Minimal validity evidence exists for scales assessing the built environment for physical activity. The purpose of this study was to assess the test-retest reliability and invariance of a three-factor model  across gender, race, geographic location, and level of physical activity.To assess measurement invariance, a random sample of 1,534 adults living in North Carolina or Mississippi completed a computer assisted telephone interview that included items examining perceptions of the neighborhood for physical activity. Construct level test-retest reliability data were collected from a purposeful sample of 106 participants who were administered the questionnaire twice, approximately two weeks apart. Fit indices, Cronbach's alpha, Mokken H and Spearman correlation coefficients (SCC) were used to evaluate configural and co/variance invarianc,e and intraclass correlation coefficients (ICC) were used to assess reliability.Construct test-retest reliability was strong (ICC 0.90 to 0.93). SCC for Neighborhood Characteristics and Crime/Safety were weak with Access (0.21 and 0.25), but strong between Crime/Safety and Neighborhood Characteristics (0.62). Acceptable fit and evidence of measurement invariance was found for gender, race (African American and White), geographic location, and level of physical activity. Fit indices consistently approached or were greater than 0.90 for goodness of fit index, normed fit index, and comparative fit index which is evidence of configural invariance. There was weak support of variance and covariance invariance for all groups that was indicative of factorial validity.Support of the validity and reliability of the three-factor model across groups expands the possibilities for analysis to include latent variable modeling, and suggests these built environment constructs may be used in other settings and populations. With the advent of ecological models, physical activity research now frequently incorporates built environment measures . While tSeveral scales exist that measure perceptions of the built environment for physical activity among adults -7. HowevIn 2005, Evenson and McGinn  developeA recent examination of the psychometric properties of 26 items from this questionnaire in a separate sample of 479 White and African American adults, along with 21 items regarding convenience of physical activity facilities from Sallis et al. , revealeUsing self-reported built environment data collected on a diverse sample of adults, this paper had two aims: 1) to confirm the factor structure, reliability, and scalability of three of the five factors  found in Gay and Smith  by gendeA telephone survey was conducted using a computer assisted telephone interview system (CATI) between January and July 2003 on a random sample of non-institutionalized adults 18 years or older residing in two regions: Forsyth County, North Carolina and the metropolitan statistical area (MSA) of Jackson, Mississippi. Disproportionate sampling was used for Forsyth County in order to ensure representation for less urban areas outside of the Winston-Salem metropolitan area within the county. Respondents were randomly chosen in two stages: the first stage at the household level and the second stage at the individual level. Surveys were only conducted in English. Each participant provided consent and the study was approved by the Institutional Review Board at the University of North Carolina. Participants were paid $5 for their participation for each survey they completed. More detail is available elsewhere .Overall 1,662 men and women completed the survey. At the end of the interview, 1,448 adults were asked if they would be willing to participate in a retest interview. The remaining 214 adults were not asked to participate in a retest interview, because the interview quota was complete. Among these 1,448 adults, 76%  agreed to be called back for the retest survey. Reliability information was collected from a 6% (n = 106) purposeful sample of women and men, to ensure approximately equal numbers of participants from both sites, by gender, and by race/ethnicity. The mean time between interviews was 16.8 days .Physical activity was assessed by asking if the adults had participated in any moderate- or vigorous-intensity activity for at least 10 minutes at a time, using questions from the year 2001 BRFSS core module on physical activity . If theyAll respondents were asked questions regarding age, gender, race/ethnicity, marital status, education, and employment. Employment was grouped into two categories: employed or not employed . Self-reported height and weight were collected to calculate body mass index (BMI).H, a measure of scale homogeneity, was also used to verify the consistency of the three factors. An H between 0.30 and 0.40 denoted a weak scale, 0.40 to .50 a moderate scale, and 0.50 to 1.00 a strong scale [The analysis includes three factors from the exploratory analysis presented in Gay and Smith : Neighbong scale .Intraclass correlation coefficients were calculated to examine the test-retest reliability of the three factors. Landis and Koch  suggest Measurement model fit holds if the goodness-of-fit index (GFI), normed fit index (NFI), and comparative fit index (CFI) are >0.90. The lower cutoff of 0.90 is used because this is not a well-established instrument that is in the formative stage. We also examine the standardized root-mean-square residual , and the root-mean-square error of approximation  and the expected cross-validation index .2 is examined between two nested models. This value follows a χ2 distribution with the degrees of freedom equal to the difference of the degrees of freedom between the nested models. If measurement invariance holds, there will be a non-significant improvement in fit. However, some have questioned the usefulness of the Δχ2 [2 may reject trivial differences in the model that do not have much practical importance. As a result, some practitioners recommend using the change of fit indices to determine whether measurement invariance holds. Hu and Bentler [Measurement invariance holds if the constraints make a significant improvement in the model fit. Typically, to assess this, the Δχ the Δχ2 ,22 since Bentler  recommenConfigural invariance is tested to determine whether the conceptual framework is the same across different groups -26. Here2 (SD = 6.26) and 61.5% of participants met physical activity guidelines .The sample consisted of 1,534 adults (mean age = 47.88 ± 17.05) living in Jackson, Mississippi (n = 741), Forsyth County, Winston-Salem, North Carolina (n = 379), and Forsyth County, North Carolina rural areas (n = 414). Nearly two-thirds of the sample was female (66.8%), 91.2% graduated high school and 42.6% attended at least 4 years of college. Just over half (61.7%) of participants were employed. Less than half of the sample was married (45.7%) with the next largest group being those who were never married (20.4%). More than one-third (36.3%) of the sample was Black, non-Hispanic while the majority were White, non-Hispanic (58.8%). The mean BMI for the sample was 27.2 kg/m H scalability coefficient was strongest for Neighborhood Characteristics (0.61) indicating a strong scale. Crime/Safety had a moderate scalability coefficient, and the H for Access was weak.Means, standard deviations, and ranges for the three constructs are provided in Table Construct test-retest reliability was assessed using intraclass correlations Table . All thr2 indicated a lack of configural measurement invariance. Additionally, both the Δχ2 and ΔCFI indicated the factor variances and covariances between factors were the same for both males and females. ΔCFI indicated that there was some evidence of error variances being equivalent for both males and females. As a result, since only the ΔCFI favored measurement invariance, there was evidence of weak measurement invariance for males and females.Measurement models for all groups produced acceptable factor loadings. Table Based on the model fit information Table , there w2 and the ΔCFI support measurement invariance across the loadings.As the GFI, NFI, and CFI were all close or above 0.90 Table  there waModel fit for Jackson, Mississippi, Winston-Salem, North Carolina urban, and Forsyth County, North Carolina  is shown in Table Measuring perceptions of the built environment for physical activity has become more prevalent as the use of ecologic models increases in the physical activity domain . MissingH scalability coefficients were slightly higher in this study for Neighborhood Characteristics and lower for Crime, but still moderate-to-strong for both scales. The Neighborhood Characteristics scale is similar to the Neighborhood Environment Walkability Scale (NEWS) Traffic Hazards subscale identified in the Baltimore, Maryland [The means, standard deviations, and ranges for the Neighborhood Characteristics and Crime scales were similar to the values found in Gay and Smith , but theMaryland  and AustMaryland . The CriThe configural invariance was tested to examine the theoretical framework across gender, race/ethnicity, physical activity group, and geographic location as the participants came from three distinct areas. There was weak measurement invariance for all group invariance tests and indications that the measurement model had acceptable fit based on the GFI, NFI and CFI. The RMSEA, generally less affected by large sample sizes, was larger than expected. However, the spectrum of fit indices indicated acceptable fit across all groups. The factor structures were the same as the a priori model resulting from the exploratory factor analysis . While tThis study is unique as we have provided initial support for the generalizability of the factor structure for perceptions of the built environment for physical activity across race/ethnicity, gender, level of activity, and perhaps most importantly geographic location. Given that the built environment, and therefore perceptions, can change by neighborhoods, cities, or rural or urban location, validity of the factor structure across geographically diverse areas encouraging. One possible implication of these findings is that this scale can be used to assess perceptions in various settings. As changing perceptions of the built environment may increase physical activity, these factors may be used to determine targets for built environmental change.The findings from this study should be taken within the context of several limitations. First, neither this sample nor the original exploratory paper had samples that included a large proportion of Hispanics or other races such as Asian or Native American. The survey and factor structure should be tested in more diverse populations and in other languages. Second, the version of the measure used in this study did not include the Convenience or Places of Worship scales . TherefoThis research contributes to the evidence by providing additional support for the factor structure of a survey measuring the perceptions of the built environment for physical activity. Currently the evidence lacks appropriate examinations of these items and subscales not only across populations, but also settings, particularly as the NEWS focuses on built environmental attributes for walking, not physical activity more broadly. We have explored the factorial structure and results indicate that the subscales apply to suburban/rural and urban settings, across race/ethnicity, gender, and whether or not physical activity guidelines were met. Having a generalizable factor structure expands the possible analyses beyond item-level variables and allows for the creation of factor scores for use in statistical analysis as well as in latent variable modeling. Using such thematic or latent analyses may allow for targeting specifics of groups of environmental characteristics that most impact physical activity. These strategies are used frequently in psychology and education domains, from which public health draws. The results from this study contribute to establishing validity for a perceptual measure of the built environment for physical activity. Furthering the measurement of perceptions of the built environment may contribute to improved interventions and ultimately increased physical activity.The authors declare that they have no competing interests.JLG conceptualized the manuscript, drafted the manuscript and conducted some statistical analyses. KRE designed the questionnaire, conducted the project from which the data are derived, and provided feedback on drafts of the manuscript. JS provided input on and conducted some statistical analyses, and provided feedback on drafts of the manuscript. All authors read and approved the final manuscript.Items, by factor, included for invariance testing.Click here for file


