Doctors have a relatively high degree of emotional distress, but seek help to a lesser degree and at a later stage than other academic groups. This can be deleterious for themselves and for their patients. Prevention programs have therefore been developed but it is unclear to what extent they reach doctors in need of help. This study describes doctors who participated in a self-referrral, easily accessible, stress relieving, counselling program in Norway, and compares them with a nationwide sample of Norwegian doctors.Two hundred and twenty seven (94%) of the doctors, 117 women and 110 men, who came to the resort centre Villa Sana, Modum, Norway, between August 2003 and July 2005, agreed to participate in the study. Socio-demographic data, reasons for and ways of help-seeking, sick-leave, symptoms of depression and anxiety, job stress and burnout were assessed by self-reporting questionnaires.Forty-nine percent of the Sana doctors were emotionally exhausted (Maslach) compared with 25% of all Norwegian doctors. However, they did not differ on empathy and working capacity, the other two dimensions in Maslach's burnout inventory. Seventy-three percent of the Sana doctors could be in need of treatment for depression or anxiety based on their symptom distress scores, compared with 14% of men and 18% of women doctors in Norway. Twenty-one percent of the Sana doctors had a history of suicidal thoughts, including how to commit the act, as compared to 10% of Norwegian doctors in general.Sana doctors displayed a higher degree of emotional exhaustion, symptoms of depression and anxiety as well as job related stress, compared with all Norwegian doctors. This may indicate that the program at Villa Sana to a large extent reaches doctors in need of help. The counselling intervention can help doctors to evaluate their professional and private situation, and, when necessary, enhance motivation for seeking adequate treatment. Emotional distress and impaired function among doctors can be deleterious for patients, as well as for the doctors themselves, their colleagues, other co-workers and families -3. DoctoInternationally it has been observed that doctors obtain treatment late in the course of emotional distress; many have been prompted by third parties such as insurance companies, police and review boards, which indicates that job performance has been impaired ,17. TreaThe conditions described above have also led to the establishment of preventive programs. Primary and secondary preventive interventions for doctors have focused on developing appropriate stress management and coping skills -24. PossIn 1998, the Norwegian Medical Association (NMA) established a short-term counselling program for doctors, called Villa Sana. The declared aims for this effort were to enhance health and life quality, strengthen professional awareness and identity and prevent burnout. A prospective study of sociodemographic and clinical characteristics of doctors entering this program over a two-year period from August 2003 was initiated. The questionnaires were chosen in order to make the data comparable to those from a nationwide sample of Norwegian doctors. In this paper, we have raised the following research questions:1. What characterizes doctors who seek help at Villa Sana with regard to gender, age and speciality compared to all Norwegian doctors?2. a) How do doctors apply for help at Villa Sana, and what reasons do they give for seeking help?b) To what degree did they seek help before coming to Villa Sana?3. Do doctors seeking help at Villa Sana differ from Norwegian doctors concerning degree of job stress, burnout and symptoms of depression and anxiety?The program offers two kinds of interventions for doctors or doctors with partners, who feel the need to reflect on their situation, related either to professional or private matters or both. One is a single day counselling session with one counsellor if the doctor comes alone, or two counsellors when there is also a partner or a spouse. The session lasts for 6–7 hours, aiming to give time and possibility to discuss the doctor's life situation and to suggest steps needed to handle the situation. This can include advice on seeking formal medical treatment including psychotherapy. The other type of intervention is a group-based, week-long course with boarding, dimensioned for eight individual doctors or four couples. There are daily lectures, group discussions and physical activity. One individual counselling session is offered during the week. Themes for the lectures are: possibilities and restraints in working life, the individual's resources and personality, concepts of identity, family relations, communication, team work and prevention of burnout. The group discussions are based on the participants' own experiences, providing the possibility to share these issues with colleagues.The idea behind Villa Sana was that the program should be easily accessible. This includes making contact procedures as simple as possible, having readily available times for counselling appointments and having few restrictions as to reasons for contact. Doctors can contact Villa Sana directly on the phone, by post or by e-mail for an appointment. No referral is needed. All applicants are welcomed, except when need for immediate medical treatment is obvious, like serious risk for suicide or psychotic breakthrough. The program has been presented in the Norwegian Medical Journal and is announced twice a year in the same Journal. There are internet links to Villa Sana from the Norwegian Medical Association's web pages, as well as from Modum Bad's web pages. Members of the staff at Villa Sana are also invited to different physician meetings to inform about the program.The Norwegian Medical Association covers all expenses, including travelling costs, making it possible for doctors from all parts of Norway to use Villa Sana. Since the program is defined as a preventive and not a clinical intervention, no medical records are kept.Of 242 eligible doctors, who participated in the Villa Sana programs between August 2003 and July 2005, 227 doctors (94%) gave their informed, written consent to participate in the study. Eighty-two percent (n = 187) came for a counselling session and 18% (n = 40) took part in the course program. The Sana doctors are compared with data from a survey of health, work conditions and life quality of Norwegian doctors from 1993 , comprisnon-specialist, general practice (GP), internal medical specialities, surgical specialities, psychiatric specialities, public health and laboratory medicine .There are five dichotomous categories . If more than one category is marked yes, only one is chosen, ranking "referral" highest, "prompting by a colleague" second, "the doctor's own initiative" third, "coming because partner asked them to" fourth and "other reasons" fifth.are defined as one or more of the following areas: health and life quality, exhaustion/burnout, professional identity (meaning identification with the role as a doctor) , work-reA 26 items version of the original 43 items Cooper's job stress questionnaire , was useMaslach's Burnout Inventory (MBI), with three sub-scales, was used – emotional exhaustion (10 items), reduced empathy (8 items), and reduced work capacity (7 items) ,29. ScorHopkin's symptom check list 5 (SCL-5) was used.Measured by three of Paykel's five items : "Have yOn sick-leave now .Due to the ten year gap between the 1993 survey and our study, we also investigated possible differences in comparable measurements with a nationwide medical student cohort followed from end of medical school (1993) throughout internship and residency (2003). The cohort is described by Tyssen et al , but theIn addition, we have used general statistical data from the Norwegian Medical Association for 2004 and 2005, including doctors < 70 years (NMA web site).Means, correlations, Students' t-test, Chi-square, ANCOVA, Logistic and Linear Regression Analysis were used, with the statistical program SPSS 13.0.The study is approved by the Regional Ethical Committee for Ethical Research in the South of Norway and by the Data Inspectorate through the Norwegian Social Science Data Services.There were 117 (52%) women and 110 (48%) men in the Sana sample. For comparison on gender, age and speciality between the Sana-population and Norwegian doctors, see Table The proportion of GPs was significantly higher in the Sana population (Odds Ratio (OR) = 1,67 95% Confidence Interval (CI) 1.20 to 2.32 p = 0.002), whereas other speciality differences between the two samples were not significant, when controlled for age and gender.Fourty-five percent of the doctors came to Villa Sana on their own initiative, 37% reported that they were prompted by a colleague, 10% were referred, 6% came because they were asked by their partner and 2% came "for other reasons", without gender or age differences.Weighty reasons for contacting Villa Sana are presented in Table Among the Sana doctors two were recipients of 100% and four of 50% rehabilitation or disability benefits, and one doctor was retired. Among the remaining doctors  41% (95% CI 33–47) were on sick-leave at the time of their first visit, with significant gender differences: 49% (95% CI 40–58) women (including 5 doctors on part-time sick-leave) versus 32% (95%CI 23–41) men (including 4 doctors on part-time sick-leave) p < 0.05. Age did not influence the proportion of doctors on sick-leave.Thirty-nine percent had a present GP- contact, and 20% were in therapy with a psychiatrist or a psychologist when contacting Villa Sana.The comparison between the Sana doctors and all Norwegian doctors regarding distress assessments showed that Sana doctors had significantly higher levels of emotional exhaustion (MBI), depression and anxiety (SCL5), all job stress dimensions and suicidal thoughts controlled for age and gender Table . They diIn the Sana group, 49% (95% CI 43 to 56) were defined as "cases" on the dimension of emotional exhaustion (MBI), compared to 25% (95% CI 22 to 28) among Norwegian doctors (p < 0.001).Concerning SCL-5, cases with scores above cut-off and thus possibly in need of treatment were 73% (95% CI 64 to 81) among male Sana doctors versus 14% (95% CI 12–17) among Norwegian male doctors. Among women, 73% (95% CI 65–81) of the Sana doctors compared with 18% (95% CI 14–22) among Norwegian doctors scored above cut-off (p < 0.001 for both men and women).Twenty-one percent (95% CI 15 to 26) of Sana doctors compared to 10% (95% CI 8 to 12) of all Norwegian doctors had seriously considered suicide, as well as having planned it (p < 0.001). Concerning attempted suicide, 2.6% (95% CI 0.6 to 4.7) of Sana-doctors compared to 1.6% (95% CI 0.8 to 2.3) of Norwegian doctors reported this (non significant difference).One of the main findings in this study is the high level of distress among the Sana doctors compared with all Norwegian doctors, assessed with regard to emotional exhaustion, symptoms of depression and anxiety  and job stress parameters. Data indicate that 73% of the doctors coming to Villa Sana could be in need of treatment. The program thus reaches doctors who potentially are in serious need of help. Villa Sana being easily accessible, and the fact that the institution is not part of the ordinary medical services, probably facilitates help-seeking. The program seems to be a way of coming into contact with emotionally distressed doctors, where counselling can help them to evaluate their professional and private situation, in addition to enhancing their motivation for treatment, when necessary. Given the reluctance among doctors to ask for help ,11, suchEmotional exhaustion has, according to Falkum , been viMost of the doctors seeking help at Villa Sana present health issues, exhaustion