de la Degradación de la Membrana Basal Microvascular Esplénica Inducida por Hipoxia de Altura

SUMMARY: To investigate changes of MMP-9 in the rat spleen and hypoxia-induced microvascular basement membrane under high altitude hypoxia. Thirty male specific pathogen-free Sprague Dawley rats were randomly divided into control and hypoxia groups, with 15 rats in each group. The rats in the control group were placed in Dingxi City, Gansu Province (2080 m above sea level) for 30 days. Rats in the hypoxia group were raised in a hypoxic environment in Maduo County, Qinghai Province (4300 m above sea level), for 30 days to establish a hypoxic rat model. Routine blood tests, MMP-9 mRNA, MMP-9 protein, and the spleen microvascular basement membrane were detected. (1) Compared with the control group, the red blood cell count, hemoglobin, and hematocrit levels of the rats in the hypoxia group were all increased; thus, a hypoxia model was successfully established. (2) Compared with the control group, the expression of MMP-9 mRNA and protein was significantly higher in the spleen of rats in the hypoxic group, and the difference was statistically significant (P <0.05). (3) Compared with the control group, the blood vessel basement membrane in the spleen of the hypoxia group was degraded. Under natural low air pressure and high altitude conditions, the expression of MMP-9 in rat spleen tissue increases and participates in the degradation of the microvascular basement membrane.

El objetivo de este trabajo fue investigar los cambios de la MMP-9 en el bazo de la rata y la membrana basal microvascular inducida bajo hipoxia a gran altura. Treinta ratas macho Sprague Dawley, libres de patógenos específicos, se dividieron aleatoriamente en dos grupos de 15 ratas cada uno, un grupo control y un grupo hipoxia. Durante 30 días las ratas del grupo control estuvieron en la ciudad de Dingxi, provincia de Gansu (2080 m sobre el nivel del mar). Las ratas del grupo de hipoxia se criaron en un entorno hipóxico en el condado de Maduo, provincia de Qinghai (4300 m sobre el nivel del mar), durante 30 días para establecer un modelo de rata hipóxica. Se realizaron análisis de sangre de rutina, ARNm de MMP-9, proteína MMP-9 y de la membrana basal microvascular del bazo. En comparación con el grupo control, el recuento de glóbulos rojos, la hemoglobina y los niveles de hematocrito de las ratas del grupo de hipoxia aumentaron; por lo tanto, se estableció con éxito un modelo de hipoxia. En comparación con el grupo control, la expresión de ARNm y proteína de MMP-9 fue significativamente mayor en el bazo de las ratas del grupo hipóxico, siendo la diferencia estadísticamente significativa (P <0,05). En comparación con el grupo control, la membrana basal de los vasos sanguíneos estaba degradada en el bazo del grupo hipoxia. En condiciones naturales de baja presión atmosférica y gran altitud, la expresión de MMP-9 en el tejido del bazo de la rata aumenta y participa en la degradación de la membrana basal microvascular.

The Healthy Taiwanese Eating Approach is inversely associated with all-cause and cause-specific mortality: A prospective study on the Nutrition and Health Survey in Taiwan, 1993-1996.

BACKGROUND: Few longitudinal studies have investigated the association between foods/dietary pattern and mortality risk in the Asian population. We investigated the prospective association between foods/dietary pattern and risk of death among ethnic Chinese adults in Taiwan. METHODS: The study population included 2475 young and middle-aged adults (aged 18-65 years at baseline) who completed the questionnaires and physical examinations in the Nutrition and Health Survey in Taiwan from 1993 to 1996. A food frequency questionnaire was administered to assess food consumption habits in a face-to-face interview. With survey data linked to the Taiwanese Death Registry, Cox proportional hazard model was used to identify the foods associated with all-cause mortality(followed until 2012), which were then tallied to calculate a dietary pattern score called Taiwanese Eating Approach(TEA) score. The TEA scores were then associated with various kinds of mortality outcomes. In addition, data from 431 elders (aged≥65 yrs) with 288 death endpoints were used to conduct a sensitivity analysis. RESULTS: A total of 385(15.6%) participants died (111 cardiovascular related deaths and 122 cancer related deaths) during the 17.8-year follow-up period(41274 person-years). Twelve foods (9 inverse [vegetables/fish/milk/tea](+1) and 3 positive[fatty meats/fermented vegetables/sweet drinks](-1)) were significantly associated with all-cause mortality risk. All adults were grouped by their cumulative food score into three diet groups: poor diet(29.3% of all subjects), average diet(44.0%), and healthy diet(26.70%). The better the diet, the lower the total, cardiovascular, and other cause mortality outcomes (trend-p < .001). The hazard ratio for the healthy diet was 0.64 (95% confidence interval:0.47-0.87) for total mortality, and 0.52(0.28-0.95) for cardiovascular death, compared with the poor diet in the multivariable models. This phenomenon was also seen in older adults for all-cause, cancer, and other cause mortalities. CONCLUSION: Consuming a healthy Taiwanese Eating Approach (TEA) diet is negatively associated with all-cause, cardiovascular, and other-cause mortalities in Taiwan.