Incidence of childhood leukemia in industrialized countries rose significantly during 1975–2004, and the reasons for the increase are not understood.α- and γ-chlordane, p,p′-DDT (dichlorodiphenyltrichloroethane), p,p′-DDE (dichlorodiphenyldichloroethylene), methoxychlor, and pentachlorophenol.We used carpet dust as an exposure indicator to examine the risk of childhood leukemia in relation to residential exposure to persistent organochlorine chemicals: six polychlorinated biphenyl (PCB) congeners and the pesticides We conducted a population-based case–control study in 35 counties in northern and central California in 2001–2006. The study included 184 acute lymphocytic leukemia (ALL) cases 0–7 years of age and 212 birth certificate controls matched to cases by birth date, sex, race, and Hispanic ethnicity. We collected carpet dust samples from the room where the child spent the most time before diagnosis (similar date for controls) using a specialized vacuum.p = 0.017). Significant positive trends in ALL risk were apparent with increasing concentrations of PCB congeners 118, 138, and 153. We observed no significant positive associations for chlordane, DDT, DDE, methoxychlor, or pentachlorophenol. The associations with PCBs were stronger among non-Hispanic whites than among Hispanics despite similar distributions of PCB levels among controls in each racial/ethnic group.Detection of any PCB congener in the dust conferred a 2-fold increased risk of ALL . Compared with those in the lowest quartile of total PCBs, the highest quartile was associated with about a 3-fold risk , and the positive trend was significant (Our findings suggest that PCBs, which are considered probable human carcinogens and cause perturbations of the immune system, may represent a previously unrecognized risk factor for childhood leukemia. Childhood leukemia is the most common childhood cancer, and the etiology is poorly understood . Acute lOrganochlorine insecticides  and polychlorinated biphenyls (PCBs) became common environmental contaminants after World War II because of their widespread use, persistence in the environment, and bioaccumulation through the food chain. Because of concerns about detrimental effects on the environment and human health, uses of DDT, PCBs, and chlordane were banned in the United States in 1972, 1977, and 1988, respectively. However, these chemicals persist indoors in carpets, where they are protected from degradation by sunlight, moisture, and microorganisms. Ingestion of house dust is an important route of chemical exposure for young children, who spend most of their time indoors and frequently put their hands in their mouths . ConcentEpidemiologic studies have implicated residential and parental exposure to pesticides as risk factors for childhood leukemia. However, specific pesticides were not identified in most studies, which relied primarily on self-reports about pesticide use. PCBs are considered probable human carcinogens and cause perturbations of the immune system . PCB conWe conducted a population-based case–control study of childhood leukemia in northern and central California , which included 17 counties in the San Francisco Bay area and 18 counties in the Central Valley. As described previously , 2005, cIn the tier 2 interview, we obtained detailed information on home and garden pesticide use, inventoried pesticides in storage, and collected carpet dust samples. We limited eligibility to younger cases and controls so that the carpet dust sample would reflect exposures over a substantial portion of the child’s life. We also took a global positioning system measurement of the home location and determined whether the residence was located in an urban, suburban, or rural area based on the 2000 U.S. census block characteristics . We mapp2 that was present before the reference date. Most samples were taken in the living room or family room. A total of 203 cases and 212 controls met the eligibility requirements for sampling and had adequate dust (~ 0.25 g) collected for analysis by at least one of the analytic methods (described below). A total of 22 cases and 32 controls either had no eligible carpet or the dust amount collected was too little for analysis. We present results for ALL (n = 184), which constituted 91% of the leukemia cases.We collected dust samples using a specialized vacuum, the high-volume small-surface sampler , from December 2001 through March 2006. Because of the longer time period involved in identifying, enrolling, and interviewing birth certificate controls in the main study, the time between the reference date and dust collection was less for cases {median [interquartile range (IQR)] years: cases, 0.96 (0.76–1.38); controls, 1.55 (1.24–1.97)}. As previously described , we askeα- and γ-chlordane (hereafter chlordane), p,p′-DDE , p,p′-DDT (hereafter DDT), dieldrin, lindane, methoxychlor, and six PCB congeners . We used an acid herbicide extraction method to measure pentachlorophenol. Detection and quantification were by gas chromatography/mass spectrometry in the multiple ion detection mode. Quality control samples included duplicates, the same duplicate spiked with 250 ng of each analyte, and a solvent method blank. We spiked carbon-13–labeled surrogate recovery standards (SRS) representing all major classes of analytes into all samples before extraction to aid in identification and as a check on method performance. All sample batches contained 12 samples, including one duplicate and at least four case and four control samples; laboratory personnel were blind to case or control status.Details of the carpet dust sample shipping, processing, and chemical analyses have been described previously . Brieflyp < 0.05) and ranged from 0.20 for PCB-105 and PCB-180 to 0.71 for PCB-153 and PCB-180. PCB congeners 118, 138, 153, and 180 were moderately correlated with chlordane, DDE, DDT, methoxychlor, and pentachlorophenol; correlations ranged from 0.18 for PCB-118 and methoxychlor to 0.40 for PCB-138 and methoxychlor.Mean sample recoveries (without SRS correction) ranged from 85% for PCB-105 to 118% for methoxychlor. The relevant SRS recovery averages ranged from 82% to 111% in the quality control samples. Results were similar when we used SRS-corrected and -uncorrected concentrations; therefore, we report the uncorrected concentrations. 2 ; controls, 1.1 g/m2 .The organochlorine concentrations distributed log normally, and analyses were based on the natural log of the concentration, our primary exposure metric. We also calculated the chemical loading, an estimate of the amount of chemical per square meter of carpet, by multiplying the concentration of the chemical by the dust loading (amount of fine dust collected divided by the sampled area). The dust loadings were similar among cases and controls: cases, median, 0.8 g/mFor chemicals that were detected in a minimum of 24% of samples, we used a single imputation method  that selFor analyses of pentachlorophenol, chlordane, and total PCBs , we categorized the distribution into quartiles based on measured and imputed values among controls because few homes had no detections. For the other chemicals that were detected in > 20% of homes, the reference group was those with no detectable concentration, and we categorized detected concentrations by tertiles or the median of the detected concentration among controls. We calculated odds ratios (ORs) and 95% confidence intervals (CIs) using unconditional logistic regression. We conducted tests for trend by including the continuous variable  in the regression models. We adjusted all analyses for age, sex, and race/ethnicity , which were study matching factors. We also adjusted for confounding factors that resulted in changes to the ORs of ≥ 10%. For the PCBs these included the age of the home (built before 1980built before 1980 or later) and whether and for how long the mother breast-fed the child . For the other organochlorines, we adjusted for income  and the year and season of the dust sampling. We evaluated potential effect modification by breast-feeding status and maternal age, because breast-feeding is a source of exposure to persistent organo-chlorine chemicals for infants, and older mothers are more likely to have higher serum concentrations.$60,000) households . Tier 2 cases and controls did not differ significantly by sex, age, race/ethnicity, urbanicity of their residence, breast-feeding status and duration, or mother’s age at their birth , a lower percentage of Hispanic children , and a greater percentage of children from higher-income (≥ ir birth . Fewer cp = 0.017) (p = 0.018), PCB-138 (p = 0.026), and PCB-153 (p = 0.017). When we measured exposure in terms of PCB loadings (nanograms per square meter), we observed no association with risk of ALL. ORs for some specific congeners were elevated but did not demonstrate significant positive trends with increasing loadings.Detection of any of the measured PCB congeners in the dust conferred a 2-fold increased risk of ALL . Compared with those in the lowest quartile of total PCBs, the highest quartile was associated with an almost 3-fold risk , and the positive trend was significant (= 0.017) . DetectiIncreasing loadings of DDE and pentachlorophenol were associated with significant inverse trends in ALL risk. There were no other significant or noteworthy findings for the organochlorine pesticides. Risk estimates for the PCB congeners were not changed by adjustment for concentrations of the organo-chlorine pesticides. The moderate to high correlation between PCB congeners precluded mutual adjustment of the individual congeners for each other. When we excluded children 2–7 years of age who lived at their tier 2 home for < 1 year before the diagnosis or reference date, we obtained similar results for both the PCBs and organochlorine pesticides.p-value for interaction = 0.016 and 0.015, respectively). We observed similar results in analyses by concentration of total PCBs and individual congeners (data not shown). ORs for PCB loadings tended to be higher among non-Hispanic whites; however, as we observed for all racial/ethnic groups combined, we found no significant trends in either group (data not shown). We found no significant differences by ethnicity for concentrations or loadings of the organochlorine pesticides (data not shown).We observed consistently higher risks of ALL associated with detections of total PCBs and individual PCB congeners in carpet dust samples among non-Hispanic whites compared with Hispanics . These dAmong controls, the distribution of total PCBs was similar for Hispanics, non-Hispanic whites, and non-Hispanics of other races ; thus, dOur study is the first evaluation of the relationship between residential concentrations of PCBs and risk of ALL in children. We observed increased risk of ALL with increasing concentrations of total PCBs and with specific PCB congeners in dust samples taken from the room in which the child spent the most time. In contrast, dust levels of the persistent organochlorine pesticides DDT, DDE, chlordane, methoxychlor, and pentachlorophenol were not associated with increased risk. PCBs are probable human carcinogens and cause perturbations of the immune system, and concentrations in house dust and plasma have been associated with increased risk of adult NHL in epidemiologic studies . Our finThe associations we observed with specific PCB congeners were consistently stronger among non-Hispanic whites compared with Hispanics. We were unable to explain this effect modification, although unmeasured factors such as cultural or biological characteristics may have been responsible. It is also possible that residential dust samples were not an important source of exposure among Hispanic children in our study or that other unmeasured sources of exposure were more important, resulting in misclassification that would have obscured positive associations with risk. For example, Hispanic children may have spent more time away from their home in the care of relatives. We did not have information on the usual amount of time spent in the home or in the room where we conducted the dust sampling, which would have partly addressed this question.Residential exposure to PCBs and childhood leukemia risk has not been evaluated previously in a population-based study. A small study comparing bone marrow concentrations of PCBs in 38 children with ALL and 15 healthy children selected from the same hospital found no significant differences in mean concentrations across the two sample pools . That stWe found no associations with childhood ALL for the organochlorine pesticides. Although self-reported parental occupational and residential exposures to pesticides have been associated with increased ALL risk in many studies , nearly Based on mechanistic studies, animal studies, and epidemiologic studies of cancer in adults, the International Agency for Research on Cancer and the U.S. Environmental Protection Agency consider PCBs to be probable human carcinogens . PCBs arin utero, through breast-feeding and other dietary sources, through inhalation, and through ingestion of house dust  and is postulated to be a more accurate indicator of exposure for small children . HoweverOur exposure assessment method is a major strength of our study. We conducted environmental sampling to measure concentrations of persistent organochlorine chemicals in the room in which the child spent the most time. Although it is desirable to do so, prospective or pretreatment exposure measurements in blood samples are difficult to obtain because of the rarity of the disease and the very young age of most children. Residential carpet dust sampling provides an alternative exposure assessment method that allows identification of individual compounds and is not subject to recall bias. Organochlorine pesticides and PCBs are known to persist in carpets, where they are protected from degradation by sunlight, moisture, and microbes, and most homes had detectable levels of these chemicals in the dust samples. Other strengths of our study include the rapid case ascertainment, population-based selection of controls, and high participation rates for the tier 2 interview.A limitation of our study was the moderate number of participants with HVS3 dust samples, particularly after stratifying by ethnicity, limiting our statistical power. Further, our study population was limited to those who had not moved since the diagnosis or reference date. If PCB and organochlorine concentrations were substantially different among those who were less residentially stable, our results may not be generalizable to the general population. Another limitation, common to many case–control studies, was the lower response rates among controls compared with cases. Our population-based controls were previously shown to be comparable with all eligible controls with respect to maternal history of fetal loss, birth weight, birth order, and time since last live birth . In the The positive association observed for PCBs and ALL could have been attributed to other chemicals in the home that were highly correlated with PCBs. Although we were able to rule out confounding by the organochlorine pesticides measured in this study, we did not measure concentrations of polybrominated diphenyl ethers (PBDEs), which have become common environmental contaminants because of their increased use as fire retardants since the 1970s. Several studies , includiIn summary, we observed an increasing risk of ALL associated with increasing residential concentrations of PCBs. PCBs are considered probable human carcinogens and cause perturbations of the immune system. We found no evidence of a relationship between ALL risk and exposure to DDT, DDE, chlordane, or pentachlorophenol. Additional studies are needed to further evaluate these highly suggestive findings.


