Pathophysiological Role of K2P Channels in Human Diseases.

The family of two-pore domain potassium (K2P) channels is critically involved in central cellular functions such as ion homeostasis, cell development, and excitability. K2P channels are widely expressed in different human cell types and organs. It is therefore not surprising that aberrant expression and function of K2P channels are related to a spectrum of human diseases, including cancer, autoimmune, CNS, cardiovascular, and urinary tract disorders. Despite homologies in structure, expression, and stimulus, the functional diversity of K2P channels leads to heterogeneous influences on human diseases. The role of individual K2P channels in different disorders depends on expression patterns and modulation in cellular functions. However, an imbalance of potassium homeostasis and action potentials contributes to most disease pathologies. In this review, we provide an overview of current knowledge on the role of K2P channels in human diseases. We look at altered channel expression and function, the potential underlying molecular mechanisms, and prospective research directions in the field of K2P channels.

Activation of AMP-activated protein kinase α1 mediates mislocalization of TDP-43 in amyotrophic lateral sclerosis.

TAR DNA-binding protein-43 (TDP-43) is a nuclear RNA-binding protein involved in many cellular pathways. TDP-43-positive inclusions are a hallmark of amyotrophic lateral sclerosis (ALS). The major clinical presentation of ALS is muscle weakness due to the degeneration of motor neurons. Mislocalization of TDP-43 from the nucleus to the cytoplasm is an early event of ALS. In this study, we demonstrate that cytoplasmic mislocalization of TDP-43 was accompanied by increased activation of AMP-activated protein kinase (AMPK) in motor neurons of ALS patients. The activation of AMPK in a motor neuron cell line (NSC34) or mouse spinal cords induced the mislocalization of TDP-43, recapitulating this characteristic of ALS. Down-regulation of AMPK-α1 or exogenous expression of a dominant-negative AMPK-α1 mutant reduced TDP-43 mislocalization. Suppression of AMPK activity using cAMP-simulating agents rescued the mislocalization of TDP-43 in NSC34 cells and delayed disease progression in TDP-43 transgenic mice. Our findings demonstrate that activation of AMPK-α1 plays a critical role in TDP-43 mislocalization and the development of ALS; thus, AMPK-α1 may be a potential drug target for this devastating disease.

Iron therapy for improving psychomotor development and cognitive function in children under the age of three with iron deficiency anaemia.