The Role of Autophagy in Cancer Radiotherapy.

BACKGROUND: Autophagy, a pathway for lysosomal-mediated cellular degradation, is a catabolic process that recycles intracellular components to maintain metabolism and survival. It is classified into three major types: macroautophagy, microautophagy, and the chaperone-mediated autophagy (CMA). Autophagy is a dynamic and multistep process that includes four stages: nucleation, elongation, autophagosome formation, and fusion. Interestingly, the influence of autophagy in cancer development is complex and paradoxical, suppressive, or promotive in different contexts. Autophagy in cancer has been demonstrated to serve as both a tumour suppressor and promoter. Radiotherapy is a powerful and common strategy for many different types of cancer and can induce autophagy, which has been shown to modulate sensitivity of cancer to radiotherapy. However, the role of autophagy in radiation treatment is controversial. Some reports showed that the upregulation of autophagy was cytoprotective for cancer cells. Others, in contrast, showed that the induction of autophagy was advantageous. Here, we reviewed recent studies and attempted to discuss the various aspects of autophagy in response to radiotherapy of cancer. Thus, we could decrease the viability of cancer cell and increase the sensibility of cancer cells to radiation, providing a new basis for the application of autophagy in clinical tumor radiotherapy.

Management trajectories in the type 2 diabetes Integrated Delivery System project in Taiwan: accounting for behavioral therapy, nutrition education and therapeutics.

BACKGROUND AND AIM: Glycated hemoglobin (HbA1c) assessment is basic to diabetes management. Little is done to describe the whole spectrum of the trajectory, its related temporal patterns of metabolic indices, and comorbidities. METHODS AND RESULTS: This was a longitudinal study. In the Diabetes Management through Integrated Delivery System project in Taiwan, enrollees had diabetes, but no major comorbidities. They were randomized into intensive or conventional education (health, diet and exercise) groups. HbA1c was classified by a groupbased trajectory model on the basis of repeated six-monthly measurements. We analyzed data from 1091 subjects who had at least two measurements on HbA1c. HbA1c exhibited three distinct ranges of low (42-53 mmol/mol), intermediate (64-75 mmol/mol) and high (97 mmol/mol), all of which persisted for 4.5 years regardless of receiving intensive education or not. Temporal changes and a time-group interaction were found for triglycerides, total cholesterol, HDL-C and LDL-C. The high trajectory was associated with the major co-morbidities of retinopathy, nephropathy, neuropathy, stroke, hypoglycemia, and ketoacidosis. Patients in the intensive education group (62.4%), which were equally distributed in the three trajectories, had significantly lower HbA1cs (-0.14%= -1.5 mmol/mol, p=0.026). The intermediate trajectory patients with intensive education had HbA1cs higher than the low trajectory patients with conventional education (ß=0.189, p=0.033). Though not significant, a similar pattern was found for DM education in the high group (ß=0.223, p=0.154). CONCLUSIONS: Novel strategies beyond current education and pharmacotherapeutic regimens are needed to lower HbA1c at least 11 mmol/mol for the high HbA1c group to minimize comorbidities.

[Types and risk factors of arrhythmia on young patients with acute coronary syndrome in Henan province].