While evidence on the cost of mental illness is growing, little is known about the cost-effectiveness of programmes in the areas of mental health promotion (MHP) and mental disorder prevention (MDP). The paper aims at identifying and assessing economic evaluations in both these areas to support evidence based prioritisation of resource allocation.A systematic review of health and non health related bibliographic databases, complemented by a hand search of key journals and analysis of grey literature has been carried out. Study characteristics and results were qualitatively summarised. Economic evaluations of programmes that address mental health outcome parameters directly, those that address relevant risk factors of mental illness, as well as suicide prevention interventions were included, while evaluations of drug therapies were excluded.14 studies fulfilled the inclusion criteria. They varied in terms of topic addressed, intervention used and study quality. Robust evidence on cost-effectiveness is still limited to a very small number of interventions with restricted scope for generalisability and transferability. The most favourable results are related to early childhood development programmes.Prioritisation between MHP and MDP interventions requires more country and population-specific economic evaluations. There is also scope to retrospectively add economic analyses to existing effectiveness studies. The nature of promotion and prevention suggests that innovative approaches to economic evaluation that augment this with information on the challenges of implementation and uptake of interventions need further development. Increasing evidence about the high social and economic costs of poor mental health has contributed to a growing recognition of the need to promote positive mental health and wellbeing, as well as to prevent the onset of mental illness -3. This One in four individuals can expect to experience mental health problems during their lifetimes . ConservIn the context of increasing budget constraints and rising demands for evidence-based health spending, evidence on effectiveness alone is insufficient for policy making; in addition to knowing what works and in what context, information on the economic costs and consequences of any intervention is required. Given the inevitable constraints on funds available for all public sector interventions, economic evaluations are increasingly used as one key input to decisions on how to allocate resources to various health system actions, most notably for assessing pharmaceuticals, medical devices and procedures . More reIt is therefore no surprise that the use of economic evaluations in the field of mental health care generally continues to grow , but litA systematic review protocol was developed in line with recommended guidelines -31 in orConsidering the fragmented pattern of scientific evidence in the MHP and MDP fields a pragmatic approach to defining inclusion and exclusion criteria was required. Firstly, those economic evaluations of mental health promotion or prevention interventions were included that addressed either mental well-being or mental disorder as an outcome parameter directly . Secondly, studies which focused on preventing outcomes specifically recognised as well-known risk factors for future mental disorder were included . Additionally, we included papers on suicide prevention, although suicide is not always related to mental health problems.While the definition of mental disorders was based on the ICD classification, studies which evaluated programmes on alcohol and drug dependency were excluded. In respect of prevention we restricted the review to studies on primary and secondary prevention alone as defined by the WHO . Thus, wThere were no date restrictions imposed on the bibliographic database search, but our analysis was limited to studies in English and German. Study selection was initially on the basis of study abstract, with data extraction and assessment conducted independently by two reviewers based on available checklists ,34. AccoThis search process resulted in 398 hits. 361 papers were excluded on the basis of abstract alone. From the 37 remaining studies, 5 could not be obtained, leaving 32 studies, 18 of which did not meet all inclusion criteria, leaving 14 studies in our analysis , the number of available studies that evaluate MHP or MDP interventions from an economic perspective is low. The broad and fragmented nature of promotion and prevention interventions meant that our hand and internet search were however able to identify 8 of the 14 studies, as they did not appear in the largely medical databases. Table Half of these studies evaluated programmes in three European countries  with the remainder being in the US. Some of these US based evaluations, in fact covered a number of programmes ,37. One While six studies were conducted prospectively alongside the collection of primary data -43, eighWhile the evaluations identified were diverse in terms of type of intervention, a high proportion of the studies dealt with measures to prevent depression, sometimes with a secondary objective of preventing suicide. The remainder focused on addressing some of the overall risk factors for mental disorders. No economic evaluations were found of interventions that address mental well-being rather than mental illness as an outcome parameter. In the following section, the main characteristics of studies are briefly presented.Smit et al. (2006)  in the NIn England, Petrou et al. (2006)  evaluateLynch et al. (2005)  evaluateValenstein et al. (2001)  evaluateFive studies looked at the economic case for suicide prevention: Sari et al. (2007)  analysedZaloshnja et al. (2003)  retrospeAppleby et al. (2000)  analysedByford et al. (1999)  in EnglaRutz et al. (1992)  conducteA further group of studies evaluated interventions that were targeted at young parents or mothers having to deal with stressful socio-economic circumstances. Two programmes to support mothers in deprived London inner-city areas have been compared to standard care in terms of maternal and child health  and costs by Wiggins et al. (2004) . Both inIn contrast to studies identified in the UK, several US studies reported quite favourable results for ECD programmes. Most of these studies do not report outcomes for mental well-being per se, but they have been included in the analysis because they address well-accepted risk factors for mental disorders.In the United States Schweinhart et al. (2005)  evaluateLynch (2004)  also useThe final study identified was a simulation study by Aos et al. (2004) . They quWith regard to quality criteria for health economic evaluations ,34 only By contrast, despite the fact that the reduction of suicide is often one of the few defined targets for population mental health in many countries, there remain few studies to date that look at the cost effectiveness of suicide prevention programmes. In many respects this is not surprising, as comparatively few interventions have been the subject of effectiveness analysis . This isWhile the number of studies identified in this area remains very limited, some analysis now suggests that the potential cost effectiveness may compare very favourably with those for other public health interventions if strategies can be demonstrated to be effective in averting suicides . This maThe variability in the quality of all studies identified is marked, although given the extra challenges, the majority of evaluators tried to develop appropriate, pragmatic and creative study designs. As with other areas of public health evaluation, the principal challenges do not relate to economic evaluation per se, but rather to the generation and attribution of effectiveness data for complex interventions with long-term outcomes.Although the knowledge about risk factors for mental disorders has grown rapidly -15,53,54Moreover, as with many other public health interventions, the long time frame between intervention and effect is a major barrier to assessing the long term effectiveness of interventions, although judicious use of modelling may help at least to look at potential cost effectiveness of interventions if different levels of effect are achieved. Nonetheless, greater investment in long-term follow up studies is required to overcome this problem.Despite this limitation, there is an evidence base indicating that many severe mental disorders which appear in late adolescence or early adulthood may be associated with risk factors that manifest themselves in early childhood e.g. ,56,57]. ,57. 56,5Another challenge, given the limited number of studies available, is the extent to which the results from the evaluations may be of use in other countries or even in different regions within the same country. Due to the specific programme context of many interventions, the scope for generalisability and transferability may be restricted. The effectiveness of two identical mental health promotion or prevention programmes may vary considerably depending on the context and setting where the intervention is implemented. This is related to the cultural, social and economic context of the study population which can have a significant influence on the intervention process and its effect. As has been shown earlier, examples include those home-visiting programmes targeted at low-income mothers which have shown favourable results in the US but failed to show benefits in the UK. This also indicates the importance of gathering qualitative data on the process by which interventions are delivered which should help understand what factors lead individuals to make use of health promoting interventions. Ideally this could be undertaken concurrently with economic evaluation and may also help policy makers elsewhere both identify and estimate the costs of adaptations required to implement interventions in their own jurisdictions.The small number of studies identified as part of this review may, to some degree, be an artefact of the difficulty in conducting a review of economic evaluations in the areas of health promotion and public health. This has been highlighted previously ,60. DesiOur exclusion criteria and review protocol also would have excluded studies which address mental health as part of general health promoting strategies, but do not distinguish between mental and physical health. Examples for this are the numerous workplace health promotion programmes that do not address mental health directly but still may have a positive impact on mental health. In addition, our reliance on the use of abstracts to determine whether or not to include or exclude studies might also mean that relevant studies might have been inadvertently excluded. Despite these limitations, our lack of economic workplace mental health promotion studies for instance, is consistent with other reviews in this area, which have reported few specific mental health orientated programmes, although stress reduction programmes are increasingly forming an element of workplace health promotion programmes .MHP and MDP interventions have a high potential to be of economic benefit to society. The evidence base at present is scant, making it difficult to formulate general recommendations on how to prioritise between individual interventions. Moreover, information to aid in the transferability of available results to different contexts and settings is limited. More country and population specific economic evaluations are required to strengthen this evidence base. Some of this, inevitably will mean commissioning