BACKGROUND: Iron deficiency and iron deficiency anaemia (IDA) are common in young children. It has been suggested that the lack of iron may have deleterious effects on children's psychomotor development and cognitive function. To evaluate the benefits of iron therapy on psychomotor development and cognitive function in children with IDA, a Cochrane review was carried out in 2001. This is an update of that review. OBJECTIVES: To determine the effects of iron therapy on psychomotor development and cognitive function in iron deficient anaemic children less than three years of age. SEARCH METHODS: We searched the following databases in April 2013: Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, CINAHL, PsycINFO, LILACS, ClinicalTrials.gov and World Health Organization International Clinical Trials Registry Platform (ICTRP). We also searched the reference lists of review articles and reports, and ran citation searches in the Science Citation Index for relevant studies identified by the primary search. We also contacted key authors. SELECTION CRITERIA: Studies were included if children less than three years of age with evidence of IDA were randomly allocated to iron or iron plus vitamin C versus a placebo or vitamin C alone, and assessment of developmental status or cognitive function was carried out using standardised tests by observers blind to treatment allocation. DATA COLLECTION AND ANALYSIS: Two review authors independently screened titles and abstracts retrieved from the searches and assessed full-text copies of all potentially relevant studies against the inclusion criteria. The same review authors independently extracted data and assessed the risk of bias of the eligible studies. Data were analysed separately depending on whether assessments were performed within one month of beginning iron therapy or after one month. MAIN RESULTS: We identified one eligible study in the update search that had not been included in the original review. In total, we included eight trials.Six trials, including 225 children with IDA, examined the effects of iron therapy on measures of psychomotor development and cognitive function within 30 days of commencement of therapy. We could pool data from five trials. The pooled difference in pre- to post-treatment change in Bayley Scale Psychomotor Development Index (PDI) between iron and placebo groups was -1.25 (95% confidence interval (CI) -4.56 to 2.06, P value = 0.65; I(2) = 33% for heterogeneity, random-effects meta-analysis; low quality evidence) and in Bayley Scale Mental Development Index (MDI) was 1.04 (95% CI -1.30 to 3.39, P value = 0.79; I(2) = 31% for heterogeneity, random-effects meta-analysis; low quality evidence).Two studies, including 160 randomised children with IDA, examined the effects of iron therapy on measures of psychomotor development and cognitive function more than 30 days after commencement of therapy. One of the studies reported the mean number of skills gained after two months of iron therapy using the Denver Developmental Screening Test. The intervention group gained 0.8 (95% CI -0.18 to 1.78, P value = 0.11, moderate quality of evidence) more skills on average than the control group. The other study reported that the difference in pre- to post-treatment change in Bayley Scale PDI between iron-treated and placebo groups after four months was 18.40 (95% CI 10.16 to 26.64, P value < 0.0001; moderate quality evidence) and in Bayley Scale MDI was 18.80 (95% CI 10.17 to 27.43, P value < 0.0001; moderate quality evidence). AUTHORS' CONCLUSIONS: There is no convincing evidence that iron treatment of young children with IDA has an effect on psychomotor development or cognitive function within 30 days after commencement of therapy. The effect of longer-term treatment remains unclear. There is an urgent need for further large randomised controlled trials with long-term follow-up.

Medical education: changes and perspectives.

As medical education undergoes significant internationalization, it is important for the medical education community to understand how different countries structure and provide medical education. This article highlights the current landscape of medical education in China, particularly the changes that have taken place in recent years. It also examines policies and offers suggestions about future strategies for medical education in China. Although many of these changes reflect international trends, Chinese medical education has seen unique transformations that reflect its particular culture and history.

Economic evaluation of methadone maintenance treatment in HIV/AIDS control among injecting drug users in Dehong, China.

The purpose of this study was to analyze the cost and cost-effectiveness of methadone maintenance treatment (MMT) program in Dehong prefecture, Yunnan province, China. The cost-effectiveness analysis used process data retrospectively collected from the MMT clinics in Dehong Prefecture, Yunnan Province, from July 2005 to December 2007, a 30-month period available at the time of the study. Alternative estimates of the number of HIV infections prevented were calculated using incidence rate from cohort studies and retrospective studies. Program costs were collected retrospectively following standard methods using an ingredients methodology. The cost for each participant treated in MMT clinics was about $9.1-16.7 per month and the intervention averted 8.4-87.2 HIV infections with a cost-effectiveness of US$ 2509.3-4609.3 per HIV infection averted. This research demonstrates that MMT is a cost-effective intervention for reducing HIV transmission among injecting drug users, but the coverage of MMT intervention should be matched with the designed volume of MMT clinics to make the best use of resources.

Modelling the potential impact of population-wide and targeted high-risk blood pressure-lowering strategies on cardiovascular disease in China.