OBJECTIVE: The types and risk factors of arrhythmia were analyzed on acute coronary syndrome (ACS) patients under the age of 44 years who were hospitalized in Henan province between September 2009 to June 2012. METHODS: Medical records of eligible patients were obtained from the information system of the First Affiliated Hospital of Zhengzhou University teleconsultation information center. Middle aged and elderly ACS patients who were hospitalized at the same period served as controls. Data on arrhythmia types, blood pressure, thyroid disease, respiratory sleep apnea syndrome, smoking history, history of alcohol consumption, eating habits, family history of early-onset arrhythmia, laboratory tests were analyzed. RESULTS: (1) Arrhythmia was detected in 110 out of young ACS patients (55%), which was significantly lower than that in the elderly ACS patients (71.05%, P < 0.01). (2) The top three arrhythmias in young ACS patients were: sinus tachycardia (30.50%), the premature ventricular contractions (19.00%), atrial flutter/atrial fibrillation (16.50%). Incidence of sinus tachycardia, atrial flutter/atrial fibrillation were significantly higher while incidence of ventricular tachycardia, ventricular fibrillation, paroxysmal supraventricular tachycardia were significantly lower in young ACS patients than in middle-aged ACS patients (all P < 0.05). The incidence of sinus tachycardia was higher while incidence of ventricular premature accelerated ventricular spontaneous cardiac rhythm, ventricular tachycardia, ventricular fibrillation, non-paroxysmal supraventricular tachycardia, atrial flutter/atrial fibrillation, paroxysmal supraventricular tachycardia, sinus bradycardia, nodal escape, atrioventricular block were significantly lower in young ACS patients than in elderly ACS patients (all P < 0.05). (3) Body mass index, incidence of smoking, coronary three-vessel disease, drinking, eating salty foods, thyroid dysfunction, sleep apnea were significantly higher in youth ACS patients with arrhythmia than in young ACS patients without arrhythmia (all P < 0. 05). (4) Logistic regression analysis found that number of diseased coronary vessels (OR = 24.293), smoking (OR = 1.112) and alcohol consumption (OR = 1.039) were independent risk factor for developing arrhythmia in young ACS patients from Henan province. CONCLUSIONS: The main types of arrhythmia are sinus tachycardia, premature ventricular contractions, atrial flutter/atrial fibrillation and the major risk factors related to the arrhythmia are number of diseased coronary vessels, smoking and alcohol consumption in young ACS patients from Henan province.

[Population characteristics and impact on heart rate variability, heart rate and blood pressure of passive smoking].

OBJECTIVE: To investigate the basic characteristics of passive smoking population, and the impact of passive smoking on heart rate variability, heart rate and blood pressure. METHODS: Eighty-six passive smokers [mean age: (52.4 ± 7.6) years] were recruited from patients and their relatives who visited cardiovascular outpatient department and excluded structural heart disease between June 2010 and June 2012, 80 normal subjects who were not exposed to smoking served as controls. Questionnaire survey, 24 hours ambulatory electrocardiogram examination and blood pressure measurement were performed in all recruited subjects. RESULTS: (1) Non-marriage rate [18.60% (16/86) vs. 3.75% (3/80), P < 0.01] was significantly higher while education level were significantly lower in passive smoking group than in control group. Passive smokers were more likely service industry workers [29.07% (25/86) vs. 15.00% (12/80), P < 0.05] and had longer daily working time [(7.56 ± 1.24) h vs. (6.02 ± 0.96) h, P < 0.01], and were less likely to be professional technology industry employers [20.93% (18/86) vs. 36.25% (29/80), P < 0.05] and managers [13.95% (12/86) vs. 38.75% (31/80), P < 0.01] compared to controls. The main place of passive smoking was workplace (67.44%, 58/86), entertainment venues (63.95%,55/86), restaurants (48.84%, 42/86). (2) Standard of the normal sinus RR intervals (SDNN), the normal consecutive sinus RR interval difference between the root-mean-square (rMSSD) and adjacent the difference between the RR interval>50 ms the number of share the percentage (PNN50) were significantly lower in passive smoking group than in the control group (all P < 0.05). Every 5 min average of the standard deviation of sinus RR cycle (SDNN index) and 24 h every 5 min sinus RR interval mean standard deviation (SDANN) were similar between the 2 groups (all P > 0.05). Ultra-low-frequency power (VLF), low frequency power (LF), high frequency power (HF) and LF/HF were significantly lower in passive smoking group than in the control group (all P < 0.01). (3) Heart rate and diastolic blood pressure were significantly higher in passive smoking group than in control group (all P < 0.05) while systolic blood pressure was similar between the 2 groups (P > 0.05). CONCLUSIONS: Marriage status, education level, profession and daily working time are independent determinants for passive smoking. Passive smoking mainly occurred in the workplace, entertainment venues and restaurants. Passive smoking is linked with reduced heart rate variability, increased 24 h average heart rate and diastolic blood pressure.

[Effect of the smoking cessation services in the out-patient department for patients with coronary heart disease].

