Inference for the initial stage of domain shuffling: tracing the evolutionary fate of the PIPSL retrogene in hominoids.

Domain shuffling has provided extraordinarily diverse functions to proteins. Nevertheless, how newly combined domains are coordinated to create novel functions remains a fundamental question of genetic and phenotypic evolution. Previously, we reported a unique mechanism of gene creation, whereby new combinations of functional domains are assembled from distinct genes at the RNA level, reverse transcribed, and integrated into the genome by the L1 retrotransposon. The novel gene PIPSL, created by the fusion of phosphatidylinositol-4-phosphate 5-kinase (PIP5K1A) and 26S proteasome subunit (S5a/PSMD4) genes, is specifically transcribed in human and chimpanzee testes. We present the first evidence for the translation of PIPSL in humans. The human PIPSL locus showed a low nucleotide diversity within 11 populations (125 individuals) compared with other genomic regions such as introns and overall chromosomes. It was equivalent to the average for coding sequences or exons from other genes, suggesting that human PIPSL has some function and is conserved among modern populations. Two linked amino acid-altering single-nucleotide polymorphisms were found in the PIPSL kinase domain of non-African populations. They are positioned in the vicinity of the substrate-binding cavity of the parental PIP5K1A protein and change the charge of both residues. The relatively rapid expansion of this haplotype might indicate a selective advantage for it in modern humans. We determined the evolutionary fate of PIPSL domains created by domain shuffling. During hominoid diversification, the S5a-derived domain was retained in all lineages, whereas the ubiquitin-interacting motif (UIM) 1 in the domain experienced critical amino acid replacements at an early stage, being conserved under subsequent high levels of nonsynonymous substitutions to UIM2 and other domains, suggesting that adaptive evolution diversified these functional compartments. Conversely, the PIP5K1A-derived domain is degenerated in gibbons and gorillas. These observations provide a possible scheme of domain shuffling in which the combined parental domains are not tightly linked in the novel chimeric protein, allowing for changes in their functional roles, leading to their fine-tuning. Selective pressure toward a novel function initially acted on one domain, whereas the other experienced a nearly neutral state. Over time, the latter also gained a new function or was degenerated.

Access to a health facility and care-seeking for danger signs in children: before and after a community-based intervention in Lusaka, Zambia.

OBJECTIVE: To assess the association of accessibility to a health facility with caregivers' care-seeking practices for children with danger signs before and after community-based intervention in Lusaka, Zambia. METHOD: Health education on childhood danger signs was started in September 2003 at the monthly Growth Monitoring Program Plus (GMP+) service through various channels of health talk and one-on-one communication in a peri-urban area of Lusaka. Two repeated surveys were conducted: in 2003 to collect baseline data before the intervention and in 2006 for 3-year follow-up data. Caregivers who had perceived one or more danger signs in their children within 2 months of the surveys were eligible for the analysis. The association between appropriate and timely care-seeking practices and socio-demographic and socio-economic factors, attendance at community-based intervention and the distance to a health facility was examined with logistic regression analysis. RESULTS: The percentage of caregivers immediately seeking care from health professionals increased from 56.1% (106/189) at baseline to 65.8% (148/225) at follow-up 3 years later (OR = 1.51, P < 0.05). Long distance to the health facility and low-household income negatively influenced caregivers' appropriate and timely care-seeking practices at baseline, but 3 years later, after the implementation of a community-based intervention, distance and household income were not significantly related to caregivers' care-seeking practices. CONCLUSION: Poor accessibility to health facilities was a significant barrier to care-seeking in a peri-urban area. However, when caregivers are properly educated about danger signs and appropriate responses through community-based intervention, this barrier can be overcome through behavioural change in caregivers.

Improvement in mothers' immediate care-seeking behaviors for children's danger signs through a community-based intervention in Lusaka, Zambia.