BACKGROUND: To estimate the impact of population-wide and high-risk blood pressure-lowering strategies on cardiovascular disease (CVD) incidence in China. DESIGN: A modelling study based on a community cohort of 30 362 men and women aged 35-74 years in urban Shanghai, China, 3.3% of whom have existing CVD. METHODS: We modelled three blood pressure-lowering strategies: population-wide salt reduction, or antihypertensive drug treatment (following Chinese guidelines) for two subpopulations with either high blood pressure (>/=150/95 mmHg), or high baseline-predicted CVD risk (>/=10% in 10 years based on a multivariate risk model). Avoidable CVD events were estimated by applying a range of relative risk reductions in CVD, 5-7.5% for population-wide salt reduction and 20-25% for drug treatment derived from meta-analyses. Drug compliance was assumed to be 50%. RESULTS: Population-wide salt reduction would avoid 240-362 events per 100 000 population over 10 years. Drug treatment for the 14.1% of people with raised blood pressure could avoid 217-273 events, whereas treating the 14.2% of people with predicted 10-year CVD risk over 10% would avoid 310-385 events. Of the prevented events, 70-80% would occur in over 60 years and almost a third of the events were predicted to occur among the 3.3% of people with prevalent CVD. CONCLUSION: Population-wide and high-risk blood pressure-lowering strategies would have a similar impact on CVD incidence in urban China. The expected epidemic of CVD could be reduced by highly targeted drug treatment while more sustainable population-wide strategies are put in place.

Social mobilization and social marketing to promote NaFeEDTA-fortified soya sauce in an iron-deficient population through a public-private partnership.

OBJECTIVE: The present pilot project aimed to assess the effectiveness of social mobilization and social marketing in improving knowledge, attitudes and practices (KAP) and Fe status in an Fe-deficient population. DESIGN: In an uncontrolled, before-after, community-based study, social mobilization and social marketing strategies were applied. The main outcomes included KAP and Hb level and were measured at baseline, 1 year later and 2 years later. SETTING: One urban county and two rural counties in Shijiazhuang Municipality, Hebei Province, China. SUBJECTS: Adult women older than 20 years of age and young children aged from 3 to 7 years were selected from three counties to attend the evaluation protocol. RESULTS: After 1 year, most knowledge and attitudes had changed positively towards the prevention and control of anaemia. The percentage of women who had adopted NaFeEDTA-fortified soya sauce increased from 8.9% to 36.6% (P < or = 0.001). After 2 years, Hb levels had increased substantially, by 9.0 g/l (P < or = 0.001) in adult women and 7.7 g/l (P < or = 0.001) in young children. CONCLUSION: Social mobilization and social marketing activities had a positive impact on the KAP of adult women, and resulted in marked improvements in Hb levels in both adult women and young children. This should be recommended as a national preventive strategy to prevent and control Fe deficiency and Fe-deficiency anaemia.

Association between angiotensinogen, angiotensin II receptor genes, and blood pressure response to an angiotensin-converting enzyme inhibitor.

BACKGROUND: To identify the genetic contribution to the variation in blood pressure (BP) response to angiotensin-converting enzyme inhibitors (ACEIs), single-nucleotide polymorphisms (SNPs) in the angiotensinogen (AGT), angiotensin receptor 1 (AGTR1), and angiotensin receptor 2 (AGTR2) genes were evaluated for their association with BP response to ACEI in Chinese patients with hypertension in a 2-stage design. METHODS AND RESULTS: We selected 1447 hypertensive patients from a 3-year benazepril postmarket surveillance trial and genotyped them for 14 SNPs in the AGT, AGTR1, and AGTR2 genes. The AGT rs7079 (C/T) SNP (3'-untranslated region) was significantly associated with the response of diastolic BP to benazepril (diastolic BP response: -7.4 mm Hg for subjects with the CC genotype, -8.9 mm Hg for CA, and -10.1 mm Hg for AA; P=0.001). Although there was no association of individual SNPs in the AGTR1 gene, there was a graded response between common haplotypes and systolic BP reduction in the order of haplotype 2 (H2)/lack of haplotype 3 (non-H3) (-13.6 mm Hg) > non-H2/non-H3 (-10.9 mm Hg) > H3/non-H2 (-6.6 mm Hg) (P=0.004). The total variations in response to ACEI therapy that were explained by the AGT SNP and AGTR1 haplotype groups were 13% for systolic and 9% to 9.6% for diastolic BP, respectively. CONCLUSIONS: AGT SNP rs7079 and AGTR1 haplotypes were associated with BP reduction in response to ACEI therapy in hypertensive Chinese patients. This will be useful in future studies, providing genetic markers to predict the hypertensive response to ACEI therapy.