OBJECTIVE: To evaluate the effects and clinical prognosis of out-patient department-based smoking cessation services for coronary heart disease (CHD) patients. METHODS: A total of 140 smoking patients diagnosed with coronary heart disease in our cardiovascular department were randomly divided into the intensive smoking cessation clinic follow-up group (intervention group, patients were informed on the importance and methods to quit smoking at the first visit and reminded for that at months interval for 6 months, n = 70) and the conventional treatment group (control group, n = 70). After 6 months, the smoking status, cardiovascular event rates, drug usage, out-patient medical costs and quality of life were compared between the two groups. RESULTS: Age, gender, concomitant diseases, drug usage were similar between the two groups at baseline (all P > 0.05). After 6 months, smoking quit rate [34.2% (24/70) vs. 5.7% (4/70), P < 0.01], drug use rates: lipid-lowering drugs [95.3% (67/70) vs. 80.4% (56/70)], ß blockers [82.4% (57/70) vs. 41.3% (28/70)], and ACEI/ARB [61.4% (43/70) vs. 34.4% (24/70)] were significantly higher in the intervention group than in the control group, while total cardiovascular event rates [21.4% (15/70) vs. 47.1% (33/70), P < 0.01] and out-patient medical costs (3789.3 RMB vs. 4984.2 RMB, P < 0.01) were significantly lower in the intervention group than in the control group. The quality of life scores derived from MYO health survey questionnaire was significantly higher in the intervention group than in the control group (P < 0.01). The top three reasons responsible for continuous smoking for all patients failed to quit smoking were: (1) others smoked more than me and still alive and healthy [90.3% (56/62)]; (2) smoking helped me to keep relaxed and reduce trouble in daily work and life [70.9% (44/62)]; (3) smoking was essential while chatting and drinking with friends [66.1% (41/62)]. The overall satisfactory rate to this smoking cessation program was 42.8% and the satisfactory rate was up to 50.0% by patients. CONCLUSIONS: Intensive outpatient smoking cessation follow-up program can significantly improve the smoking cessation rates, the guideline drug use rate and the quality of life while reduce medical costs for coronary heart disease patients.

Association of clinical symptomatic hypoglycemia with cardiovascular events and total mortality in type 2 diabetes: a nationwide population-based study.

OBJECTIVE: Hypoglycemia is associated with serious health outcomes for patients treated for diabetes. However, the outcome of outpatients with type 2 diabetes who have experienced hypoglycemia episodes is largely unknown. RESEARCH DESIGN AND METHODS: The study population, derived from the National Health Insurance Research Database released by the Taiwan National Health Research Institutes during 1998-2009, comprised 77,611 patients with newly diagnosed type 2 diabetes. We designed a prospective study consisting of randomly selected hypoglycemic type 2 diabetic patients and matched type 2 diabetic patients without hypoglycemia. We investigated the relationships of hypoglycemia with total mortality and cardiovascular events, including stroke, coronary heart disease, cardiovascular diseases, and all-cause hospitalization. RESULTS: There were 1,844 hypoglycemic events (500 inpatients and 1,344 outpatients) among the 77,611 patients. Both mild (outpatient) and severe (inpatient) hypoglycemia cases had a higher percentage of comorbidities, including hypertension, renal diseases, cancer, stroke, and heart disease. In multivariate Cox regression models, including diabetes treatment adjustment, diabetic patients with hypoglycemia had a significantly higher risk of cardiovascular events during clinical treatment periods. After constructing a model adjusted with propensity scores, mild and severe hypoglycemia still demonstrated higher hazard ratios (HRs) for cardiovascular diseases (HR 2.09 [95% CI 1.63-2.67]), all-cause hospitalization (2.51 [2.00-3.16]), and total mortality (2.48 [1.41-4.38]). CONCLUSIONS: Symptomatic hypoglycemia, whether clinically mild or severe, is associated with an increased risk of cardiovascular events, all-cause hospitalization, and all-cause mortality. More attention may be needed for diabetic patients with hypoglycemic episodes.

[The mechanistic rote of KCNH2 gene L413P and L559H mutations in long QT syndrome].

OBJECTIVE: To investigate the molecular pathogenesis for two novel mutations L413P and L559H of KCNH2 found in Chinese patients with long QT syndrome. METHODS: L413P and L559H mutant constructs were generated by site-directed mutagenesis using human wild-type (WT) pcDNA3-HERG cDNA as a template. WT and mutant constructs were transiently transfected into human embryonic kidney 293 cells using lipofectamine method. After transfection, the recording of HERG current was performed using patch clamp technique. The expression and cellular localization of HERG protein were studied with Western blot and immunofluorescence methods. RESULTS: Electrophysiological recordings showed that L413P and L559H mutations did not express HERG current. Western blot analysis revealed that only 135 000 immature HERG protein was expressed in L413P and L559H-transfected cells, whereas both mature and immature forms of HERG protein were observed in WT-transfected cells. Immunofluorescence study showed that L413P and L559H mutant proteins were predominantly localized around the nucleus, suggesting that the mutant channels are retained in the endoplasmic reticulum. When L413P or L559H was co-transfected with equal amount of WT plasmids, both 135 000 and 155 000 forms of HERG protein were observed, and the HERG current was not significantly changed as compared with that of WT transfection alone. Low temperature and E-4031could not rescue these two mutant channels. CONCLUSIONS: The L413P and L559H mutations resulted in protein trafficking defects with failure of mutant proteins to reach the plasma membrane. However, both biochemical and electrophysiological results showed that the mutations did not have a dominant-negative effect on WT, indicating that the mechanism of the L413P and L559H mutations might be haploinsufficiency.

