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.

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.

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.

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.

Association between ambient temperature and blood pressure and blood pressure regulators: 1831 hypertensive patients followed up for three years.

Several studies have suggested an association between ambient air temperature and blood pressure. However, this has not been reliably confirmed by longitudinal studies. Also, whether the reaction to temperature stimulation is modified by other factors such as antihypertensive medication is rarely investigated. The present study explores the relationship between ambient temperature and blood pressure, without and with antihypertensive medication, in a study of 1,831 hypertensive patients followed up for three years, in two or four weekly check ups, accumulating 62,452 follow-up records. Both baseline and follow-up blood pressure showed an inverse association with ambient temperature, which explained 32.4% and 65.6% of variation of systolic blood pressure and diastolic blood pressure (P<0.05) respectively. The amplitude of individual blood pressure fluctuation with temperature throughout a year (a 29 degrees centigrade range) was 9.4/7.3 mmHg. Medication with angiotensin converting enzyme inhibitor benazepril attenuated the blood pressure fluctuation by 2.4/1.3 mmHg each year, though the inverse association of temperature and blood pressure remained. Gender, drinking behavior and body mass index were also found to modify the association between temperature and diastolic blood pressure. The results indicate that ambient temperature may negatively regulate blood pressure. Hypertensive patients should monitor and treat blood pressure more carefully in cold days, and it could be especially important for the males, thinner people and drinkers.

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.

Interactions of renin-angiotensin system gene polymorphisms and antihypertensive effect of benazepril in Chinese population.

AIM: Angiotensin-converting enzyme inhibitors are widely used antihypertensive drugs with individual response variation. We studied whether interactions of AGT, AGTR1 and ACE2 gene polymorphisms affect this response. MATERIALS & METHODS: Our study is based on a 3-year field trial with 1831 hypertensive patients prescribed benazepril. Generalized multifactor dimensionality reduction was used to explore interaction models and logistic regressions were used to confirm them. RESULTS: A two-locus model involving the AGT and ACE2 genes was found in males, the sensitive genotypes showed an odds ratio (OR) of 1.9 (95% CI: 1.3-2.8) when compared with nonsensitive genotypes. Two AGT-AGTR1 models were found in females, with an OR of 3.5 (95% CI: 2.0-5.9) and 3.1 (95% CI: 1.8-5.3). CONCLUSION: Gender-specific gene-gene interactions of the AGT, AGTR1 and ACE2 genes were associated with individual variation of response to benazepril. Further studies are needed to confirm this finding.

Health status and epidemiological capacity and prospects: WHO Western Pacific Region.

BACKGROUND: This article on the state of epidemiology in the WHO Western Pacific Region (WPR) is the first in a series of eight articles commissioned by the International Epidemiological Association (IEA) to identify global opportunities to promote the development of epidemiology. METHODS: Global mortality and disease data were used to summarize the burden of mortality, disease, risk factor and patterns of inequalities in the region. Medline bibliometrics were used to estimate epidemiological publication output by country. Key informant surveys, Internet and literature searches and author knowledge and networks were used to elicit perspectives on epidemiological training, research, funding and workforce. Findings The WPR has the lowest age-standardized disability-adjusted life-years (DALY) rate per 1000 of the six WHO regions, with non-communicable disease making the largest percentage contributions in both low- and middle-income countries (LMICs, 68%) and high-income countries (HICs, 84%) in the WPR. The number of Medline-indexed epidemiological research publications per year was greatest for Japan, Australia and China. However, the rate per head of population was greatest for Micronesia and New Zealand. The substantive focus of research roughly equated with burden of disease patterns. Research capacity (staff, funding, infrastructure) varies hugely between countries. Epidemiology training embedded within academic Masters of Public Health programmes is the dominant vehicle for training in most countries. Field epidemiology and in-service training are also common. The Pacific Island countries and territories, because of sparse populations over large distances and chronic workforce and funding capacity problems, rely on outside agencies (e.g. WHO, universities) for provision of training. Cross-national networks and collaborations are increasing. CONCLUSION: Communicable disease surveillance and research need consolidation (especially in eastern Asian WPR countries), and non-communicable disease epidemiological capacity requires strengthening to match disease trends. Capacity and sustainability of both training and research within LMICs in WPR are ongoing priorities. China in particular is advancing quickly. One role for the IEA in building capacity is facilitating collaborative networks within WPR.

Heritability of smoking, alcohol use, and psychological characteristics among adolescent twins in Qingdao, China.

BACKGROUND: Previous studies of genetic and environmental influences on adolescent substance use have been limited to Western samples. METHODS: This study assesses genetic and environmental contributions to cigarette smoking, alcohol use, and psychological variables (depression, anxiety, aggression, hostility) among 602 pairs of adolescent twins, 11 to 19 years old, in Qingdao, China. RESULTS: Heritable influences were more pronounced for alcohol use than cigarette smoking. In univariate analyses, no heritable effects were found for depression or aggression, and modest heritability was found for anxiety. Hostility was relatively more heritable in girls than boys. Bivariate associations between substance use and psychological measures could be attributed to a combination of common genetic and environmental factors. CONCLUSIONS: Among Chinese adolescents, experimentation with tobacco is familial, and experimentation with alcohol is heritable. The genetic and environmental architecture of hostility differs by gender. Consistency of univariate results with Western adolescent samples appears limited to the alcohol use measures.

The China Seven Cities Study (CSCS) consortium: adapting evidence-based prevention science from west to east.

Chronic, noncommunicable diseases (NCDs) have surpassed infectious diseases as the primary cause of death and disability in most developing nations. Nowhere is this more evident than in China where NCDs account for 80% of all deaths and skyrocketing medical costs. Driving the escalation of NCDs are high rates of tobacco use, longer life spans, and changes in the traditional Chinese diet and lifestyle bolstered by unprecedented economic growth and the new global culture. Despite the epidemic of NCDs, few evidence-based interventions either to prevent or retard their progression exist in China. We present a case for the development and adoption of such strategies as effective tools to combat China's greatest health threat. Finally, we offer an example of a collaborative network linking Chinese public health and academic institutions with US researchers to promote the translation of western evidence-based interventions that fully incorporate local knowledge, culture, and capacity.

Cognitive attributions for smoking among adolescents in China.

To design more effective health communication messages for smoking cessation and prevention, it is important to understand people's own perceptions of the factors that influence their decisions to smoke. Studies have examined cognitive attributions for smoking in Western countries but not in the Chinese cultural context. In a study of 14,434 Chinese adolescents, exploratory factor analysis grouped 17 cognitive attributions into 8 factors: curiosity, coping, social image, social belonging, engagement, autonomy, mental enhancement, and weight control. The factors were ranked based on the participants' self-reports of importance and by the strength of their associations with smoking behavior. Among all smokers, curiosity was the most frequently-ranked attribution factor at the early stages of smoking but not for daily smoking. Coping was highly-ranked across smoking stages. Social image and social belonging were more highly-ranked at earlier stages, whereas engagement and mental enhancement were ranked more highly at later stages of smoking. More attributions were associated with smoking among males than among females. This information could be useful for the development of evidence-based anti-smoking programs in China.

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.

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.

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.