The large number of child deaths in developing countries is associated with delays in care-seeking by families, but the community-based efforts of the Integrated Management of Childhood Illnesses developed by WHO/UNICEF has remained ineffectual. To improve caregivers' ability to recognise potentially life-threatening symptoms of major childhood illnesses, we provided education about the importance of danger signs and immediate care-seeking practices through a community-based intervention of 'the Growth Monitoring Programme Plus (GMP+)' in low-income areas of Lusaka, Zambia. Using repeated cross-sectional data from interviews, we compared attendance and non-attendance groups to assess the impacts of intervention on mothers' care-seeking. Of 1717 and 1546 attendance mothers in the baseline and the final survey, 1097 and 1035, respectively, sought care from a health centre after perceiving the danger signs. The proportion of mothers with immediate response increased from 35.7% (392/1097) to 51.5% (533/1035) (p < 0.01). In the final survey, the attendance mothers became more likely to respond immediately to the danger signs than the non-attendance mothers (adjusted odds ratio: 2.140, 95% confidence interval: [1.408-3.252]), and the higher educational level the attendance mothers had, the more likely they were to respond immediately to the danger signs (primary level: 2.067 [1.050-4.068], secondary level and above: 2.174 [1.098-4.306]). In conclusion, GMP+ with danger sign education can improve mothers' care-seeking for severely sick children. Therefore, GMP+ has the potential to reduce child death in developing countries, i.e., contribute to the Millennium Development Goal 4 aiming at reducing child mortality by two-thirds by 2015.

Effects of exercise in overweight Japanese with multiple cardiovascular risk factors.

PURPOSE: The effects of exercise in subjects with multiple cardiovascular risk factors (RF) have never been tested in a large-scale randomized controlled trial. The favorable results from our observational study led to this randomized controlled trial. METHODS: The participants, recruited from a community, were overweight, with two of the following three risk factors: hypertension, hyperlipidemia, or glucose intolerance (N=561; 44% male; mean age (SD) 67 (6); mean BMI 26.4 (2.0)). All participants received a standard health exam with counseling, followed by randomization. The intervention group (INT) was to exercise two to four times per week for 6 months at a fitness club. RESULTS: Dropout rate was 11% for INT and 10% for the controls. INT exercised an average of 2.6 times per week. Among primary outcome measures, there was a marginally significant between-group difference in changes in systolic blood pressure (intervention minus control, -2.46 mm Hg). Reductions in LDL cholesterol (-1.9 mg.dL) and hemoglobin A1c (-0.042%) were not significant. Among secondary outcomes, between-group differences were significantly greater (P<0.05) for INT in mean body weight (-1.60 kg), waist circumference (-1.8 cm), triglyceride (-7 mg.dL), hsCRP (-0.063 mg.L), and estimated VO2peak (2.0 mL.kg.min). All directional mean RF changes consistently favored INT. A cardiovascular risk reduction estimated from the changes in RF was about 24%. A greater improvement was also found in health-related quality-of-life measures (SF-36) in INT. No difference was found in the adverse event rate. CONCLUSIONS: Exercising an average of 2.6 times per week for 6 months produced a significant improvement in cardiovascular risk profile in subjects with multiple cardiovascular risk factors through cumulative results of modest yet pervasive changes in all conventional risk factors, without increased adverse effects.

The impact of community-based outreach immunisation services on immunisation coverage with GIS network accessibility analysis in peri-urban areas, Zambia.

BACKGROUND: Accessibility to health services is a critical determinant for health outcome. OBJECTIVES: To examine the association between immunisation coverage and distance to an immunisation service as well as socio-demographic and economic factors before and after the introduction of outreach immunisation services, and to identify optimal locations for outreach immunisation service points in a peri-urban area in Zambia. METHODS: Repeated cross-sectional surveys were conducted for two groups of children born between 1999 and 2001, and between 2003 and 2005.The association between immunisation coverage for DPT3 and measles, and access distance, child sex, female headed households, and monthly household income were assessed using logistic regression analysis. Optimal locations for outreach service points were identified using GIS network analysis and genetic algorithms. RESULTS: Before the introduction of outreach services, longer distances to the service points were associated with lower DPT3 and measles immunisation coverage (OR=0.24, 95% CI 0.10 to 0.56, p<0.01 for DPT3; and OR=0.38, 95% CI 0.17 to 0.83, p<0.05 for measles). However, access distances were not an impediment to immunisation coverage once the outreach services were introduced. The average distance to immunisation services could be decreased from 232.3 to 168.4 metres if the current 12 outreach service points were repositioned at optimal locations. CONCLUSION: Access distance to immunisation services was a critical determinant of immunisation coverage in a peri-urban area. Intervention via outreach services played an important role in averting the risk of missing out on immunisation. Optimal location analysis has the potential to contribute to efficient decision making regarding the delivery of immunisation services.