new studies, which may take some time to deliver results; those who fund effectiveness evaluations might be encouraged to include economic analysis in their terms of reference for prospective applicants.In the short term, another way of developing the evidence base, would be to retrospectively conduct economic evaluations making use of existing effectiveness data and attaching local estimates of resource use and costs to these interventions. This practice is common in other areas of economic evaluation, and some initiatives have been started to apply it in the area of MHP and MDP. Again, despite all their limitations, careful use of economic models might also help to provide some indication of the potential long term impact and economic consequences of interventions.It will also be important when looking, not just at MHP or MDP, but all areas of health promotion and public health, that innovative evaluation designs are used. Conventional health economic evaluation does not typically consider issues governing the uptake and appropriateness of interventions to different populations. It is important to build into evaluation an assessment of the costs and resources required to implement interventions in different settings, cultures and contexts, and to obtain qualitative information on the success and obstacles to implementation. This type of analysis does not typically fall within the provenance of health economists and emphasises the need for a multi-disciplinary approach to evaluation. Much work remains to be done in order to gain more evidence as well as to foster methodological development.The researchers declare their independence of funding and declare that they have no competing interests.IZ had the main responsibility for the research design and drafting of the manuscript. All authors have made substantial contributions to conception and design as well as to study selection and study analysis. All authors read, contributed to and approved the final manuscript. The MHEEN group made substantial contributions to study identification and methodological discussions.No full economic evaluation (n = 10):Suizid bei Depression. Verlorene Lebensjahre und Bruttosozialprodukt. Was bringt die Suizidprävention? Psychiatrische Praxis 1998, 25:139–141.1. Wolfersdorf M, Martinez C: Suizid und Gesundheitsökonomie: Rentiert sich eine Suizidprävention? In Suizidforschung und Suizidprävention am Ende des 20 Jhdts. Edited by Wolfersdorf M, Franke C. Regensburg: Roderer; 20002. Oberender P, Zerthh J: Impact of Primary Care Depression Intervention on Employment and Workplace Conflict Outcomes: Is Value Added? The Journal of Mental Health Policy and Economics 2002, 5:43–49.3. Smith JL, Rost K, Nutting PA, Libby AM, Elliott CE, Pyne JM: Cost Assessment of a School-Based Mental Health Screening and Treatment Program in New York City. Mental Health Services Research 2004, 6:155–166.4. Chatterji P, Caffray C, Crowe M, Freeman L, Jensen P: Primary Prevention of Child Mental Health Problems using Primary Health Care Professionals. Cost Comparisons. International Journal of Mental Health Promotion 2005, 7:95–102.5. Knapp M, Barrett B, Byford S, Hallam A, Davis H, Tsiantis J, Puura K, Ispanovic-Radojkovic V, Paradisiotou A: Healthy People – Healthy Business: A Critical Review of Stress Management Programs in the Workplace. American Journal of Health Promotion 1998, 2:5–12.6. Pelletier KR, Lutz R: Opportunities for Cost-effective Prevention of Late-Life Depression. Archives of General Psychiatry 2006, 63:290–296.7. Smit F, Ederveen A, Cuijpers P, Deeg D, Beekman A: Impact of a Preventive Job Search Intervention on the Likelyhood of Depression Among the Unemployed. Journal of Health and Social Behaviour 1992, 33:158–167.8. Price RH, Van Ryn M, Vinokour A: Der ökonomische Nutzen betrieblicher Gesundheitsförderung. Prävention 2002, 4:106–109.9. Bödeker W, Kreis J: Economic Implications of Workplace Health Promotion Programs: Review of the Literature. Journal of Occupational Medicine 1988, 30:106–112.10. Warner KE, Wickizer TE, Wolfe RA, Schildroth JE, Samuelson MH: Prevention of alcohol dependency (n = 4):Cost-Effectiveness of Strategies to Market and Train Primary health Care Physicians in Brief Intervention Techniques for hazardous Alcohol Use. Social Science and Medicine 1998, 47:203–211.1. Gomel M, Wutzke SE, Hardcastle DM, Lapsley H, Reznik RB: Alcohol advice in primary health care. Is it a wise use of resources? Health Policy 1998, 45:47–56.2. Lindholm L: Reducing the Global Burden of Hazardous Alcohol Use: A Comparative Cost-Effectiveness Analysis. Journal of Studies on Alcohol 2004, 65:782–793.3. Chisholm D, Rehm J, Van Ommeren M, Monteiro M: Workplace Health Promotion and Utilization of Health Services. The Journal of Behavioural Health Services & Research 2005, 32:306–319.4. Deitz D, Cook R, Hersch R: Too general/no focus on MHP/MDP (n = 2):A Review and Analysis of the Clinical- and Cost-effectiveness and Disease Management Programs at the Worksite: 1998–2000 Update. American Journal of Health Promotion 2001, 16:107–116.1. Pelletier KR: A Review and Analysis of the Health and Cost-Effective Outcome Studies of Comprehensive Health Promotion and Disease Prevention Programs. American Journal of Health Promotion 1991, 5:311–313.2. Pelletier KR: (Drug)therapy studies (n = 2):Prescribing selective serotonin reuptake inhibitors as strategy for prevention of suicide. British Medical Journal 1994, 309:249–253.1. Freemantle N, House A, Song F, Mason JM, Sheldon TA: A Community Study of Depression Treatment and Employment Earnings. Psychiatric Services 1999, 50:1209–1213.2. Zhang M, Rost K, Fortney JC, Smith GR: The pre-publication history for this paper can be accessed here:


Parkinson's disease (PD) is the second most common neurodegenerative disorder. As there is no definitive diagnostic test, its diagnosis is based on clinical criteria. Recently transcranial duplex scanning (TCD) of the substantia nigra in the brainstem has been proposed as an instrument to diagnose PD. We and others have found that TCD scanning of substantia nigra duplex is a relatively accurate diagnostic instrument in patients with parkinsonian symptoms. However, all studies on TCD so far have involved well-defined, later-stage PD patients, which will obviously lead to an overestimate of the diagnostic accuracy of TCD.We have therefore set out to conduct a prospective study testing the diagnostic accuracy of TCD in patients with a parkinsonism of unclear origin.We will enrol 250 consecutive patients, who are referred to neurology outpatient clinics of two teaching hospitals, for analysis of clinically unclear parkinsonism. Patients, whose parkinsonism is clearly diagnosable at the first visit, will be excluded from the study. All patients will undergo a TCD of the substantia nigra. As a surrogate gold standard we will use the consensus clinical diagnosis reached by two independent, blinded, movement disorder specialist neurologists after 2 years follow-up. At the time of TCD, patients will also undergo a SPECT scan of the brain.As this prospective trial enrols only patients with an early-stage parkinsonism, it will yield data on the diagnostic accuracy of TCD that is relevant to daily clinical practice: The neurologist needs a diagnostic tool that provides additional information in patients with a clinically indefinable parkinsonian syndrome. The above described observational longitudinal study was designed to explicitly study this aspect in the diagnostic process.(ITRSCC) NCT00368199 Parkinson's disease (PD) is the second most common neurodegenerative disorder with a life-time risk of 2 percent in males and 1.3 percent in females [The gold standard for the diagnosis of PD is post-mortem neuropathological examination. Clinicopathological studies show that 2–25 % of the patients with IPD are classified incorrectly in the final stage of their disease, even by specialists in movement disorders, with MSA and PSP accounting for most false positives ,5. DiagnA reliable test to diagnose PD is important for two reasons. Prognosis and medical treatment in the various parkinsonian syndromes differ considerably and an objective disease marker would facilitate the development of neuroprotective therapies ,8. SeverAt the moment neuro-imaging techniques like PET and SPECT are the most widely used diagnostic tools . PET is A more recent addition to the diagnostic armamentarium of the neurologist is transcranial duplex scanning (TCD) of the substantia nigra (SN) in the brainstem. In 1994 Becker discovered that patients with PD had bilateral hyperechogenicity of the SN , probablThis technique has high inter-observer reliability ,25,29. IBased on this study we hypothesized that TCD of substantia nigra is a tool deserving a place in the diagnostic work-up of PD/Parkinsonism patients. TCD is less costly and less invasive than SPECT . Since aObservational, prospective, longitudinal study.Consecutive patients will be recruited from the Neurology Outpatient Clinic of two hospitals: the University Hospital Maastricht in Maastricht and the Maasland Hospital in Sittard, The Netherlands. TCD will be done in the departments of Clinical Neurophysiology of the two above mentioned hospitals. SPECT scanning will be done in the departments of Nuclear Medicine of the two hospitalsThe Institutional Review Board (IRB) of the University Hospital Maastricht has approved the study . . All patients will be asked for informed consent through a standardised information form that is also approved by the Institutional Review Board.250 consecutive patients with new parkinsonian signs and symptoms (of unclear origin at the time of visit) referred to the Neurology Outpatient Clinics of the University Hospital Maastricht (n = 150) and the Maasland Hospital Sittard, (n = 100).1. Patients with parkinsonian signs and symptoms of unclear origin at the time of visit at the Neurology Outpatient Clinic. In his/her differential diagnosis the treating neurologist should be considering one of the following conditions: PD, MSA, and PSP. ET, VP or DIP.2. Age older than 18 years.1. Patients presenting with a clear unequivocal diagnosis of their parkinsonism.2. Patients whose life expectancy is less than the required follow-up of two years.After informed consent all subjects will undergo a structured interview, neurological examination . In the structured interview a standard form with the following items are discussed: medical history, used drugs and effect, intoxications, duration of complaints, and most affected body- side (See attachment 1). The following clinimetric scales are scored: UPDRS  , Hoehn a123I-ioflupane, Nycomed, Amersham, U.K.) is used as presynaptic radiotracer. Medication  which could interfere with the radiotracer is discontinued at least 5 half life times. After intravenous injection of the tracer, SPECT measures baseline dopamine transporter integrity in the brain. SPECT is performed with a triple head camera  equipped with high-resolution collimators. A semi-automatic template model programme is used to calculate the ratios between left striatal and right striatal and occipital regions respectively. Total time of acquisition is 30 minutes (45 seconds per frame for 40 views per detector). Zoom factor: 1.00 and the matrix size: 128 × 128. Filtered back-projection acquisition is performed. Images are filtered using a Butterworth filter with a cut-off value of: 0.4–0.5 and an order of 5. A division between the caudate nucleus and putamen is made. The ratios are corrected using Alderson's brain phantom, with known activities