and burnout as weighty reasons for coming. This is in line with the aims of the program, since it was established for potentially exhausted doctors. Among the younger doctors, problems with professional identity were found to be an important reason for help-seeking. This is consonant with a Finnish study, in which plans for changing career were associated with burnout especially among young doctors , as wellAlthough some studies indicate that female doctors have a higher prevalence of depression or minor psychiatric disease than male doctors ,5,6,37, The relative over-representation of GPs in the Sana group indicates that also Norwegian GPs experience more stress than other specialists, as found elsewhere ,39,40.Of the doctors who were already in therapy when contacting Villa Sana, many, according to our experience, wanted to discuss aspects of work. We have no registration of the intensity or type of therapy offered to these doctors and there might be several reasons for contacting Villa Sana while in therapy. One possibility is that some therapists and/or doctors view Villa Sana as a place of competence regarding problems related to doctors' work.The comparative data used were collected ten years prior to our study, which is a limitation to interpreting the results. On the other hand, a more recent study in 2003 of Norwegian doctors, demonstrates that there is little difference between doctors in 1993 and 2003 on some important measures relevant to this study, indicating that the level of distress and mental health problems among Norwegian doctors has not changed dramatically over this period.Another limitation is the self-reported information, including possible influence of distress symptoms on self-assessment of empathic aptitude and work capacity. The comparable data and studies referred to also use self-reporting forms, thus validating the comparison. There is, however, great need for a more objective evaluation of the relation between self-assessment and objective assessment as underlined in a recent review-article .The major strength of this study is that it recruits a group of doctors seeking help at a counselling program, few studies of this kind having been done previously. The possibility to compare the help-seeking group with Norwegian doctors in general strengthens the design. The prospective aspect of the study enables us to follow the course of distress in the Sana doctors, one and three years after the short-term intervention they have been offered, and to document further help-seeking patterns.In comparison with all Norwegian doctors, this study shows high levels of emotional exhaustion, symptoms of depression and anxiety and job-related stress in doctors coming to an easily accessible, short term counselling program. In view of doctors' general reluctance to seek treatment, it is important to document that making a program easily accessible seems to be a way of reaching doctors in need of help. The counselling intervention can help doctors to evaluate their professional and private situation, and, when necessary, enhance motivation for treatment. Our prospective study will have the potential to document whether distress levels are reduced with time, and whether advice to seek treatment, given during the Sana intervention, is followed.Norwegian Medical Association (NMA)General Practioner (GP)Hopkin's Symptom Check List with 5 items (SCL 5)Maslach's Burnout Inventory (MBI)Odds Ratio (OR)Confidence Interval (CI)Non significant (ns)The author(s) declare that they have no competing interests.KIR has had the main responsibility for this manuscript, with study design, development of the questionnaire used, data collection with analysis and interpretation and manuscript development.TG has contributed to study design, development of the questionnaire used, to data analysis and interpretation and to manuscript development.OA is responsible for data collection of the comparison sample, has participated in constructing the specific questionnaire used, and has contributed to manuscript revision.All authors read and approved of the final manuscript.The pre-publication history for this paper can be accessed here:


We previously found that there is a subtle difference in the global methylation state of blood leukocyte DNA between male subjects with and without schizophrenia. The aim of the current study was to determine whether this difference was a primary effect of the disease state, or a secondary effect of antipsychotics administered to these patients.We examined the methyl cytosine (mC) content of DNA from the leukocytes, brain, and liver of rats using high performance liquid chromatography. A total of 40 male and female rats received for 21 days daily injection of haloperidol or vehicle solution alone.P = 0.028, n = 10), similar to our previous observations in human peripheral leukocytes. No difference in mC content between the sexes was observed in the brain or liver in buffer-treated animals. Haloperidol treatment slightly decreased the mC content of leukocytes in male rats, but unexpectedly, increased the mC content of leukocytes in females. We observed a trend toward a higher level of mC in the liver in both sexes following haloperidol treatment, compared to buffer-treated animals. In contrast, haloperidol treatment resulted in a decrease in mC content in the brain in females, and this difference was statistically significant (P = 0.026).In control rats injected with buffer only, there was a sex-dependent difference in mC content in leukocyte DNA (male > female; These results indicate that haloperidol can affect DNA methylation states in the brain, as well as in certain other tissues, and raise the possibility that antipsychotic drugs play a role in the observed disparity in mC content in male subjects with and without schizophrenia. MECP2) [alpha-thalassemia/mental retardation X-linked (ATRX) syndrome is caused by mutations in ATRX, which encodes a member of the SWI/SNF family of chromatin remodeling proteins. Patients with ATRX syndrome exhibit severe mental retardation as well as alpha-thalassemia [Epidemiological studies have established that genetic factors play a major role in the development of schizophrenia. However, the discordance rate for schizophrenia between monozygotic twins is approximately 50%, suggesting that epigenetic and/or environmental factors are also involved in the development of the disease. Despite extensive research, the molecular etiology of schizophrenia remains enigmatic ,2. The uMECP2) , and alplassemia .Unlike Rett and ATRX syndromes, symptoms of schizophrenia appear later in life, suggesting that environmental factors contribute to the development of the disease. The methylation state of the genome undergoes highly dynamic changes, extensive demethylation and reconstruction during early embryogenesis, yet once established, is very stable . NeverthIn developing a model of schizophrenia , we examad libitum through out the experiment. Haloperidol was kindly provided by Dainippon Sumitomo Pharma Co., Ltd. . The bulk powdered chemical was dissolved in 0.1 M glacial acetic acid buffered to pH6.0 with NaOH at concentration of 0.25 mg/ml [Eight-week-old male and female Sprague-Dawley rats  were purchased from Kyudo Co., Ltd. , housed in standard cages in a controlled environment at a constant room temperature (24 ± 2°C) and humidity (50–70%), and maintained on a 12 h light-dark cycle. Food and water were provided 25 mg/ml . All aniTen male and 10 female rats were administered 0.5 mg/kg haloperidol intraperitoneally on a daily basis . ControlmC content in blood leukocyte DNA was evaluated using high performance liquid chromatography (HPLC). All reagents and conditions for HPLC analysis have been described previously . Global P value was less than 0.05.Statistical analyses were performed using Stat View software . Differences in mean mC content between the two groups were evaluated with the Mann-Whitney U test. Results were considered statistically significant when the All rats treated with haloperidol grew as well as control rats and did not exhibit noticeable abnormal behavior during the course of the experiment. Body weights and blood concentrations of haloperidol and prolactin at the time the animals were sacrificed are summarized in Table In a previous study, we found a sex-dependent difference in the mC content of human leukocyte DNA, with the level in males being greater than that in females ,19. In tP = 0.064). Thus, the sex-dependent difference in mC content of leukocyte DNA between male and female rats appeared to be ameliorated by haloperidol treatment. Global methylation in the brains of haloperidol-treated rats was lower than in the brains of female control animals, and this difference was statistically significant (P = 0.026). There was a higher level of methylation of liver DNA in the drug group compared to the control group, for both males and females, and in males, this difference was statistically significant (P = 0.013). These results are summarized in Table p = 0.570 in leukocytes; ρ = -0.220, p = 0.205 in the liver; ρ = -0.193, p = 0.279 in the brain).We next compared the mC content in haloperidol-injected rats (drug group) to buffer treated control animals (control group) by sex and tissue type. In males, the mean level of mC content of leukocyte DNA was slightly lower in the drug group than in the control group, but the difference was not statistically significant. In contrast, in female leukocytes, we observed a trend toward higher mC levels in the drug group compared to the control group, although again, the difference did not reach a statistically significant level , similar to what was previously observed in humans ,19 The aP = 0.064). Although the reasons why haloperidol treatment would have opposite effects on global methylation in male and female rats are not clear from this study, it is possible that these differences are the result of disruptions in the balance of hormones in these animals. This is supported by observations that there are sex-dependent differences in the immune response to certain hormones, and in the frequency of occurrence of some autoimmune diseases [Haloperidol-treatment resulted in a decrease in the amount of mC in leukocyte DNA in male rats, although the difference did not reach a statistical significance. In contrast, we found a trend toward higher levels of mC in leukocyte DNA in female rats treated with haloperidol . In the brain, haloperidol treatment resulted in a decrease in females, and the decrease was statistically significant (P = 0.026). The differential effect of haloperidol on DNA methylation in various tissues suggests that the regulation of global DNA methylation by this drug occurs through multiple, indirect pathways. In these pathways, sex-specific hormones may play a role in modifying the methylation state of DNA, since haloperidol also disturbs the normal regulation of sex-hormone secretion.In the liver, haloperidol increased global DNA methylation in both males and females, and the difference was statistically significant in males (Several studies have established that there are gender differences among patients with psychiatric disorders, suggesting that sex-specific hormones play a role in the pathogenesis of these disorders, including schizophrenia -29. It rIn the current study, using a limited number of rats, we were unable to demonstrate a causative effect of haloperidol on the observed hypomethylation of leukocyte DNA in male patients with schizophrenia. However, we did uncover several sex- and tissue-specific effects of haloperidol on DNA methylation, which helps the researchers interpret the data in epigenetic studies in schizophrenia, and also would shed light on the mechanism of action of antipsychotics.