Effect of sodium iron ethylenediaminetetra-acetate (NaFeEDTA) on haemoglobin and serum ferritin in iron-deficient populations: a systematic review and meta-analysis of randomised and quasi-randomised controlled trials.

We aimed to synthesise evidence to assess the effect and safety of NaFeEDTA on Hb and serum ferritin in Fe-deficient populations. We performed a systematic review, identifying potential studies by searching the electronic databases of Medline, Cochrane Library, Embase, WHO Library and China National Knowledge Infrastructure. We also hand-searched relevant conference proceedings and reference lists. Finally, we contacted experts in the field. The selection criteria included randomised or quasi-randomised controlled trials of NaFeEDTA compared with placebo. Hb, serum ferritin and adverse effects were outcomes of interest. Inclusion decisions, quality assessment and data extraction were performed by two reviewers independently. Seven studies met the inclusion criteria. All included studies assessed the effect of NaFeEDTA on Hb concentration, four studies assessed the effect on serum ferritin concentration, and one study on serum Zn concentration. After the intervention, Hb concentration and serum ferritin concentration were both higher in the NaFeEDTA group compared with the control group. For Hb, data from six studies could be pooled and the pooled estimate (weighted mean difference) was 8.56 (95 % CI 2.21, 14.90) g/l (P = 0.008). For serum ferritin, data from four studies could be pooled and the pooled difference was 1.58 (95 % CI 1.20, 2.09) microg/l (P < 0.001). Subgroup analysis indicated that a lower baseline Hb level was associated with a greater increase in Hb concentration. No significant difference in serum Zn concentration was found. We concluded that NaFeEDTA increased both Hb concentration and serum ferritin concentration substantially in Fe-deficient populations, and could be an effective Fe preparation to combat Fe deficiency.

A genetic epidemiologic study of social support in a Chinese sample.

Accumulated evidence suggests that social support is influenced by genetic and environmental factors. However, there are little data that examine this issue from Asian samples. We reported results from a preliminary study that examined familial effects on social support in a Chinese adult twin sample. We administered a 10-item social support instrument that measures three dimensions of social support (i.e., objective support, subjective support, and utilization of support) developed for the Chinese population. Two hundred forty-two same-sex twin pairs, where both members of the pair completed the personal interview, were included in the final analysis. Structural equation modeling was used to estimate additive genetic (A), shared environmental (C), and nonshared environmental (E) effects on each dimension of social support. Familial factors (A+C) explained 56.63% [95% CI = 45.48-65.72%] and 42.42% [95% CI = 29.93-53.25%] of the total phenotypic variances of subjective support and utilization of support, respectively. For the objective support, genetic effects did not exist, but common environmental effect explained 37.56% [95% CI = 26.17-48.28%] of the total phenotypic variances. Neither gender nor age effects were seen on any dimension of social support. Except for objective support, genetic factors probably influence variation in subjective support and utilization of support. Shared environmental factors may influence all dimensions of social support.

Risk factors for adolescent smoking in urban and rural China: findings from the China seven cities study.

Cigarette smoking is rising among urban Chinese adolescents and poses a significant public health concern. The majority of Chinese youth live in rural areas, but most research on the risk factors for smoking has been conducted in urban areas of China. This study examined the associations between parental smoking, peer smoking, and low refusal self-efficacy and smoking among urban and rural Chinese youth. This analysis used a cross-sectional sample of 3412 ninth grade students in urban and rural areas under the administrative jurisdiction of seven large cities in China. Multilevel logistic regression models were used to associate the risk factors with lifetime and current smoking, separately in boys and girls. Adolescent smoking was not strongly associated with parental smoking. However it was strongly associated with peer smoking and low refusal self-efficacy across both the urban and rural samples. Students with lower refusal self-efficacy were approximately 5-17 times more likely to be lifetime or current smokers than those with higher refusal self-efficacy. Smoking prevention interventions in China may need to focus on raising adolescents' refusal self-efficacy.

mTOR signaling in the nucleus accumbens mediates behavioral sensitization to methamphetamine.