in the caudate nucleus and putamen. A binding of two standard deviations below healthy controls is considered as abnormal (FP-CIT 8.25 +-1.85 for putamen and 7.76 +-1.77 for caudate nucleus). Beside quantitative the scans will be also judged visually by the same nuclear specialist blinded for the final clinical diagnosis. If quantitative and visual judgments do not agree the conclusion of visual judgment is taken (unpublished data).All subjects will undergo SPECT scanning within 6 weeks of inclusion in the study. In this study FP-CIT  by an experienced sonographer, blinded for the clinical data and SPECT results. The quality of the temporal bone window, the SN and Raphe nuclei (RN) of all subjects are scored directly by the sonographer blinded for the final clinical diagnosis and SPECT result. The quality of the bone window is scored as good, moderate or inconclusive.2 is classified as characteristic for PD. The RN are scored as: invisible (= iso-intense), just visible, visible (= hyper-intense) or inconclusive .Two different methods are applied for the evaluation of the echointensity of the SN. Firstly, the presence or absence of an obviously visible bilateral hyperechogenic SN is scored . The SN are scored as hyperechointens, not hyperechointens or inconclusive . Secondly, the area of an eventually hyperechogenic SN will be measured quantitatively (quantitative method). Both the right and left SN are measured from both sides, i.e. both temporal bone windows. After encircling, the area is automatically calculated. A hyperechogenic area of at least 0.2 cmTo determine inter-observer variability and to increase the power of the study a second sonographer will also judge the acquired echo data. A loop of 64 images of each patient will be acquired scanning the brainstem cranio-caudally and will be stored in order to allow for off-line analysis. Off-line the quality of the temporal bone window, SN and RN will scored by the second sonographer.The initial treating neurologist will remain responsible for the regular outpatient management of the patient included in the study. He or she will discuss the test results with the patient, and base his/her treatment plan on these. All further clinical decisions will be made by the treating neurologist.Two years after inclusion, all patients will be re-examined separately by two independent movement disorder specialist neurologists blinded for the tests results. They will also be blinded for the clinical records of the treating neurologist. The same standard form as in the first visit is filled in )/n → p1 = 0.9, sd 0.02, implying n = 190 patients, needed who have the hyperintensity of SN with TCD scanning.In our pilot study 15% of the patients had an insufficient temporal bone window, so 224 patients are needed to compensate for the amount of inconclusive TCDs . Based oAdditionally we will determine the predictive value of TCD compatible with PD for an abnormal FP-CIT SPECT scan. Finally the inter-observer reliability for SN and RN judgement by TCD will be determined (Cohen's kappa test).SPSS 11.0 for windows  and StataSE9  will be used for statistical analysis.The hitherto published literature on TCD in parkinsonian syndromes are cross-sectional studies on clinically well-defined patient populations -30,45. AThe above described observational longitudinal study was designed to explicitly study this aspect in the diagnostic process. We arbitrarily choose the clinical diagnosis after two years as the surrogate gold standard. This is, of course, not ideal, as there will always remain a small proportion of patients that is not definitely diagnosable after two years, and misdiagnoses  are still possible. In an effort to tackle his last obstacle we require the final diagnosis to be shared by two independent, blinded, experienced movement disorders specialist neurologists.We included SPECT scans in the study to enable us to make a direct comparison between SPECT and TCD as to their diagnostic accuracy. Although the use of SPECT scans in the diagnostic work-up of parkinsonian patients is still debated, it is widely used ,19,46. W4 years . Start recruiting 1-9-2006. Expected study completion date 1-10-2010.123I-ioflupane; TCD, transcranial duplex scanning; SN, substantia nigra; RN, Raphe nuclei; UPDRS, United Parkinson's Disease Rating ScalePD, Parkinson's disease; MSA, multiple system atrophy; PSP, progressive supranuclear palsy; VP, vascular parkinsonism; DIP, drug induced parkinsonism; ET, essential tremor; SPECT, Single Photon Emission Computer Tomography; PET, Positron Emission Tomography; FP-CIT, The author(s) declare that they have no competing interests.All authors have read and approved the final manuscript. WM and WW initiated the study. AV, WW, ST, AK, and WW wrote the protocol. AV, AB, AW and WW will do the patient inclusion. AW will do the clinical examination after two years for a final diagnosis. AV, WW and AK will do the statistical calculations. AV, AB, AW, WW, WM, MK and ST will write the first draft of the paper.The pre-publication history for this paper can be accessed here:Standard clinical scorings form. Standard form used to collect clinical data as described.Click here for file


We investigated the patient- and treatment-system dependent factors affecting treatment outcome in a two-year cohort of all treated culture-verified pulmonary tuberculosis (TB) cases to establish a basis for improving outcomes.Medical records of all cases in 1995 – 1996 were abstracted to assess outcome of treatment. Outcome was divided into three groups: favourable, death and other unfavourable. Predictors of unfavourable outcome were assessed in univariate and multivariate analysis.Among 629 cases a favourable outcome was achieved in 441 (70.1%), 17.2% (108) died and other unfavourable outcome took place in 12.7% (80). Significant independent risk factors for death were male sex, high age, non-HIV -related immunosuppression and any other than a pulmonary specialty being responsible for stopping treatment. History of previous tuberculosis was inversely associated with the risk of death. For other unfavourable treatment outcomes, significant risk factors were pause(s) in treatment, treatment with INH+RIF+EMB/SM, and internal medicine specialty being responsible at the end of the treatment.We observed a significant association with unfavourable outcome for the specialty responsible for treatment being other than pulmonary, but not for the volume of cases, which has implications for system arrangements. Poor outcomes associated with immunosuppression and advanced age, with frequent comorbidity, stress a low threshold of suspicion, availability of rapid diagnostics, and early empiric treatment as probable approaches in attempting to improve treatment outcomes in countries with very low incidence of TB. Early diagnosis of tuberculosis and effective treatment are the key elements in reduction of transmission of infection and finally achieving elimination of TB . World HIn many industrialized countries with good treatment facilities and a secured supply of drugs free of charge for patients, treatment results have not reached the targets set by WHO -18. The The specific reasons for unsuccessful outcomes are important in order to improve treatment systems. In a recent outcome analysis from Norway, where the large majority of TB cases are in immigrants, only high age and isoniazid (INH) resistance were significant risk factors for non-successful outcome . In earlIn low incidence countries, many of the clinical units treating tuberculosis patients have small and decreasing numbers of patients. This necessitates an assessment of the need to concentrate patients in fewer units to retain the level of experience sufficient for successful outcomes. There is varying evidence from assessments made in other areas of complex treatments, such as leukaemia, AIDS, demanding surgery and myocardial infarction, that the volume of treatments has an effect on the outcome ,24. It iWe assessed the patient and treatment system dependent factors affecting treatment outcome in a national, population-based two-year cohort of all culture-verified pulmonary tuberculosis cases in Finland, with a TB incidence of 12,5 per 100 000 per year during the study period, to establish a basis for improving the proportion of favourable outcomes.st, 1995, to December 31st, 1996 (N = 1059), present in either the National Infectious Disease Register (NIDR) or through a separate query to all microbiological laboratories has been described elsewhere [The method of identifying all culture-confirmed tuberculosis cases in Finland, with the first positive culture sample date between January 1lsewhere .M. tuberculosis in sputum or bronchoalveolar lavage (BAL), or as a culture finding for M. tuberculosis from another sample type in a case with sputum smear positive for acid fast bacilli. With this definition, 737 (70 % of the whole cohort) cases with pulmonary tuberculosis were identified. Species identification for Mycobacterium tuberculosis was carried out in every case. There were altogether 660 isolations of mycobacteria other than M. tuberculosis during the study period. Only culture positive cases were taken into the study in order to be able to study only the fully confirmed cases.A case of tuberculosis was defined for the study as pulmonary using the case definition of NIDR, i.e. as a culture finding for Out of the 737 pulmonary tuberculosis cases, complete medical records were available from 711 (96%). Among these 711 cases, twenty-two (3.1%) had previously been treated for tuberculosis after the year 1970, and were excluded from the outcome analysis as re-treatment cases. Of the 689 cases, 33 were still on treatment at 12 months, and were also excluded from the analysis. Of the remaining 656 cases, 27 were not treated, among them 19 (70.4%) were men and 8 (29.6%) women. Of this group, with a median age of 82.0 years, 24 died before treatment and 3 were left untreated. Those without treatment were excluded from the main analysis of 629 actually treated cases , cytotoxic or cyclosporine treatment, or radiation therapy during the preceding year. For inclusion in the group of social risk factors, a case should have a history of alcohol abuse, unemployment, imprisonment or homelessness recorded in patient records. Diabetes was defined as juvenile or adult onset disease on medication.Specialty responsible for treatment was that of the unit treating patient as an inpatient or outpatient. Change of specialty included any change from one speciality to another during treatment.The ethics approval for this study was acquired from the National Research and Development Centre for Welfare and Health.We used multinomial logistic regression model to assess the relationships between all potential predictors, listed in the univariate analysis, and a 3-class outcome variable, in which reference class was favourable outcome. To the final model significant predictors were selected using forward stepwise methods. Any variable whose univariable test had a p-value <0.20 was included in the multivariable analysis. P-values under 5% were considered as significant. For univariate results Chi squared test and Fisher's exact test were used.In the study cohort of 629 cases, 386 (61.4%) were men and 243 (38.6%) women. The mean age was 62.9 years, the median 67.2. The proportion of cases aged ≥65 years was 339 (53.9%). The proportion of immigrants was 4.1% (26 cases), mainly from developing countries (Table A favourable outcome was achieved in 441 (70.1%) of the