Most proteins function by interacting with other molecules. Their interaction interfaces are highly conserved throughout evolution to avoid undesirable interactions that lead to fatal disorders in cells. Rational drug discovery includes computational methods to identify the interaction sites of lead compounds to the target molecules. Identifying and classifying protein interaction interfaces on a large scale can help researchers discover drug targets more efficiently.. It contains both inter-chain (between chains) interfaces and intra-chain (within chain) interfaces. InterPare uses three methods to detect interfaces: 1) the geometric distance method for checking the distance between atoms that belong to different domains, 2) Accessible Surface Area (ASA), a method for detecting the buried region of a protein that is detached from a solvent when forming multimers or complexes, and 3) the Voronoi diagram, a computational geometry method that uses a mathematical definition of interface regions. InterPare includes visualization tools to display protein interior, surface, and interaction interfaces. It also provides statistics such as the amino acid propensities of queried protein according to its interior, surface, and interface region. The atom coordinates that belong to interface, surface, and interior regions can be downloaded from the website.We introduce a large-scale protein domain interaction interface database called InterPare InterPare is an open and public database server for protein interaction interface information. It contains the large-scale interface data for proteins whose 3D-structures are known. As of November 2004, there were 10,583 (Geometric distance), 10,431 (ASA), and 11,010 (Voronoi diagram) entries in the Protein Data Bank (PDB) containing interfaces, according to the above three methods. In the case of the geometric distance method, there are 31,620 inter-chain domain-domain interaction interfaces and 12,758 intra-chain domain-domain interfaces. Proteins are the most important class of molecules in a cell. Most proteins function by interacting with other molecules, especially other proteins. The interactions among proteins are highly regulated and tightly conserved throughout evolution, ,2 mainlyet al. [Since the 1970s, there has been much effort to determine the principles of protein-protein recognition. Pioneers in the field of protein-protein interaction, such as Chothia and Janin [et al. ,11 focuset al.  studied et al. ,14. Joneet al.  introducet al. ,17 invesRecently, there has been a new trend in the study of protein interfaces. Several groups have introduced computational geometric and topology methods for the study of protein interfaces. Most importantly, the Voronoi diagram ,19,23 haDespite all the efforts to unveil the underlying principles of protein-protein interaction for over 30 years, there has not been much progress at the fundamental level since the research by Chothia and Janin . The int or ). InterPare presents interfaces between protein domains identified by three methods. First, the interface is detected by calculating the geometric distance between subunits of multidomain proteins or protein complexes in the PDB [Here, we introduce a large-scale protein interaction interface database called InterPare  Calculating the geometric distance between atoms in different domains (PSIMAP method).2) Detecting the differences of Accessible Surface Area (ASA) from all the residues in two states: the detached individual subunit state and the multimeric state.3) Calculating Voronoi diagrams.1. The geometric distance method checks the distance between atoms in two interacting domains.Two domains are assumed to interact with each other if there are at least 5 residue pairs whose atomic distance falls within 5 Angstrom distance (5-5 rule), according to the PSIMAP algorithm -34. In t2. The Accessible Surface Area (ASA) method detects protein regions that are buried and hence excluded from a solvent when forming a multimer or a complex.2 solvent accessible surface area (ASA) upon aggregation or complexation [If two or more subunits form a protein complex or aggregate, they have to lose a portion of area that was accessible by a solvent . With the ASA method, we define interface residues as residues that have lost more than 1 Ålexation ,38,39. I) in a SCOP domain and their corresponding residues  in a PDB entry,  and  can be either an interface residue  = 1) or a non-interface residue  = 0) based on the difference of ASA in that residue. The threshold (1 Å2 in our case) can be selected by the user on the InterPare website (from 1 Å2 to 5 Å2). As the threshold gets higher, the number of interface residues gets smaller. An interface region, in a domain, that consists of at least 10 interface residues is acceptable, and those having less than 10 residues are considered as artifacts. InterPare only serves domain interaction interfaces having at least 10 interface residues. We calculated the ASA of protein molecules using a program called NACCESS [For all residues  (n is number of atoms in the protein) [First of all, a three dimensional power-diagram s Figure . Power-dprotein) ,47 whereP . The default van der Waals radii of atoms were taken from Chothia . PolygonP Figure , if two  provides files that are required to view molecules with InterFacer. Atom coordinate files of three different regions are available to download. In addition, 1) the size of the interface and surface area, and 2) amino acid compositions on the surface, interior, and interface regions are provided on the results page.InterPare contains protein surface, interior, and interface information from PDB entries. There are three query interfaces to access the information in InterPare. Queries can be 1) keywords, 2) PDB or SCOP IDs, or 3) protein sequences in FASTA format. In the case of a protein sequence, InterPare provides a structural domain assignment module using PDB-ISL  and PSI-The protein interfaceome can be defined as the whole set of protein interaction interfaces found in cells. There can be many methods to define such an interface data set. We use the concept of the hierarchical classification of protein domains from SCOP. We extend the SCOP classification to molecular interfaces. The advantage of this approach is that each interface can be classified in the context of domain evolution. SCOP Superfamily is the level of classification where protein structures are clearly known to be related within the classification group. The protein Family level in SCOP is a more functionally relevant class, where each member of the Family is related and functionally similar. Below Family, there are individual domains. We applied three algorithms to find interfaces associated with SCOP. Any protein domain classification system, such as FSSP  and CATHWe expect that hierarchically similar clusters in the interfaceome will have highly conserved interfaces to maintain their interaction partners. This can provide a new level of functional prediction capability for the designing of novel molecules that can interface with proteins and hence control protein activities.InterPare is an open and public database server for protein interaction interface information. It contains large-scale interface data for proteins whose 3D-structures are known. We identified 31,620 inter-chain interfaces and 12,758 intra-chain interfaces. At this moment, there are 10,583, 10,431, and 11,010 PDB entries whose domain interaction interfaces have been identified according to geometric distance, ASA, and Voronoi diagram methods, respectively. These interfaces are based on protein domains which are from the SCOP database. By using SCOP, InterPare is tightly associated with the domain classification hierarchy, making the search and lookup convenient.. InterPare is jointly maintained by the National Genome Information Center (NGIC) of Korea, Object Interaction Technologies, Inc., Daejeon, Korea, and the BiO Center . It is free to any user.InterPare is available through PSIMAP: Protein Structural Interactome mapPDB: Protein Data BankSCOP: Structural Classification Of Protein structureFSSP: Fold classification based on Structure-Structure alignment of ProteinsSSG worked on the ASA part, drafted the manuscript, and managed this project. CBP implemented a program regarding the Voronoi diagram. JSK developed the InterPare webpage. ISJ and DMB identified protein interfaces using the PSIMAP algorithm. HSC implemented molecular viewer named InterFacer. JSL made C version of PSIMAP program. DSK supervised the development of Voronoi diagram method. DHO and JB supervised this project and revised the manuscript. All authors have read and accepted the final manuscript.