The impact of an immunization programme administered through the Growth Monitoring Programme Plus as an alternative way of implementing Integrated Management of Childhood Illnesses in urban-slum areas of Lusaka, Zambia.

A time-lag study design was used to examine the effects of an immunization programme implemented through an integrated community-based child health approach called the Growth Monitoring Programme Plus (GMP+) in peri-urban areas of Lusaka, Zambia. The immunization coverage and sociodemographic data of eligible children and households were obtained from three repeated surveys in two intervention areas. Logistic regression analysis was performed to explore the factors affecting immunization coverage. For assessing the timeliness of immunization, a Computerised Immunization Coverage Calculation System (CICCS) was used. Full immunization coverage significantly increased in both the primary intervention (P<0.001) and lagged intervention (P = 0.011) areas after the initiation of the GMP+. Frequent attendance to GMP+ sessions played a significant role in the improvement of immunization coverage (P<0.001 for the final survey in the primary intervention area), whereas other sociodemographic characteristics of the child and caretaker were not associated with immunization coverage. Analysis of the timeliness of three doses of diphtheria, pertussis and tetanus DPT3 immunization by CICCS showed that coverage in the primary intervention area had significantly improved compared to the lagged intervention area. Our study indicated that immunization coverage was improved effectively with the intervention of the GMP+ as a model of an integrated immunization programme for child health in line with the Integrated Management of Childhood Illnesses (IMCI) and the Global Immunization Vision and Strategy (GIVS).

Spatial analysis of risk factor of cholera outbreak for 2003-2004 in a peri-urban area of Lusaka, Zambia.

A cholera outbreak occurred in Lusaka city between November 28, 2003 and June 8, 2004, and 6,542 cases with 187 deaths (case fatality rata: 2.86) were reported. We analyzed the distribution of cholera cases, the mode of cholera transmission, and the risk factors affecting cholera infection in a peri-urban area of Lusaka by using a Geographic Information System (GIS) and a matched case-control method. Chloropleth mapping of the incidences of cholera showed variation of the incidences in the study area. Our analysis indicated a significant association between the lack of latrine and drainage systems surrounding houses and high incidence of cholera. The matched case-control study showed the protective role of chlorination of drinking water and of hand washing with soap for cholera prevention. We concluded that cholera occurred because of personal behavior and the environment conditions of daily life.

Sapporo Fitness Club Trial (SFCT)--design, recruitment and implementation of a randomized controlled trial to test the efficacy of exercise at a fitness club for the reduction of cardiovascular risk factor--.

BACKGROUND: The annual health check followed by lifestyle recommendations has long been the standard national strategy to improve cardiovascular disease (CVD) risk factors in Japan. Exercise at fitness clubs, now widely accessible in major cities, has a novel appeal as a strategy with the additive effect of CVD risk reduction. The Sapporo Fitness Club Trial (SFCT) is a randomized controlled trial to compare the efficacy of the national standard alone (control) with the standard plus exercise at a fitness club (intervention) for the reduction of CVD risk factors. METHODS: The SFCT has recruited and randomized 561 relatively inactive overweight men and women, aged 40-85 years, with elevated levels of 2 or more of the following: systolic blood pressure, fasting blood glucose, and low-density lipoprotein cholesterol. The intervention group was required to exercise at a fitness club 2-4 times per week. At the end of 6 months, risk factors, aerobic capacity, health-related quality of life measures, and adverse effects are to be compared. CONCLUSION: The SFCT is expected to have a major impact in Japan on public health recommendations on exercise for the reduction of lifestyle-related disease.