cases, consisting of those cured 199 (31.6%) and treatment completed 242 (38.5%). There were no treatment failures in the cohort. The proportion of cases defaulting or transferring out was 32 (5.1 %). For 48 (7.6%) cases, treatment was stopped prematurely by physician. Death was the outcome in 17.2 % (108/629) cases.In univariate analysis, patient-related risk factors which were significantly associated (p < 0.05) with death, were age ≥65 years, social risk factor, immunosuppression and malignancy Table . TreatmeSignificant independent risk factors for death in multinomial logistic regression model were male sex, high age, immunosuppression and any other than a pulmonary specialty being responsible at the end of the treatment. History of previous tuberculosis was inversely associated with the risk of death p = 0.044). For other unfavourable treatment outcomes, significant risk factors were pause(s) in treatment, treatment group B and internal medicine being responsible at the end of the treatment , high age (p = 0.03), pause(s) in treatment (p < 0.001), treatment group other than A (p = 0.003) and any other than a pulmonary specialty being responsible for ending the treatment (p < 0.001). Earlier TB was a significant factor for favourable outcome (p = 0.012).When we analysed all 656 cases in the cohort with known outcome, including those 27 without treatment, the associations observed in univariate and multivariate analysis as significant were the same as with the 629 cases of the presented analysis.We analysed a large 2-year national cohort of culture-proven pulmonary tuberculosis cases for patient- and treatment-system related risk factors of unfavourable outcome. Apart from previously known patient-related risk factors for an unfavourable outcome, we observed a significant association with unfavourable outcome for the specialty responsible for treatment being other than pulmonary, but not for the volume of cases that the unit treated per year.Due to the strictly controlled data collection process and high coverage, as reported previously , the datDue to relatively small number of deaths, the power of the study to investigate death as outcome was limited. The study was retrospective. Therefore, despite the meticulous conduct, it is possible that not all factors such as co-morbid conditions were recorded in the case notes.Due to the fact that the TB patients in Finland are exceptionally old , contribIn our aging population of TB cases, in the absence of TB/HIV co-infections, we found immunosuppression, virtually all due to other causes than HIV infection, from concomitant diseases and their medical treatment to be a risk factor for death, as has been previously reported ,14. For In the analysis of treatment system -related factors, we found in univariate analysis significant or patterns of close to significant associations to death with specialty other than pulmonary beginning or ending the treatment, and with a switch in the specialty responsible for treatment. However, in multivariable analysis only the specialty service responsible for cessation of treatment being other than pulmonary was associated with death. Even though our data allowed controlling for a range of comorbid states, it is possible that in a patient population where half of the cases are older than 65 years, there could be more comorbidity in the group that ends up being treated in internal medicine and geriatric services.An interesting finding in the univariate analysis for system-related risk factors was a reverse association of death with the number of cases treated per year by the unit in charge of ending the treatment. However, this association did not remain an independent predictor in multivariable analysis. For other unfavourable outcomes, there was no suggestion from univariate or multivariate analysis of an association with number of patient treated per year. While the volume of TB cases seen by each treating unit is becoming small, it is relevant to observe that favourable outcomes have been associated with increasing number of procedures for some other medical interventions such as treatment of leukaemia, AIDS and myocardial infarctions -25. PulmPause(s) in treatment were not found to be a risk factor for death. This can be due to deaths concentrating in the beginning of the treatment period in our study, leaving less possibility for pauses. On the other hand, pauses of treatment were a risk factor for other unfavourable outcome both in univariate analysis and in multivariate analysis. Pauses can be caused by side effects of treatment as well as non-compliance of a patient. There were more pauses in the initiation phase than in the continuation phase. Pauses during initiation may be more disadvantageous than in the later phase.The potentially protective effect of history of earlier tuberculosis, although of borderline statistical significance, was an interesting finding. It seems likely that knowledge of tuberculosis in the past raises the early suspicion of the rare disease earlier, both in the patient as well as in treating doctor, leading to shorter delay in diagnostics and starting treatment, reported to affect outcome .For unfavourable outcomes other than death, in univariate analysis association was found for being an immigrant, internal medicine service ending the treatment, belonging to treatment group B (commonly used when adverse effects necessitate switching of drugs or liver complications are anticipated), change in treatment group, and pauses in any stage of treatment. In multivariable analysis, however, only the system-related risk factors of internal medicine ending treatment, pause(s) and belonging to treatment group B remained independently associated with other unfavourable outcome. Earlier studies have found immigration as a significant risk factor ,12,16. FA high proportion of deaths as TB treatment outcome are typical in low-prevalence countries ,12,15-18The author(s) declare that they have no competing interests.TV checked the data, led the analysis and interpretation of the data, and prepared an initial draft of the manuscript. PH and JO performed the statistical analyses and contributed to drafting the manuscript. KL contributed to designing the study, analysis and interpretation of the data, and to drafting the manuscript. MK led the collection of data and critically revised the manuscript. PR conceived of and coordinated the project, contributed to analysis and interpretation of the data, to drafting the manuscript, and critically revised the manuscript. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:


Paracoccidioides brasiliensis in hyperendemic areas has provided a valuable opportunity for understanding the role of this mammal in the eco-epidemiology of Paracoccidioidomycosis (PCM), one of the most important systemic mycoses in Latin America.Several pathogens that cause important zoonotic diseases have been frequently associated with armadillos and other xenarthrans. This mammal group typically has evolved on the South American continent and many of its extant species are seriously threatened with extinction. Natural infection of armadillos with P. brasiliensis in different xenarthran species , by molecular and mycological approaches, in samples obtained by one of the following strategies: i) from road-killed animals (n = 6); ii) from naturally dead animals (n = 8); iii) from animals that died in captivity (n = 9); and iv) from living animals captured from the wild (n = 2). Specific P. brasiliensis DNA was detected in several organs among 7/20 nine-banded armadillos (D. novemcinctus) and in 2/2 anteaters (M. tridactyla). The fungus was also cultured in tissue samples from one of two armadillos captured from the wild.This study aimed to detect P. brasiliensis infection in wild animals, from PCM endemic areas, may be more common than initially postulated and reinforces the use of these animals as sentinels for the pathogen in the environment.Members of the Xenarthra Order, especially armadillos, have some characteristics, including a weak cellular immune response and low body temperature, which make them suitable models for studying host-pathogen interaction.  Paracoccidioides brasiliensis, Histoplasma capsulatum and Coccidioides immitis [Great advances have been made over the last few years in understanding the evolutionary aspects of fungal groups that attach themselves to animal hosts . Xenarth immitis .Paracoccidioides brasiliensis is an important pathogenic fungus that causes paracoccidioidomycosis (PCM), a systemic mycosis with broad distribution in Latin America. The infection is caused by inhalation of airborne propagules of the mycelial phase of the fungus that reach the lungs and differentiate into the yeast parasitic phase [ic phase .P. brasiliensis has remained undefined, even after a century of ongoing discoveries about the disease. The high frequency of isolation or molecular detection of the fungus in armadillos has created new opportunities for the study of the role of xenarthrans in the ecology of this microorganism. The first isolation of P. brasiliensis was observed in armadillos from the Amazon region [The precise habitat of n region , a findin region -10 and Cn region ,12.P. brasiliensis infection in tissue samples of several xenarthran members, by using molecular and traditional mycological procedures. The data indicate that, besides armadillos, the pathogen may occur in other xenarthran terrestrial species.The present study aimed to evaluate The xenarthran animals (n = 25) were obtained in the Botucatu endemic PCM area, in São Paulo State, Brazil, by one of the following strategies: i) road-killed animals (n = 6), that had been recently killed (1-7 hours) and presented no exposure of the internal organs; ii) naturally-dead armadillos (n = 8), which were found in the field of the Lauro de Souza Lima Institute (ILSL), Bauru County, a center of leprosy study located in a savanna reserve; iii) armadillos that died in captivity (n = 9), after having been maintained in the armadillo facility of ILSL; iv) armadillos captured from the wild (n = 2) in Cerqueira César County, that proved to present one of the highest prevalences for human PCM disease ,14. The The data on the geographical location of the animals and results are summarized in Table The DNA extraction was performed by grinding the liquid-nitrogen frozen tissue sample with mortar and pestle as proposed by Corredor et al. . The molP. brasiliensis were detected in several tissue fragments of seven D. novemcinctus armadillos and two M. tridactyla anteaters  among the ones found dead in the field or those had been recently introduced into captivity, when compared with the ones that had died after a long period in captivity .P. brasiliensis sequences deposited at the GenBank , supplemented with gentamicin (50 μg/mL) and incubated for 4 weeks at 36°C, as already described . The chaThe study was performed in accordance with the Brazilian Agency for Protection of the Environment and Renewable Resources  and Animal Research Ethics Committees  at the Institute of Biosciences, UNESP-Botucatu.P. brasiliensis in nine-banded armadillos and also provides the first indication that the infection occurs in the anteater M. tridactyla, another xenarthran that also has the habit of foraging in soil. In a previous study of road-killed wild animals, it was observed that besides the nine-banded armadillo (D. novemcinctus), the seven-banded armadillo (Dasypus septemcinctus) also might be infected by the fungus [P. brasiliensis from the naked-tailed armadillo