As in many developing countries, the high prevalence of very low BMIs in India represents an important public health risk. Tobacco, smoked in the form of cigarettes or bidis (handmade by rolling a dried rectangular piece of temburni leaf with 0.15–0.25 g of tobacco) or chewed, is another important determinant of health. Tobacco use also may exert a strong influence on BMI.Body mass index [BMI, weight (kg)/height (m2) and tobacco use was examined using data from a representative cross-sectional survey of 99,598 adults  carried out in the city of Mumbai (formerly known as Bombay) in western India. Participants were men and women aged ≥ 35 years who were residents of the main city of Mumbai.The relationship between very low BMI . For smokers, the adjusted odds ratio (OR) and 95% confidence interval (CI) were OR = 1.80(1.65 to 1.96) for men and OR = 1.59(1.09 to 2.32) for women, respectively, relative to non-users. For smokeless tobacco and mixed habits (smoking and smokeless tobacco), OR = 1.28(1.19 to 1.38) and OR = 1.83(1.67 to 2.00) for men and OR = 1.50(1.43 to 1.59) and OR = 2.19(1.90 to 3.41) for women, respectively.Tobacco use appears to be an independent risk factor for low BMI in this population. We conclude that in such populations tobacco control research and interventions will need to be conducted in concert with nutrition research and interventions in order to improve the overall health status of the population. In addition, use of smokeless tobacco, in a variety of forms, is widespread among both men and women. The most common form of smokeless tobacco use is mishri, a black powder obtained by roasting and powdering tobacco, which is then applied to the gums using a finger. Another common form is chewing of betel-quid, a combination of betel-leaf, areca nut, slaked lime, tobacco, and condiments; combinations of ingredients are altered according to individual preferences. Use of all forms of tobacco is associated with higher all-cause mortality in the Indian population. [In India, tobacco is used in various forms.  In additulation. -11 Previulation.  The highThe data presented in this report were obtained from a baseline cross-sectional survey conducted between 1992–1994 for a cohort study on tobacco-attributable mortality.  The survInvestigators approached all individuals aged ≥ 35 years  listed in the selected polling stations for interview and anthropometric measurements. Individuals not present on the voters' list also were interviewed and included in the sample if their residence status was confirmed by their having a 'ration card.' These cards, issued by the Bombay Municipal Corporation, act as a proxy for residence cards and permit access to all city and state government services (including receiving certain food items at subsidized prices). Such individuals comprised about 5% of the sample. Less than 1% of individuals approached refused for interview and/or allow anthropometric measurements to be taken. A total of 99,958 adults, 40,071 males and 59,527 females, were recruited and surveyed. The study satisfied all criteria of ethical treatment of human subjects; especially those formulated by the Indian Council of Medical Research.The survey included two components: 1. measurement of height, weight, blood pressure; and 2. interviewer-administration of a structured questionnaire to obtain information on age, occupational history, education, religion, language, and tobacco-related behaviour. Weight was measured using a bathroom scale accurate to 0.5 kg. The scale was kept on a flat surface and the subject was requested to step on it in bare feet without holding on to anything. Subjects were measured in normal apparel, which in Mumbai is light cotton because of the tropical weather year around. The weight was recorded to the nearest kg. Height was measured using a specially constructed instrument consisting of a steel platform to which was attached a steel measure tape. With the subject standing erect on the steel platform, the tape was pulled vertically above the head, and then brought down to touch the flat ruler placed horizontally on the crown of the head. Height was recorded to the nearest cm.All data were entered directly in a handheld computer in the field and transferred to a PC once a week in the Project office. Respondents were classified according to present and past tobacco use as (a) having never used tobacco, (b) ex-smoker, (c) ex-smokeless tobacco use, (d) ever smoker, (f) ever smokeless tobacco user, and (g) ever mixed habit (smokeless and smoking). Ever smokers and ever mixed users clubbed together were further divided into those who smoked i) cigarettes ii) bidis and iii) cigarettes + bidis. The smokeless-tobacco use further divided into -i) mishri ii) mishri + other forms of tobacco iii) betel quid iv) other tobacco and v) areca nut. For analysis of educational background, respondents were classified as (a) illiterate - received no education (b) primary - up to five years of education (c) middle - 6 to 8 years of education (d) secondary - 9 to 12 years of education (e) college - those who have received education past secondary level. Religion and mother tongue was used for analysis of cultural background. For mother tongue, the categories used were- Marathi, Hindi, Gujarati, Tamil, Urdu and other. For religion, the respondents were classified as Hindu, Muslim, Christian, Jew, Buddhist, and other.Descriptive statistics  were calculated for the total survey population and by tobacco use for both men and women separately. Because the number of ex smokers and cigarette smokers among women was small, separate analyses were not conducted on these two categories.2. These are the conventional cut points indicating underweight and overweight, respectively. Three possible models corresponding to these two cut-off points were fit. Age (in 5-year age groups), education, mother tongue, religion and tobacco use were fit as independent variables in the final model. For dose response, the number of times (per day) tobacco was smoked, chewed or applied was refereed as frequency of habit per day and grouped as 1 to 5/day, 6 to 10/day and ≥ 11/day.Multivariable analysis was performed using logistic regression. The response variable, BMI, was converted into a dichotomous variable by using two cut points: 18.5 and 25.0 kg/mIn general, non-users of tobacco had higher BMI values in this population Table . In wome2) was higher amongst all forms of tobacco users. Amongst smokers, the prevalence of low BMI was 2.5 times higher in bidi-smokers. However, the prevalence of underweight in cigarette smokers was not very different compared to non-tobacco users. Smokeless tobacco users, of all types had high prevalence of low BMI.Table Table Table Table On comparing adjusted odds ratios with unadjusted odds ratios (data not shown), the adjusted odds ratios were always smaller indicating that controlled variables were confounders. The differences however, were not large; the highest reduction in odds ratio was from 2.79 to 2.19 for women with BMI < 16.0 and frequency of smokeless tobacco use > 10 per day; suggesting that there was little possibility of residual confounding affecting the results.2). [In India, nearly half of all rural adults and a quarter of urban adults have a low BMI . . Althoug2). ,16. ThisPreviously we have reported that illiteracy is an independent risk for low BMI in this population .  In MumbaIn the present study, we found bidi- smoking was associated with the highest risk of low BMI (adjusted for education). All forms of tobacco produce free radicals that deplete antioxidants like Vitamin C, E and carotenoids and cause oxidative damage to DNA, proteins and lipids. -21 ConceAntioxidant-rich foods such as green-leafy vegetables and fruits that may help reduce the oxidative stress caused by tobacco  are usuaBesides the direct physiological effect, tobacco use among the economically disadvantaged is known to reduce the resources available to purchase food, clothing, health, and education, all factors that contribute to poor nutritional status.  This expSmoking is not yet very common among Indian women. However, smokeless tobacco use among women is high. In our survey population 59% of women used smokeless tobacco. This is similar to that reported in other South Asian female populations. Some 49% of the UK- Bangladeshi female population and 59% of rural Malaysian females use smokeless tobacco. ,35 In adThere should be no question that a major emphasis of any competent public health programs should be on preventing youth from starting to use tobacco and in supporting tobacco cessation efforts among those already addicted. Also, it is known that tobacco effects dietary requirements. For example, in the UK, the recommendations for vitamin C intake for smokers is higher (80 mg/day) compared to non-smokers (40 mg/day).  Thus farThe results in this paper are from a cross-sectional study so all limitations of cross-sectional data apply to them. In cross-sectional studies, exposure and outcome are assessed at the same time point, and one may not be sure which one came before the other? In the present data set there does not appear any specific reason to suggest that those with low BMI were more prone to start using tobacco. Cross sectional study results may also be affected by differential mortality rates in different subgroups of exposure and outcome. In our study the highest mortality would be most probably in low BMI – tobacco user group and lowest in normal BMI – non tobacco user group. Both these groups contribute to the numerator of odd ratio so the bias if any, is not unidirectional. Another limitation may seem to be the fact that we have not focused on overweight (BMI >25). This is however deliberate; the inverse association between overweight and tobacco use is well established and the same was reported in current data set.  The overThe effects of tobacco use on the incidence of certain diseases, particularly cancers of the aerodigestive tract and urinary bladder are well documented. The findings of this study that all forms of tobacco use are associated with low BMI  suggest a strong need for further research on as tobacco use may have even more far-reaching public health implications in India than previously thought. If the association is evaluated as causal then tobacco control research and intervention also will benefit other public health goals on improved nutritional status and consequential health benefits,. These results have potential to affect the population living in the developing world.The author(s) declare that they have no competing interests.MS Pednekar conceptualized and conducted all data analysis presented here and participated in preparation and finalisation of the article. PC Gupta, HC Shukla, and JR Hebert participated in all aspects of the conceptualization and preparation of the article. All authors read and approve the final manuscript.The pre-publication history for this paper can be accessed here:


It has been suggested that periodontal disease may be an independent risk factor for the development of atherosclerosis. However, the relationship between periodontal disease and atherosclerosis has not been fully elucidated. This study aimed to assess the effects of periodontal disease on atherosclerosis.The study design was a cross-sectional study. Subjects were 291 healthy male workers in Japan. We used the Community Periodontal Index of Treatment Needs (CPITN) score, average probing depth and gingival bleeding index (rate of bleeding gums) to assess the severity of periodontal disease. We also used the Brachial-Ankle Pulse Wave Velocity (baPWV) as the index for the development of atherosclerosis.The unadjusted odds ratio (OR) of atherosclerosis in relation to the CPITN score was 1.41 [95% CI: 1.16–1.73]. However, after adjustment for age, systolic blood pressure and smoking, the CPITN score had no relationship with atherosclerosis (adjusted OR: 0.91 [0.68–1.20]).Our results show no relationship between mild periodontal disease and atherosclerosis after appropriate adjustments. For many people, periodontal disease causes problems in day-to-day life due to loss of teeth. Recently, it has been argued that periodontal disease may be an independent risk factor for the development of atherosclerosis. The potential mechanisms that could explain a role for periodontal disease in atherosclerosis are general inflammatory mechanisms and specific bacterial interactions. One hypothesis is that the cause of atherosclerosis is direct injury to vascular endothelial cells by an infecting organism; another is that inflammatory cytokines contribute to atherosclerosis ,2. It haMore than 70% of all people have gum problems . Among JWe defined atherosclerosis by using Pulse wave velocity (PWV), an index of arterial stiffness ,14 regarIn this study, we assessed the effect of periodontal disease on atherosclerosis from the viewpoint of the relationship between CPITN score and Brachial-Ankle Pulse Wave Velocity (baPWV), by which we non-invasively assessed the progress of atherosclerosis.This was a cross-sectional study. The setting was a Japanese chemical company. After receiving approval from the ethical committee of Keio University School of Medicine, we obtained informed consent from 291 male employees of the chemical company who were selected for participation in the cross-sectional study. In September 2004, we gave the participants questionnaires about their daily life and dental habits. Oral and medical examinations were performed in October 2004, at which time the questionnaires were also collected.We used the CPITN