Chronic psychostimulant treatment in rodents readily produces behavioral sensitization, which reflects altered brain function in response to repeated drug exposure. Numerous morphological and biochemical investigations implicate altered neural plasticity in striatal medium spiny neurons (MSNs) as an essential component in behavioral sensitization. The mammalian target of the rapamycin (mTOR) signaling pathway, a key regulator of synaptic neuroplasticity, in the ventral striatum of methamphetamine (METH) -sensitized mice was investigated to determine if a link exists with the development of METH sensitization. Behaviorally, METH-sensitized mice possessed increased levels of phosphorylated mTOR/S2448 and its down-stream regulator p70S6K and pS6 in the ventral striatum. Systemic treatment with rapamycin, a specific mTOR inhibitor, coincident with a daily METH injection suppressed the induction of METH sensitization and reduced the number of dendritic spines in the shell and core of the nucleus accumbens. The infusion of lentivirus-expressing mTOR-shRNA into the shell region of the nucleus accumbens inhibited the induction of behavioral sensitization to METH, which was comparable to the effect of rapamycin. These results suggest that mTORC1-mediated signaling in the nucleus accumbens mediates the development of behavioral sensitization to METH.

Stroke in China: epidemiology, prevention, and management strategies.

In this review, we examine the current status of stroke epidemiology, prevention, and management strategies in mainland China. The main findings suggested that total age-adjusted incidence of first-ever stroke in China is not very different from that in developed countries. Stroke incidence, mortality, and prevalence varied widely among different regions within China, with a noticeable north-south gradient. The proportion of intracerebral haemorrhage was high and reached 55% in one city. Hypertension is the most important risk factor for stroke. The mass approach combined with a high-risk approach for stroke prevention showed encouraging effects, and various unconventional local therapeutic traditions are commonly used to treat stroke in China. Several national guidelines on stroke prevention and treatment have been developed. Because of methodological limitations in the epidemiology studies, data are unreliable in terms of making any firm conclusions. Up-to-date, well-designed, and well-done epidemiological studies and therapeutic trials in China are urgently needed.

Utility of the theory of reasoned action and theory of planned behavior for predicting Chinese adolescent smoking.

One third of smokers worldwide live in China. Identifying predictors of smoking is important for prevention program development. This study explored whether the Theory of Reasoned Action (TRA) and Theory of Planned Behavior (TPB) predict adolescent smoking in China. Data were obtained from 14,434 middle and high school students (48.6% boys, 51.4% girls) in seven geographically varied cities in China. TRA and TPB were tested by multilevel mediation modeling, and compared by multilevel analyses and likelihood ratio tests. Perceived behavioral control was tested as a main effect in TPB and a moderation effect in TRA. The mediation effects of smoking intention were supported in both models (p<0.001). TPB accounted for significantly more variance than TRA (p<0.001). Perceived behavioral control significantly interacted with attitudes and social norms in TRA (p<0.001). Therefore, TRA and TPB are applicable to China to predict adolescent smoking. TPB is superior to TRA for the prediction and TRA can better predict smoking among students with lower than higher perceived behavioral control.

Heritability of cigarette smoking and alcohol use in Chinese male twins: the Qingdao twin registry.