Cabassous centralis [P. brasiliensis infection in wild animals, from PCM endemic areas, may be more common than initially postulated, especially in armadillos and probably other xenarthrans. These animals have some peculiar physiological and ecological characteristics such as a low body temperature, besides the fact that most of them, such as armadillos, live literally immersed in soil and organic matter, mainly in tropical and subtropical regions, under biotic and abiotic conditions that promote multiple encounters with a diverse group of pathogens and vectors. Furthermore, these animals are thought to possess a weak cellular immune response. At first, this seems to be somewhat controversial since no animal presenting PCM disease has been detected; however, the damage to the host does not depend only on the pathogen, but also on the host response. Casadeval and Pirofisk [P. brasiliensis to be a pathogen whose ability to provoke disease also depends on host immune response. Since the cellular immune response is weak in armadillos, it is possible to detect yeast cells in many of their organs; however, this is not sufficient to cause disease as observed in human hosts. Taken together, these factors make xenarthrans suitable models for studying host-pathogen interaction [The present study confirms the frequent occurrence of e fungus . In a Coentralis . As alrePirofisk  clarifiePirofisk . Therefoeraction . Given tP. brasiliensis and anneal in the ITS1 region, known to be variable among different species. The specificity of this primer set has been previously verified and no amplification has been detected in several other related species such as Histoplasma capsulatum, Blastomyces dermatitidis, Coccidioides spp. and Emmonsia parva [The molecular approach applied herein is both sensitive and specific, since the inner primers used in the second PCR were designed specifically for ia parva ,17.P. brasiliensis was detected in three of the four captured animals that were evaluated by fungal culture and molecular detection [In the group of armadillos originally obtained in the savanna reserve at Bauru/SP, the positivity of Nested-PCR appears to show two distinct situations: while the positivity was relatively high in the animals found dead of natural causes in the field and in those that died soon after being introduced into captivity, the molecular detection was negative in all samples from the animals that had been maintained for a long period in captivity. Although keeping the animal corpses frozen until the necropsy may harm the molecular analysis, it could also be argued that during captivity, the animals had become free of the pathogen. Recently, we have also confirmed that the armadillos living in this area are highly infected by the fungus, since etection . A surveetection . In an aetection . These fetection ,20.P.brasiliensis was also isolated from the spleen and mesenteric lymph node in one of the two armadillos captured in the Cerqueira César County, a location identified as presenting one of the highest prevalences of human PCM cases in our hyperendemic area [In the present study, mic area ,14,21. Imic area ,8,20. Onmic area . A possimic area ,9,20.P. brasiliensis has great affinity for shade and moist vegetation, near rivers [P. brasiliensis in armadillos from savanna areas indicates the presence of the pathogen in this environment that tends toward an acidic pH and a large quantity of aluminum cations (H+Al) in the soil, which is considered unsuitable for the fungus [Since many xenarthrans, especially armadillos, present restricted home ranges, with no migration habits, they may be used for mapping risk areas for infection as well as for understanding the fungus's ecology. Exploring some ecological features, the culture-positive animal was captured in an area of natural vegetation, corresponding to a semideciduous tropical forest, near a watercourse, corroborating the idea that r rivers ,7,14,23.P. brasiliensis detection in armadillos and other xenarthrans, in connection with the associated ecological factors, represent an apt strategy to obtain fundamental information about the pathogen's ecology as well as the manner in which this fungus interacts with its several hosts, including humans.In conclusion, studies on The authors declare that they have no competing interests.VBRP: Study design, animal necropsy, fieldwork and data collection, laboratory tests, analysis and interpretation of data, writing manuscript. SMGB: Study design, analysis and interpretation of data, writing manuscript. RCT: Fieldwork, analysis and interpretation of data. LB: Geographical location of animals. SCBP: Fieldwork, animal necropsy, analysis and interpretation of data. PSR: Data collection, analysis and interpretation of data. EB: Coordination, study design, fieldwork, analysis and interpretation of data, writing manuscript. All authors read and approved the final manuscript.


Evidence suggests that risk of chronic diseases may be programmed during the foetal and early life of the infant. With high rates of low birthweight coupled with a rapid nutritional transition, low-income countries are facing an epidemic of chronic diseases. Follow-up of a cohort of adults born during 1964–1978 in an urban slum in Lahore, Pakistan, is presented in this paper. In 695 of these adults , blood pressure, fasting blood glucose, and body mass index (BMI) were measured to assess early-life predictors of risk of chronic diseases. Sixteen percent of the study population was born with a low birthweight . A significant positive association (p=0.007) was observed between birthweight and BMI; additionally, adjusting for age and gender, the association with BMI was highly significant (p=0.000). Conversely, a significant negative association (p=0.016) was observed between birthweight and adult levels of fasting plasma glucose; after adjustment for age and gender, the association was more significant (p=0.005) No association was observed between birthweight and adult blood pressure. The results suggest that low birthweight may increase later risk of impaired glucose tolerance in urban Pakistani adults. Further research in this area is warranted. The effect that the early-life environment has on later health and survival is presently the subject of much scientific interest and debate, with rates of both pre- and postnatal growth linked to later risk of disease ,2. A conThe vast majority of low-birthweight babies are born in developing countries and, with such high rates of foetal growth restriction, one would presume a high later risk of disease. Arguably however, the foetal origins hypothesis might not be of great significance in such countries if the population remains lean, fit, and frugal . HoweverAlthough the foetal origins hypothesis has been much debated and frequently re-examined in affluent populations, long-term record-keeping has not been a high priority in developing countries, meaning that the opportunities for follow-up are extremely rare in the very populations, in which the hypothesis may have the greatest public-health significance. The increasing prevalence of obesity, dyslipidaemia, and diabetes mellitus in middle age, particularly in females, needs immediate attention in terms of prevention and health education in such economically-deprived populations .According to the National Health Survey, obesity is more common among females than among males in Pakistan for all age-groups and in both urban and rural areas . In most2. Furthermore, it has been observed that these small Indian babies have a low muscle mass, small viscera, and a relative excess of fat, a body composition particularly likely to lead to insulin resistance . However, at the start of the project, the rate of registration was quite low and, as such, a monetary incentive was given to the TBAs to encourage the prompt registration of all births. The project team then obtained information about new births through daily visits to the office of the local authority located in the study area. Despite this procedure and the incentive offered, many infants were still not registered immediately and, hence, the recruitment of the infants into the study started at any time between birth and two months of age. Furthermore, during interactions with the families, the team learned that, in the Indo-Pakistan subcontinent, deaths during the traditional ‘Chilla period); after this, mothers were encouraged to bring the child to the health clinic monthly until six months, quarterly until two years, and then yearly until 12 years of age. The visits were less frequent after 1–2 year(s), as most often the mother was pregnant again. Nearly 55% of the children were examined 3–9 times during the first two years, while 30% were examined 10–39 times. At each visit, the mother was encouraged to have the child weighed using a beam scale and length measured by a locally-manufactured portable length metre. Milestones of development and history of feeding and illnesses for each child were also recorded. The World Health Organization (WHO) standards were taken for the evaluation of growth  had early-life data available and were considered for follow-up in the present study. Of these, 584 (30.6%) could not be found, 63 (3.3%) refused to participate in the study, and 205 (10.5%) had died since their initial registration, while 118 (6.2%) were either out of the city or out of the country. In total, 932 (49%) adults were successfully recruited into this follow-up study. No attempt was made to trace 566 subjects for whom only socioeconomic data were recorded during infancy; for these subjects, early anthropometric data were not available as the field team was not permitted to measure the newborn. Figure A new questionnaire was administered to each adult enrolled into the study (n=932) to record the current health status, and a trained doctor conducted a complete physical examination. A Tanita electronic scale  was used for measuring weight, and height was measured using a portable stadiometre. Blood pressure was measured in triplicate, with subjects seated and at rest, using a sphygmomanometer  . In totaThe Medical Ethics Committee for Research of King Edward Medical College, Lahore, Pakistan, and the Ethics Committee of University of Gothenburg, Sweden, approved the study.Of the 932 subjects traced to follow-up, 695 (74.6%) had fasting blood glucose levels determined. Of these, 583 (83.9%) had a birthweight measured within one week (excluding premature infants and twins) and were, therefore, included in the analysis of the associations between birthweight and adult variables. As mentioned, the infants were measured only when the mothers chose to bring their infants for growth monitoring. Thus, the number of infants measured at each specific age points was limited and varied according to time point.Simple linear and multiple linear regression models were used for relating the birthweight with adult variables: BMI, blood sugar, and systolic and diastolic blood pressure. Some influential cases were removed from regression analysis based on high leverage values and DFBetas ,20.t-test was used for comparing plasma glucose level in subjects who were short and obese with those who were tall and obese.Independent samples Birthweight was used as a continuous variable for exploring associations with the adult variables. Associations of birthweight with the adult variable were analyzed using three Models. Model 1 was without making any adjustments, Model 2 with adjustment with age and gender, and Model 3 with age, gender, and BMI.Standard