score, average probing depth and gingival bleeding index (rate of bleeding gums) to determine the severity of periodontal disease. Dental examinations were conducted by two dentists who, according to the WHO protocol, used flat dental mirrors and periodontal probes . Teeth nWe used baPWV as the index for atherosclerosis. Nurses measured the baPWV and blood pressure of each subject twice using a baPWV/ABI device  while the subject was at rest in a supine position. This device, approved by the US Food and Drug Administration as VP-2000/1000, can monitor bilateral brachial and ankle pressure wave forms simultaneously using the volume plethysmographic method, with two optional tonometry sensors for carotid and femoral arterial wave measurements. The nurses practiced baPWV measurements beforehand and made arrangements for standardization.Age and smoking status were self-reported, and medical history was acquired by interview. We applied pack-years (smoking period [years] × number of packs [/day]) as the cumulative smoking index. Height, weight, systolic and diastolic blood pressures (SBP and DBP), fasting blood glucose level, serum lipid levels  and HbA1c were measured in all subjects.t-test was applied. For age, as the distribution was skewed and not log-normal, the Wilcoxon's rank sum test was applied. The other variables were regarded as normally distributed, and the Student's t-test was applied.The distributions of triglyceride, HDL cholesterol and HbA1c were skewed and regarded as log-normal. Therefore, these data were logarithmically transformed, and the Student's We divided the subjects based on CPITN score, average probing depth and gingival bleeding index. Subjects with CPITN scores of 0, ≧1, ≧3 and ≧4 were defined as healthy, having periodontal disease, having advanced periodontal disease and having severe periodontal disease, respectively. Similarly, for average probing depth and gingival bleeding index, we placed the subjects in four groups. The boundary values for average probing depth were 2 mm, 3 mm and 4 mm, and those for gingival bleeding index were 25%, 50% and 75%.We defined atherosclerosis as baPWV ≧1400 (cm/sec), which is an independent variable for risk stratification by the Framingham score and for the discrimination of patients with atherosclerotic cardiovascular disease. It is the commonly used cut-off value in clinical practice .p < 0.05.Odds ratios (ORs) and 95% CIs were calculated using logistic regression analysis. All statistical analyses were performed using SPSS for Windows version 12.0 , and statistical significance was accepted at 2 (mean ± SD), respectively, which are typical values in healthy male Japanese workers. The maximum and minimum ages were 21 and 63. The biochemical values of blood did not reveal any significantly abnormal characteristics. The distribution of the CPITN score was typical in Japanese people and in people from other countries [p value = 0.029).Mean age and body mass index were 46.6 ± 11.5 years and 23.4 ± 3.66 kg/mountries ,12,26-28The results of logistic regression are shown in Tables The results showed that mild periodontal disease tended to have a weaker relationship with atherosclerosis than did severe periodontal disease Table . The adjDespite the existence of many reports, the relationship between periodontal disease and atherosclerosis has not been fully elucidated. Because the absence of a standard definition and measures for periodontal disease complicate the interpretation of results, as do potential confounding risk factors that are common to both conditions, we have no basis for comparison . In the We used three indices of periodontal disease: CPITN score, average probing depth and gingival bleeding index. Average probing depth is similar to AL. Although AL accurately indicates gum recession and is the best index of periodontal disease, its measurement is very time-consuming. On the other hand, it takes just 3 minutes per person to measure the average probing depth. Our investigation showed the same trend as the report that used AL (Beck's study) . The CPIp values were less than 0.05, which agrees with reports and hypotheses that are currently in existence [et al. reported that, after adjustment for known cardiovascular risk factors, gingivitis was not associated with CHD (hazard ratio (HR): 1.05, 95% CI: 0.88–1.26) in 2000 [In our study, before adjustment, the indices of periodontal disease showed a relationship with atherosclerosis. The ORs of atherosclerosis related to the three indices of periodontal disease were more than 1, and their xistence ,29-34. H in 2000 , and the in 2000 . They al in 2000 . In addi in 2000 -39. Theret al. reported a similar trend [We examined the presence of a monotonic dose-response association in three ways Table . With adar trend .There were several limitations to our study. First, the number of subjects was relatively small, and the results of this study need to be assessed in a larger sample size. However, the sample size was small because the strength of the relationship that we observed was weaker than the relationship that we had assumed from the previous studies. Second, our cross-sectional study design lacked information on the time sequence of events and so did not permit identification of the causal relationship. To investigate this relationship, it will be necessary to follow this cohort. Finally, the problem of imperfect measurement of confounders can exist. However, it is not a serious problem because adjustments were made for the major confounders. For example, the adjustment for smoking intensity is very important. Hujoel pointed out that the studies that either did not adjust or adjusted poorly for smoking showed a positive chronic periodontitis (CP)-CHD association, while the results of studies controlling for smoking suggested that CP was either not at all or weakly associated with CHD . In addiIn conclusion, we found no relationship between mild periodontal disease and atherosclerosis after appropriate adjustments from this cross-sectional study.The author(s) declare that they have no competing interests.MK conceived the study, designed the protocol, enrolled participants, participated in data collection and analysis, and helped to draft the manuscript. MK participated in data collection and analysis and in drafting the manuscript. MN, TN and KH gave advice on key concepts of the study and participated in data collection. AH and ST participated in data collection. TN was responsible for the study design and organization, interpretation of the data and project oversight. All authors were involved in data interpretation and contributed to the writing of the paper.The pre-publication history for this paper can be accessed here:


The ability to maintain a steady gait rhythm is impaired in patients with Parkinson's disease (PD). This aspect of locomotor dyscontrol, which likely reflects impaired automaticity in PD, can be quantified by measuring the stride-to-stride variability of gait timing. Previous work has shown an increase in both the variability of the stride time and swing time in PD, but the origins of these changes are not fully understood. Patients with PD also generally walk with a reduced gait speed, a potential confounder of the observed changes in variability. The purpose of the present study was to examine the relationship between walking speed and gait variability.Stride time variability and swing time variability were measured in 36 patients with PD (Hoehn and Yahr stage 2–2.5) and 30 healthy controls who walked on a treadmill at four different speeds: 1) Comfortable walking speed (CWS), 2) 80% of CWS 3) 90% of CWS, and 4) 110% of CWS. In addition, we studied the effects of walking slowly on level ground, both with and without a walker.Consistent with previous findings, increased variability of stride time and swing time was observed in the patients with PD in CWS, compared to controls. In both groups, there was a small but significant association between treadmill gait speed and stride time variability such that higher speeds were associated with lower (better) values of stride time variability (p = 0.0002). In contrast, swing time variability did not change in response to changes in gait speed. Similar results were observed with walking on level ground.The present results demonstrate that swing time variability is independent of gait speed, at least over the range studied, and therefore, that it may be used as a speed-independent marker of rhythmicity and gait steadiness. Since walking speed did not affect stride time variability and swing time variability in the same way, it appears that these two aspects of gait rhythmicity are not entirely controlled by the same mechanisms. The present findings also suggest that the increased gait variability in PD is disease-related, and not simply a consequence of bradykinesia. Falls are one of the most serious complications of the gait disturbance in Parkinson's disease (PD) -7. BeyonThe mechanisms underlying the increased stride variability in PD have not been widely investigated. The increased stride variability and impaired rhythmicity of gait in PD may reflect reduced automaticity and damaged locomotor synergies ,16,21. IPreviously, we described the effects of a treadmill on the gait of patients with PD at their comfortable walking speed . Here weThirty-six patients with idiopathic PD, as defined by the UK Brain Bank criteria , were reThe study population was characterized with respect to age, gender, height, weight, Mini-Mental State Exam (MMSE) scores  . Subjects were tested four times on the walkway and four times on the treadmill at different speeds. Each test lasted two minutes. On level ground , subjects were tested under four conditions in the following order: a) at their comfortable walking speed (CWS), b) at a self-selected slow speed, i.e., specifically, subjects were asked to walk at about 20% less than their CWS, c) at their self-selected CWS while using a walker , and d) at a self-selected slow speed while using the walker . On the treadmill, subjects were studied at four treadmill speeds: 1) the CWS observed when using a walker on the level walkway; 2) 80% of this CWS; 4) 90% of this CWS; and 4) 110% of this CWS. The order of the walking conditions on the treadmill was randomized.After providing informed consent, subjects were familiarized with walking on a 35 meter walkway and walking on a motorized treadmill , the gait speed under condition (1), i.e., comfortable walking on the treadmill, was set to the gait speed under condition (c).Initially, subjects walked up and down the 35 meters walkway to become familiar with the testing conditions. Before testing on the treadmill, subjects were given time to walk on the treadmill. This familiarization period was completed when the subject reported feeling comfortable walking on the treadmill at his or her preferred gait speed. Afterwards, subjects were given 5 minutes of rest to minimize any fatigue effects. Measurements on the treadmill were taken after about 30 seconds of gradually increasing the treadmill speed to the desired speed i.e., data collection was started only after subjects had reached a steady pace.A previously described computerized force-sensitive system was used to quantify gait and stride-to-stride variability ,39. The Descriptive statistics are reported as mean ± SD. We used the Student's t and Chi-square tests to compare the PD and control subjects with respect to different background characteristics . To evaluate the effect of speed on gait parameters and to compare the groups, we used Mixed Effects Models for repeated measures. For each gait parameter, a separate model was applied. The dependent variable was the gait parameter and the independent variables were the group (PD patients or controls), the walking condition , walking speed, and the interaction term group × walking condition × walking speed. P values reported are based on two-sided comparison. A p-value = 0.05 was considered statistically significant. All statistical analyses were performed using SPSS 11.5 and SAS 8.2 (Proc Mixed).Demographic, anthropometric, and clinical characteristics of the patient and control groups are summarized in Table Table Table For all gait measures, the effects of the different walking speeds on treadmill were similar in the patients with PD and the control subjects . As can be discerned from the examples shown in Figure Consistent with previous studies, we find a reduced stride length and average swing time, and an increased stride time variability and swing time variability in patients with PD ,14-20. TYamasaki et al described a U-shaped relationship between stride length variability and gait speed when healthy subjects walked on a treadmill . MinimumIn previous studies that quantified stride time variability and swing time variability, these two measures were typically affected by disease and aging to similar degrees ,16,46. WWhile more studies are needed to further clarify the relationship between gait speed and variability, the present findings support two conclusions. First, dysrhythmicity in gait in PD is caused by disease-related pathology. Stride time variability is influenced to a small degree by gait speed, but a close look at Table The author(s) declare that they have no competing interests.SFT, NG, and JMH designed the study. SFT and TH participated in data collection. CP, JMH and LG performed the data analysis. SFT and JMH drafted the manuscript. All authors helped with the interpretation of the results, reviewed the manuscript, and participated in the editing of the final version of the manuscript.