[Novel mutations of potassium channel KCNQ1 S145L and KCNH2 Y475C genes in Chinese pedigrees of long QT syndrome].

OBJECTIVE: Hereditary long QT syndrome (LQTS) is a cardiac disorder characterized by prolongation of QT interval on electrocardiograms (ECGs) and syncope and sudden death caused by a specific multi-polymorphic ventricular tachyarrhythmia known as torsade de pointes. LQTS is caused by mutations in cardiac sodium channel gene SCN5A; potassium channel subunit genes KCNQ1, KCNH2, KCNE1, KCNE2, KCNJ2; calcium channel gene Cav2.1. and ankyrin-B gene ANK2. METHODS: We characterized 77 Chinese LQTS patients with clinical manifestations and mutations in the main LQTS genes, KCNQ1 and KCNH2 using PCR and sequence analysis. RESULTS: The spectrum of ST-T-wave patterns of 24 (31.2%) probands were considered as LQT1, 42 (54.5%) as LQT2 and 3 (3.9%) as LQT3. The remaining 8 (10.3%) could not be characterized. The average age for this population of LQTS patients was (27.6 +/- 16.4) years and the average QTc (561 +/- 70) ms, and the age of the first syncopal attack was (17.6 +/- 14.7) years. The triggering factors for cardiac events happening in these mutation carriers included physical exercise, emotional excitement and auditory irritation. We identified 4 KCNQ1 mutations and 7 KCNH2 mutations. Six of them were first identified with some data already shown. In this paper we showed the data of 6 other mutations. CONCLUSIONS: LQT2 is the most common type of LQTS in Chinese; 2 mutations of KCNQ1 and KCNH2 were first identified in this report; there are some differences between Chinese and North American or European LQTS patients in clinical characters and ECG.

[The characteristics during exercise test in long QT syndrome patients and the effects of left cardiac sympathetic denervation].

OBJECTIVE: To explore the mechanism of the left cardiac sympathetic denervation (LCSD) surgery to reduce the incidence of cardiac events for long QT syndrome (LQTS) patients. METHODS: 12 LQTS patients were selected to do exercise test (ET) to mimic sympathetic activation. The dynamic alterations on ECG during exercise and recovery phases (Rec) were observed and the exercise test characteristics for LQTS patients before and after surgery were summarized and compared. RESULTS: The QTc at resting was shortened from 0.54 s +/- 0.04 s to 0.50 s +/- 0.04 s, P = 0.026, while the maximum heart rate during exercise decreased from 141 beat/min +/- 18 beat/min to 124 beat/min +/- 14 beat/min, P = 0.003. QTc was shortened during exercise, however, it was prolonged during the early recovery phase (before ET 0.54 s +/- 0.02 s, ET 10 min 0.46 s +/- 0.02 s, Rec 4 min 0.55 s +/- 0.03 s); LCSD could reduce such abrupt alteration of QTc during early recovery phase (after surgery: before ET 0.53 s +/- 0.03 s, ET 10 min 0.48 s +/- 0.03 s, Rec 4 min 0.53 s +/- 0.05 s). QT/RR interval slope, representing the adaptation response of QT interval to heart rate, became steeper after exercise (from 0.61 +/- 0.06 to 0.71 +/- 0.07 after exercise, P < 0.01). LCSD made the slopes become less steep both before exercise (from 0.61 +/- 0.06 before surgery to 0.55 +/- 0.07 after surgery, P = 0.013) and after exercise (from 0.71 +/- 0.07 before surgery to 0.66 +/- 0.06 after surgery, P = 0.018). Notched T wave alterations occurred in 7 patients at the end of exercise and/or during early recovery phase before surgery, and LCSD diminished such alteration in 4 patients. CONCLUSION: The slope between QT and RR both the pre-exercise and post-exercise slopes, interval becomes less steep after LCSD, which suggests that exaggerated delay in repolarization with decreasing heart rate for LQTS patients is improved by LCSD. This may be one of the mechanisms of LCSD efficacy for treating LQTS patients. Exercise test is one of tools to evaluate the effect of LCSD on LQTS patients.