deviation (SD) scores were calculated using data from local Pakistani upper-middle class population groups as reference . For stuThe characteristics of the infants collected during the initial study in 1964–1978 are summarized in the next few paragraphs.Table Details of infant-feeding practices are shown in Table Figure In total, 205 deaths were recorded in the cohort during 1964–2003. Data on mortality were collected using a previously-validated verbal autopsy tool . Two doc2), 25% had average nutritional status (BMI 18.5–22.9 kg/m2), 25.2% were overweight and at risk (BMI 23–24.9 kg/m2), 29% were obese stage 1 (BMI 25–29.8 kg/m2), and 10.8% very obese stage II (BMI >30 kg/m2), i.e. nearly 40% were obese.Characteristics of the subjects by gender, at follow-up are detailed in Table The mean systolic and diastolic blood pressure was 116.5 mm Hg and 79.3 mm Hg in males and 110.7 mm Hg and 75.1 mm Hg for females respectively. Both systolic and diastolic blood pressure levels were significantly higher in males than in females. No trend with age was observed in the blood pressure values. Of the 695 adult subjects analyzed, 6.4% had raised systolic blood pressure (≥140 mm Hg), and 16.6 % had raised diastolic blood pressure (≥90 mm Hg).The mean fasting levels of blood glucose were 85.7 mg/dL for males and 87.4 mg/dL for females. Fasting blood glucose levels were impaired in 43 (6.2%) of the adult subjects (≥110 mg/dL) (Table A significant positive association was observed between birthweight and BMI (p=0.007); additionally, adjusting for age and gender, the association was highly significant with BMI (p=0.000). Conversely, a significant negative association was observed between birthweight and adult levels of fasting plasma glucose (p=0.016), and after adjusting for age and gender, this was even more significant (p=0.005). No association was observed between birthweight and adult blood pressure: systolic (p=0.098) and diastolic (p=0.068). Even after adjustment for age, gender, and BMI, no significant association was observed between systolic and diastolic blood pressure and birthweight. The association between short and obese and adult variables was not different from those who were tall and obeseData were also analyzed according to infant-feeding status. Grouping infants in predominantly-breastfed, partially-breastfed, or bottle-fed at three months of age showed no significant mean differences with adult variables (data not shown).More than 90% of the world's low-birthweight babies are born in developing countries, and the aetiology of many of these can still be attributed to poor maternal nutritional status. At the same time, many of these countries are undergoing a rapid nutritional transition with increasing affluence and the associated emergence of chronic disease. The implications of the ‘developmental origins of health and disease’ hypothesis are, therefore, of greatest public-health relevance in such countries, and opportunities to investigate these relationships are of importance in understanding the mechanisms of this hypothesis in more detail ,24 and aIn this population group, the prevalence of foetal undernutrition was high, with 16% of the study subjects born of a low birthweight. When this population group was revisited during adulthood, a contrasting picture was observed, and using the proposed classification of BMI for Asians , 25% of In the present study, impaired glucose tolerance was observed in 6.2%, diabetes in 3.2%, raised systolic blood pressure in 6.4%, and raised diastolic blood pressure in 16.6% of the subjects. Higher levels are quoted for developing countries . The Natin utero, or during early infancy is a strong predictor of later glucose intolerance and diabetes risk (et al., our study did not show any association between the short obese and adult variables compared to tall obese (A negative association was found with fasting plasma glucose levels, a strong positive association was found with adult BMI, and no association was found with adult blood pressure. The suggestion of an inverse relationship between birthweight and plasma glucose levels is consistent with data from India, indicating that poor growth tes risk . With inll obese .Using the data from the present study, we were unable to find any significant associations between rates of growth during infancy and later risk of chronic disease. It is possible that this is a consequence of the high rates of infant malnutrition and, hence, a comparatively low number of infants demonstrating accelerated growth between birth and later infancy and childhood. Singhal and colleagues have recently demonstrated an association between feeding of breast milk during infancy and an improved metabolic profile in adolescence , providiIn relation to the observations of the present study, it is of interest to note that a subsample of subjects from this cohort have been used for exploring the hypothesis that immune function is programmed by events in early life. Using antibody response to vaccination, a significant positive association was observed between small size at birth and a reduced response to a polysaccharide typhoid vaccine . This fiLimitations of the current study include: the small range of markers of chronic disease measured; the fact that birthweight was not always measured immediately after delivery; selection bias, in that this subsample from the original cohort does not reflect the whole cohort; or that the adults in this cohort are too young to detect any such association and that one might predict the emergence of disease with an increase in age, especially in view of their developing levels of overweight and obesity. Dyslipidaemia was not explored due to the high cost of the test. Despite these limitations, we have shown that small size at birth in Pakistani adults born in an urban slum is correlated with higher levels of fasting plasma glucose, suggesting that small size at birth, followed by adequate nutrition in adult life, may be a risk factor for later chronic disease. This study further highlights the importance of improving the nutritional status of women of reproductive age, especially in populations undergoing rapid economic transition.The Government of Pakistan financed the original cohort study, and the Nestlé Foundation financed the follow-up study. The authors are grateful to both.


The studies on the association between serum cholesterol level and the risks of neurodegenerative diseases risk are debated. Some prospective studies have found that high serum cholesterol may increase the risks of dementia/Alzheimer's disease and ischemic stroke. However, other studies have found no association or a decreased risk of hemorrhagic stroke with increasing levels of serum total cholesterol. Little is known about the association between serum total cholesterol or a history of hypercholesterolemia and Parkinson's disease (PD) risk. Only a few case-control studies and four prospective epidemiological studies have examined this association, but the results are inconsistent. An inverse association between serum total cholesterol and the risk of PD has been found in one prospective study; however, no significant association is reported in the case-control studies and other two prospective studies. Recently, one large prospective study from Finland suggests that high total cholesterol at baseline is associated with an increased risk of PD. Further studies, especially large clinical trials, are needed. Parkinson's disease (PD) is the second most common neurodegenerative disease of the elderly . PD is aCholesterol is a lipid found in the cell membranes of all animal tissues and is transported in the blood plasma of all animals. Most of the cholesterol is synthesized by the body and some have dietary origin. Cholesterol is more abundant in tissues which either synthesize more or have more abundant densely-packed membranes, for example, the liver, spinal cord, and brain. It plays a central role in many biochemical processes, such as the composition of cell membranes and the synthesis of steroid hormones.There is good evidence that high serum total cholesterol level increases coronary heart disease risk in both middle- and old-aged people and in people at all blood pressure levels . HoweverUntil now, only four case-control studies –11 and fIn two small case-control studies, serum total cholesterol did not differ significantly between PD patients and controls , 9 Tabl. In one The prospective association of serum total cholesterol or a history of hypercholesterolemia with PD risk has been assessed recently , 14–16. P for trend = .035) in men, 1.00, 1.55, 1.57, and 1.86 (P for trend = .113) in women, and 1.00, 1.42, 1.56, and 1.86 (P for trend = .002) in men and women combined  (n = 371), sex- and multivariate-adjusted hazard ratios of PD at different levels of total cholesterol  were 1, 1.42 (95% CI 0.99–2.02), 1.54 (95% CI 1.09–2.18), and 1.85 (95% CI 1.30–2.61) (P for trend = .002) ..P for trTo our knowledge, this Finnish study is the first large prospective study to find out that high total cholesterol may increase PD risk. However, no significant association is reported by the case-control studies and other two prospective studies, and an inverse association has been found in one prospective study. Several reasons for the inconsistency of these studies can be considered. First, potential bias in the case of PD could be substantial in these case-control studies –11. SecoEven though the Finnish study finds an increased PD risk associated with high levels of total cholesterol, the mechanisms of this association are poorly understood. Several putative mechanisms may be proposed. This association may however not be completely unexpected given that brain is the most cholesterol rich organ in the whole body; disturbances in cholesterol homeostasis may therefore influence the structure, function, and maintenance of neuronal cell membranes and synapses . The aggIt could also be hypothesized that high total cholesterol might increase the risk of PD partly through excess body weight. The results from the Honolulu Heart Program and our study have demonstrated that excess weight is associated with an elevated PD risk , 23. In P = .1 for trend) but not in women [Results from case-control studies have suggested an association between PD and dietary factors, such as total, saturated, and animal fat intake and energy intake , 29, butin women . It coulThe studies on the association between serum total cholesterol and a history of hypercholesterolemia and the risk of PD are few the results are inconsistent. A decreased risk of PD with higher serum levels of total cholesterol has been found in one prospective study; however, no significant association is reported in the case-control studies and other two prospective studies. The result from one recent large Finnish prospective study has shown that high total cholesterol at baseline is associated with an increased risk of PD. This increased risk of PD associated with increasing levels of serum total cholesterol was present both in subjects aged 25–44 years and 45–54 years at baseline, and no association was found among subjects aged 55 years or more at baseline. Since most above studies only had baseline measurement of total cholesterol and changes in the levels of total cholesterol were not available during followup, further studies, especially large clinical trials, are needed in the next several years. It would be important to find out mechanisms behind the association between serum total cholesterol and PD risk.