In spite of the fact that self-rated health is such an important factor, little is known about the aetiological background to poor perceived health and also less is known about the impact of life satisfaction on health in a primary care practice population. The aim of this study was to evaluate the effect of socio-demographic characteristics, lifestyle factors, symptoms, somatic and psychiatric conditions as well as health status measures and life satisfaction on perceived health in a multi-ethnic Swedish health practice population.Four-hundred and seventy adult patients, who visited the Jordbro Health Care Centre District (JHC), Haninge Municipality, participated in this study. A general questionnaire with questions about socio-demographic characteristics, lifestyle, health status and chronic disease were used. In addition to that, the Primary Care Evaluation of Mental Disorders (PRIME-MD) was used. Furthermore, physical examinations were conducted. Unconditional logistic regression in successive models was used, adjusted for socio-demographic variables and other confounders.Life satisfaction is the strongest predictor of poor perceived health in addition to country of birth, number of symptoms and depression. Being born in Sweden or other Nordic countries were related to lower OR as compared to those born outside Europe. The OR for non-depressed vs. depressed was 0.29 (0.17–0.48) and for non-symptomatic vs. symptomatic (1–3 symptoms) 0.25 (0.46–0.48). The OR and 95% CI for low satisfaction with life was 15.40 (5.28–44.97) in comparison to those who are satisfied with life.Country of birth, depression, number of symptoms and life satisfaction are factors related significantly and independently to perceived health. Life satisfaction is the strongest predictor of perceived poor health. During the past two decades, interest in subjects' perceived health has become one of the important research fields in epidemiology and research concerning health services -4. At thNumerous reports have shown a strong association between various indicators of individual socio-economic positions -24. A stIt is evident that subjective health assessment is a valid indicator of health status in middle-aged populations, and that it can be used in cohort studies and monitoring of a population's health ,25. The The present investigation is part of a comprehensive programme entitled "Improving Health Care in Jordbro (IHCJ)" to assess the influence of socio-demographic characteristics, including country of birth, as well as morbidity on health care and drug utilisation in patients resident in Jordbro, a small multi-ethnic sub-community in Stockholm, Sweden. In this study we explore the relations between socio-demographic characteristics, lifestyle factors, somatic and psychiatric symptoms as well as health status measures and perceived health.The aim of this study was to evaluate the effect of socio-demographic characteristics, lifestyle factors, symptoms, somatic and psychiatric conditions as well as health status measures, and life satisfaction on perceived health in a multi-ethnic Swedish health practice population. The Committee on Research Ethics at the School of Medicine, Karolinska Institute, approved the study.A full description of the methodology is provided elsewhere . The patThe JHC has a catchment area of 9 500 patients and approximately 9 000 patients are registered at the health centre. At the time of the study the proportion of patients >15 years old was 77%, i.e. 7 296 patients. The study population consists of patients who were registered consequently during the first four weeks of the study period and only six patients provided insufficient data, i. e. only six patients did not fulfil the survey completely. All adult patients (≥ 16 years) who visited the health care centre were included but not the emergency cases.The study consisted of three parts: (a) a general questionnaire ,36, (b) a) The general questionnaire dealing with questions on socio-demographic characteristics, lifestyle, health status and medicine use was handed out to the patients. The socio-demographic variables included, in addition to age and gender, family situation  and country of birth. In addition to that, the questionnaire included questions on 16 common somatic diseases and one on whether the respondents perceived themselves to be healthy or not. They were also asked to indicate the degree of life satisfaction, perceived health and health status. Patients were asked to state whether they had any chronic disease.Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) . Also, different parts of the questionnaire used here were previously validated in other investigation ,36,49,51-53. AlsoAlthough this study is not prospective, causal relations cannot be drawn from this investigation. The most of the literature on this issue are cross-sectional studies and not suited for statement or implications. Further prospective research is needed to clarify the direction of association. The new finding in this study is the strong association between life satisfaction and perceived health apart from country of birth, symptoms and depression, and also the fact that perceived health has a stronger correlation with psychiatric than somatic conditions. The strength of this study is that this represents a primary care patient population which makes it unique. Furthermore, the fact that we have controlled for a large number of confounders makes it more unique.In conclusion, country of birth, depression, number of symptoms and life satisfaction are factors related significantly and independently to perceived health. Life satisfaction was the strongest predictor of poor health.OR = Odds ratio95% CI = 95% Confidence IntervalPrime-MD = Primary Care Evaluation of Mental DisordersPQ = Patient questionnaireJHC = Jordbro Health Care CentreVC = Vital capacityFEV1 = Forced vital capacity during one secondPEF = Peak expiratory flowPPH = poor perceived healthr = Spearman's correlation coefficientBMI = body mass index


AR gene with diabetic macroangiopathy has not been investigated. Therefore, the present study was conducted to determine whether genetic variations of AR may determine susceptibility to diabetic macroangiopathy.The aldose reductase (AR) gene, a rate-limiting enzyme of the polyol pathway, has been investigated as a candidate gene in determining susceptibility to diabetic microangiopathy. However, the association of the There were 378 Type 2 diabetic patients enrolled in this study. A single nucleotide polymorphism in the promoter region (C-106T) was genotyped and the AR protein content of erythrocytes measured by ELISA.P = 0.019 and P = 0.012). The erythrocyte AR protein content was increased in patients with the CT and TT genotype compared with those with the CC genotype. After adjustment for age, duration of diabetes, body mass index, systolic blood pressure, HbA1c, and serum creatinine, triglycerides, and total cholesterol in multivariate logistic-regression models, the association between this AR genotype and stroke remained significant.There were no significant differences in genotypic or allelic distribution in patients with or without ischaemic heart diseases, but there was a significant increase in the frequency of the CT + TT genotype and T allele in patients with stroke (AR gene might be a genetic marker of susceptibility to stroke in Type 2 diabetic patients. This observation might contribute to the development of strategies for the prevention of stroke in Type 2 diabetic patients.Our results suggest that the CT or TT genotype of the  AR gene may be one of the factors that determine genetic susceptibility to diabetic microvascular complications [There is familial clustering in the incidence of diabetes-related chronic complications , which sications ,4. Recenications –12.in vivo[in vitro[AR gene could also be a predisposing factor to diabetic macroangiopathy. However, the association of the AR gene with macroangiopathy in diabetic subjects has never been reported.Other reports have indicated a role of polyol pathway hyperactivity in the development of diabetic macroangiopathy in vivo,14 and i[in vitro,15,16. TAR gene determines susceptibility to diabetic macroangiopathy, such as ischaemic heart disease and cerebrovascular disease, in Japanese Type 2 diabetic patients and non-diabetic subjects.To clarify these issues, the present study investigated whether the C-106T polymorphism of the We screened 417 consecutive patients attending Nagoya University Hospital. Patients with Type 1 diabetes (14), malignant diseases (13) and other types of diabetes  were excluded. During screening, two patients declined to participate. A total of 378 Type 2 diabetic outpatients  were enrolled. A total of 334 non-diabetic subjects  who underwent a medical check-up in our hospital from April 2001 to December 2003 served as the control group. They had fasting blood glucose levels < 6.1 mmol/l and had no family history of diabetes. Five had an abnormal electrocardiogram and 20 a history of atherosclerotic diseases.Assessment and definition of diabetic macroangiopathy was based on the following criteria. Cardiovascular disease was defined by a history of ischaemic cardiovascular diseases . Stroke (ischaemic cerebrovascular disease) was diagnosed by means of neurological signs and symptoms, together with computed tomography or magnetic resonance imaging. According to the Acute Stroke Treatment (TOAST) classification , only laAR gene was determined by the polymerase chain reaction restriction fragment length polymorphism method using the primers and conditions described by Kao et al. [Bfa-I at 37°C. Before enzymatic digestion with Bfa-I, the product was purified with QIAquick PCR Purification Kit (Qiagen). The AR protein content in erythrocytes was measured by ELISA using anti-human AR monoclonal antibody .DNA samples were prepared from whole blood using a QIAamp DNA Blood Mini Kit . The C-106T polymorphism of the o et al. . The presd, unless otherwise indicated. Statistical significance of the differences between the groups was determined by chi-square (χ2) tests, unpaired Student's t-tests or anova where