BACKGROUND: China has the world's largest concentration of smokers (350 million) and rising alcohol consumption, yet little is known about tobacco and alcohol use aetiology. In 2000, the Chinese National Twin Registry was established to provide a genetically informative resource for investigation of health behaviour including tobacco and alcohol use. METHODS: Using standard twin methodology, this study aimed to examine the relative contribution of genetic and environmental influences on cigarette smoking and alcohol drinking in a sample of adult Chinese twins (n = 1010 individual twins). More than half of the male twins were smokers (58%), and 32.5% reported alcohol consumption. Among male smokers, 46.4% smoked 20 or more cigarettes per day (heavy smokers) and among drinkers, 32.8% consumed one or more drinks per day. Nearly all female twins were non-smokers (99.2%) and non-drinkers (98.7%); therefore, genetic analysis was limited to male data. RESULTS: In men, current smoking was significantly heritable [75.1%, 95% confidence interval (CI) 56.7-87.5] with no evidence for a significant contribution of shared environmental effects. Heavy smoking was more strongly influenced by genes (66.2%, 95% CI 0-88.4) than shared environment (8.7%, 95% CI 0-71.0). Similarly, current drinking was more strongly influenced by genetic effects (59.5%, 95% CI 0-87.8) than by shared environmental effects (15.3%, 95% CI 0-72.1). Amount of alcohol consumed was influenced to a similar degree by genetic (42.4%, 95% CI 0-91.8) and shared environmental factors (39.2%, 95% CI 0-82.7). CONCLUSIONS: These results support findings from twins of Western origin on the aetiology of tobacco and alcohol use and encourage further work in Chinese twins.

The Qingdao Twin Registry: a focus on chronic disease research.

With the changing patterns of morbidity and mortality in China, noncommunicable chronic diseases have become the major threats to the health of the Chinese population. The causes of chronic diseases include genetic factors and behavioral risk factors such as the use of tobacco, alcohol, and other drugs, unhealthy dietary behaviors, and lack of physical activity. Twin studies offer a unique opportunity to disentangle the genetic and environmental risk and protective factors for chronic disease. The Qingdao Twin Registry (QTR) was initiated in 1998 as part of the National Chinese Twin Registry. Over 11,000 pairs of twins and multiples of all ages have been recruited into the registry. Several studies of physical and mental health are underway. Many of the adult twins have completed health and behavioral risk factor surveys, and the adolescent twins are participating in a study of gene-environment interactions in tobacco and alcohol use. Studies of the heritability of personality factors have been conducted. In 2002, Qingdao established the Qingdao Twin Health Promotion Association, a nonprofit organization that supports health services for twins and their parents, organizes special events and health-related activities for twins, and raises funds to conduct twin health examinations. The QTR will be a useful resource for future studies of population genetics in human health and disease.

Finite time stability of nonlinear impulsive systems and its applications in sampled-data systems.

In this paper, we establish finite time stability (FTS) criteria for the nonlinear impulsive systems. By using a new concept called average impulse interval (AII), less conservative conditions are obtained for the FTS problem on the impulsive systems. Then we consider the linear time-invariant sampled-data systems by modeling such systems as linear impulsive systems. It is proved that when the AII of a sequence of impulsive signals ζ is equal to τα, the upper bound of the impulsive intervals could be very large, while the lower bound of the impulsive intervals could be also small enough. The obtained results are less conservative than the ones in the literature obtained for variable sampling intervals.

Aberrant activation of AMP-activated protein kinase contributes to the abnormal distribution of HuR in amyotrophic lateral sclerosis.

Distorted mRNA metabolism contributes to amyotrophic lateral sclerosis (ALS). The human antigen R (HuR) is a major mRNA stabilizer. We report that abnormal localization of HuR was associated with enhanced AMP-activated protein kinase (AMPK) activity in the motor neurons of ALS patients. Activation of AMPK changed the location of HuR in mouse motor neurons and in a motor neuron cell line via phosphorylation of importin-α1. Stimulation of the A2A adenosine receptor normalized the AMPK-evoked redistribution of HuR. This suggests that aberrant activation of AMPK in motor neurons disrupts the normal distribution of HuR, which might imbalance RNA metabolism and contribute to ALS pathogenesis.