appropriate. The Hardy–Weinberg test was performed using a standard observed-expected χ2 test. Multiple logistic-regression analyses were used to assess the association of the CT + TT genotype with diabetic complications. Odds ratios (ORs) and their confidence intervals (CIs) were used to estimate relative risk. A two-sided P-value less than 0.05 was considered statistically significant.Statistical analyses were performed using SPSS for Windows version 12.0 . Data are presented as means ± The clinical characteristics of diabetic patients and non-diabetic subjects are presented in AR gene were 259 (68.5%) for CC, 105 (27.8%) for CT, and 14 (3.7%) for TT in the diabetic group, and 213 (63.8%) for CC, 113 (33.8%) for CT, and 8 (2.4%) for TT in the non-diabetic group. The frequencies of the C allele were 82.6% in the diabetic group and 80.7% in the non-diabetic group. The distribution of genotypes was in Hardy–Weinberg equilibrium. There were no significant differences between the two groups .The genotype distributions of the C-106T polymorphism of 1c and fasting blood glucose levels, SBP, DBP, serum levels of total cholesterol, triglycerides, HDL cholesterol, low-density lipoprotein (LDL) cholesterol and creatinine.Because the number of diabetic patients with the TT genotype was only 3.7%, subjects with the CT and TT genotypes were combined for further analyses. The genotypes were not associated with gender, duration of diabetes, age, diabetes treatment, BMI, HbAP = 0.002 and 0.001 vs. CC; We then compared the AR protein content in erythrocytes among the genotypes. The AR content was significantly increased in a genotype-dependent manner , SBP (P < 0.001), serum creatinine levels (P = 0.008) and serum levels of triglycerides (P = 0.048) were higher in patients with a history of stroke.Age (P = 0.019). Furthermore, in model 2, after additional adjustment for HbA1c, BMI, serum total-cholesterol levels and duration of diabetes, this relationship remained .AR gene as a candidate gene for susceptibility to diabetic macroangiopathy, and found that the CT or TT genotype is associated with increased risk of stroke in Type 2 diabetic patients.We have investigated the C-106T polymorphism in the promoter region of the Diabetes mellitus is one of the major risk factors of coronary heart disease and cerebrovascular disease. The high prevalence of these macrovascular diseases in diabetic patients can be explained by hyperglycaemia per se, as well as by the increased frequency of conventional risk factors such as hypertension, dyslipidaemia, and obesity.Accelerated proliferation of vascular smooth muscle cells (SMCs) is one of the characteristic features of atherosclerosis , and it et al. [AR gene in patients with nephropathy. Furthermore, the CT or TT genotypes and the T allele of this polymorphism have been identified as genetic markers of susceptibility to diabetic microangiopathy in several reports [AR gene. However, a functional reporter gene assay reported by Yang et al. [Hodgkinson et al.  reported reports –12. Therg et al.  showed tAR promoter region are thought to be a risk factor for stroke. Some independent effects of genetic variants  on the risk of cerebral ischaemia have been reported previously [AR gene exerts a stronger effect on the risk of stroke.We showed that the CT and TT genotypes and the T allele of the C-106T polymorphism in the eviously . Compareet al. reported, for the first time, the relationship between the C-106T polymorphism of the AR gene and erythrocyte AR content in Type 2 diabetic subjects [AR gene influence erythrocyte AR content and the development of diabetic complications. Unfortunately, however, a significant relationship between the AR content in erythrocytes and the prevalence of stroke was not observed in our study.Makiishi subjects . The resAR gene was limited to a single marker from the 5′ region of the gene. Thus, it cannot be excluded that this AR polymorphism is in linkage disequilibrium with an unidentified polymorphism strongly related to stroke risk. This could explain the lack of correlation between AR content in erythrocytes and the prevalence of stroke. Hyperglycaemia, hyperosmolality, and oxidative stress all regulate erthrocyte AR content [Our findings should be cautiously interpreted because there are some limitations to the present study. Our analysis of the  content –28, and AR gene were associated with an increased risk of stroke, and the significance of these genotypes remained high even after adjustment for other risk factors. In addition, the erythrocyte AR content was higher in the subjects with these genotypes. Therefore, it may be speculated that polymorphisms of the AR gene, concomitant with an increase in erythrocyte AR content, would increase vulnerability of brain arteries resulting in stroke. However, prospective intervention studies with aldose reductase inhibitors would be required to confirm the influence of the AR gene polymorphism and AR content on the development of stroke.There are several well-known conventional risk factors for macrovascular diseases  but little is known about inherited factors that could predispose to diabetic macroangiopathy. Among the conventional risk factors, in the present study, age and systolic blood pressure were higher in the subjects with stroke than those without stroke, although the significance was weak after adjustment for various risk factors. In contrast, the CT + TT genotype and the T allele of the AR gene with ischaemic heart disease. It can be speculated that brain vessels are more sensitive to polyol pathway-induced hyperosmolar stress than coronary vessels. Precise investigation will be required to clarify this issue.In contrast, it is noteworthy that the influence of this polymorphism on the development of ischaemic heart disease is less than that on stroke. There are important differences in risk factors for stroke and ischaemic heart disease. For stroke, hypertension is the most adverse risk factor, whereas for ischaemic heart diseases LDL cholesterol is the strongest. This suggests that there are differences in the pathogenesis of ischaemic heart disease and stroke, which might explain our lack of association of the AR polymorphisms in other populations. Although various studies have reported the relationship between diabetic microangiopathy and AR polymorphisms [It is important to replicate our results in other populations. No previous study has investigated the relationship between diabetic macroangiopathy and orphisms –12, consAR gene is associated with an increased risk of stroke in Type 2 diabetic patients. This observation might contribute to the development of further strategies for the prevention of stroke in Type 2 diabetic patients.In conclusion, we have found that the C-106T polymorphism in the promoter region of the


Exposure to metals may promote atherosclerosis. Blood cadmium and lead were associated with peripheral arterial disease (PAD) in the 1999–2000 National Health and Nutrition Examination Survey (NHANES). In the present study we evaluated the association between urinary levels of cadmium, lead, barium, cobalt, cesium, molybdenum, antimony, thallium, and tungsten with PAD in a cross-sectional analysis of 790 participants ≥40 years of age in NHANES 1999–2000. PAD was defined as a blood pressure ankle brachial index < 0.9 in at least one leg. Metals were measured in casual (spot) urine specimens by inductively coupled plasma–mass spectrometry. After multivariable adjustment, subjects with PAD had 36% higher levels of cadmium in urine and 49% higher levels of tungsten compared with noncases. The adjusted odds ratio for PAD comparing the 75th to the 25th percentile of the cadmium distribution was 3.05 ; that for tungsten was 2.25 . PAD risk increased sharply at low levels of antimony and remained elevated beyond 0.1 μg/L. PAD was not associated with other metals. In conclusion, urinary cadmium, tungsten, and possibly antimony were associated with PAD in a representative sample of the U.S. population. For cadmium, these results strengthen previous findings using blood cadmium as a biomarker, and they support its role in atherosclerosis. For tungsten and antimony, these results need to be interpreted cautiously in the context of an exploratory analysis but deserve further study. Other metals in urine were not associated with PAD at the levels found in the general population. Peripheral arterial disease (PAD) is a consequence of atherosclerotic occlusion of blood flow in the muscular arteries of the lower extremities. Because traditional risk factors for atherosclerosis, such as age, smoking, hypertension, and diabetes, do not completely explain the distribution of PAD in the population, there is considerable interest in identifying novel, nontraditional risk factors. Certain metals may promote atherosclerosis by increasing oxidative stress  or by aBlood cadmium and lead, at levels well below current safety standards, were associated with an increased prevalence of PAD in the 1999–2000 National Health and Nutrition Examination Survey (NHANES) . CadmiumThe objective of this study was to evaluate the association of metal levels in urine with the prevalence of PAD in NHANES 1999–2000, a representative sample of the civilian, noninstitutionalized U.S. population. In epidemiologic studies, PAD is usually defined by the presence of a low (< 0.9) blood pressure ankle-brachial index (ABI)—that is, when the systolic blood pressure measured at the ankle is < 90% of the systolic blood pressure measured at the arm . We hypoThe NCHS has conducted a series of cross-sectional health and nutrition surveys beginning in the 1960s. These surveys have used a stratified, multistage probability cluster design to provide data representing the noninstitutionalized U.S. population . In 1999n = 2,465). NHANES 1999–2000 included a detailed lower-extremity examination that involved ABI measurements in subjects ≥40 years of age with no bilateral amputations and weighing < 400 lb . From these 796 participants, we excluded one participant with an ABI value > 1.5 [usually related to noncompressible vessels in the legs  urine specimen was collected from the participants after confirmation of no background contamination in collection materials . UrinaryInformation on age, sex, race/ethnicity, education, and smoking was based on self-report. Urinary creatinine was determined using an enzymatic reaction measured with a CX3 analyzer .All statistical analyses were performed using SUDAAN software  to account for the complex sampling design and weights in the NHANES 1999–2000 metal subsample. The jackknife “leave-one-out” method was used to obtain appropriate standard errors of all estimates.Urinary metal levels were right skewed and were log-transformed to improve normality. For each metal, the ratio of the geometric mean urinary level and its 95% confidence interval (CI) comparing subjects with PAD versus subjects without PAD were estimated using linear regression models on log-transformed metal levels. For risk analyses, logistic regression was used to obtain the adjusted odds ratios and 95% CIs of PAD comparing the 75th with the 25th percentile of the distribution of each metal assuming a log-linear relationship between urinary metals and PAD. We also used restricted cubic spline transformations to assess nonlinear relationships. All models were adjusted for age, sex, race, and education level. In addition, we evaluated the impact of further adjusting for smoking status, a source of cadmium, lead, and cobalt . Metal lThe overall prevalence of PAD in the study sample was 5.4% (54 cases). After adjusting for demographic variables, smoking status, and creatinine in urine, subjects with PAD had 36%  higher mean levels of cadmium in urine compared with subjects without PAD . Levels Cadmium levels in urine were 36% higher in subjects with PAD than in those without PAD. This association was similar but actually stronger than the previously reported association between blood cadmium and PAD in NHANES 1999–2000, where blood cadmium was 16% higher in PAD cases than in noncases . The strin vivo  and makes it possible that we missed weak associations between some metals and PAD. At the same time, our prior hypotheses regarding the associations of cadmium and lead with PAD were specific, but for the other metals our analyses were exploratory and need to be confirmed in future studies.Other limitations include the cross-sectional design of the study, the possibility of residual confounding by socioeconomic status or urbanization, the use of a single measurement of urinary metals, and the lack of 24-hr urine collection to better account for short-term variability in metal excretion and urine dilution. To correct for urine dilution, we adjusted for urinary creatinine. However, creatinine in urine is a marker of both urine dilution and creatinine production, and it is associated with factors that affect production such as sex, age, race, and muscle mass. The adequacy of correcting for creatinine has been questioned , and in Despite these limitations, this study is the first systematic investigation of a panel of metals in urine with PAD. The use of a representative sample of the U.S. population, rigorous laboratory methods with extensive quality control, and the availability of a standardized procedure to measure ABI add to the strengths of this study.Urinary cadmium was strongly associated with PAD in a representative sample of the general U.S. population. This finding strengthens similar results from a previous study in the same population using blood cadmium as a biomarker of exposure  and furt


Data on the health status of the Roma people in Central and Eastern Europe are sparse and the reasons for their poor health are not clear. The objective of this study was to quantify the differences in birth outcomes between Roma and non-Roma mothers in the Czech Republic and to investigate the potential causes of such differences.A population-based study recruited 8938 non-Roma and 1388 Roma hospitalised singleton births that occurred in two Czech districts (Teplice and Prachatice) between 1995 and 2004. During their stay in hospital, mothers completed a questionnaire on their demographic and socioeconomic characteristics and maternal smoking and alcohol consumption. Data on maternal height and weight and on infants' birth weight and gestational age were taken from hospital records.th percentile of birth weight for gestational age); controlling for all covariates reduced these odds ratios to 1.7 (1.3–2.2), 1.5 (1.1–2.0) and 1.3 (1.0–1.6), respectively. Maternal education made the largest contribution to the ethnic differences; the role of health behaviours was relatively modest.Birth weight and gestational age of Roma infants was 373 (SE 15) g and 0.92 (0.05) weeks, respectively, lower than in non-Roma infants. Controlling for demographic, socioeconomic and behavioural factors reduced these differences to 133 (18) g and 0.57 (0.06) weeks, respectively . In terms of binary outcomes, the Roma vs. non-Roma odds ratios were 4.5 (95% CI 3.7–5.4) for low birth weight (< 2500 g), 2.8 (2.2–3.4) for preterm birth (< 37 weeks of gestation), and 2.9 (2.5–3.4) for intrauterine grown retardation (<10There are striking differences in birth outcomes between Roma and non-Roma mothers. The causes of these differences are complex but largely socioeconomic. The Roma people  are the most important ethnic minority in Central and Eastern Europe. It has been known for a long time that the socioeconomic conditions of most Roma people in Central and Eastern Europe are worse than those of the general population, and it has been suspected that their health follows a similar pattern. However, the main conclusion of two recent reviews was that there is a striking lack of information about the Roma people ,2; even Available data suggest that the health of the Roma people is poor ,2. SimilIn this paper, we analysed a large population based study of births in two Czech communities. The study was originally designed to investigate the effect of air pollution on birth outcomes  but it aAs mentioned above, the study was set up to examine the effects of air pollution . It was During hospitalisation, women completed a self-administered questionnaire with a help of a specially trained nurse. Ethnicity was based on maternal self-report; the dataset contained the following options: Asian; European; Roma, and "other".Mother reported their highest attained education , marital status , smoking (cigarettes per day) and consumption of alcohol (drinks per week) before and during pregnancy. Data on mothers' height (in cm), pre-pregnancy weight (in kg), birth weight (in grams) and gestational age (in weeks) were taken from hospital records. The study attempted to collect data on fathers but we did not use these data because of the high rate of missing values .th gender-specific percentile of birth weight for gestational age) defined as binary variables. Finally, we examined the extent to which the differences between Roma and non-Roma birth outcomes can be explained by available covariates. The statistical models (for both binary and continuous outcomes) were built as follows. First, crude effects of ethnicity were estimated. Second, the ethnic differences were adjusted separately for: (i) demographic characteristics of the infant (gender and district of birth); (ii) maternal demographic characteristics ; (iii) maternal social characteristics ; (iv) maternal size (height and weight); and (v) maternal behaviours . Finally, all these covariates were entered into one model. All analyses were conducted using the STATA statistical software .Because the numbers of Asian and "other" infants were too small for meaningful analyses , the final dataset was restricted to European and Roma babies. The statistical analysis was conducted in several steps. First, socioeconomic and life style variables were tabulated by ethnicity. Second, we compared crude differences between the two ethnic groups in the following birth outcomes: birth weight and gestational age measured as continuous variables, and low birth weight (< 2500 g), preterm birth , and intrauterine growth retardation  occurred among Roma women. The distribution of socioeconomic characteristics and behaviours is shown in table Table Results of logistic regression for binary outcomes were similar table . For lowIn additional analyses, we found no evidence for an interaction between ethnicity and calendar year: the differences between Roma and non-Roma groups remained constant over the study period (not shown in table). There was also no interaction between ethnicity and district; despite the difference in the size of the Roma population between the two districts, the differences between Roma and non-Roma groups were similar in Teplice and in Prachatice (not shown in table).This study in a representative community sample of births found striking ethnic differences in all birth outcomes studied and in most socio-demographic characteristics. The covariates available in the study, particularly maternal education, explained a considerable part of these differences.Several limitations of the study should be considered when interpreting the results. First, more detailed data would provide a more complete picture of the family environment. It is likely that if information on economic and material conditions  would contribute further to the explanation of the ethnic differences. Data on husbands would also help but, as explained above, the proportion of missing data on fathers was too high to be used in the analyses. Data on household assets would also be valuable to improve the assessment of families' socioeconomic status. Similarly, data on factors that could mediate the link between ethnicity, socioeconomic characteristics and birth outcomes, such as nutrition, would be also useful. Finally, ethnic differentials in birth outcomes may be further exacerbated by unmeasured area-level characteristics .Second, some of the measurements might have been inaccurate. In particular, the definition of ethnicity is a difficult issue. Some misclassification is likely; some Roma mothers may have identified themselves as non-Roma. However, self-reported ethnicity, used in this study, has been suggested as the preferred method , and altFinally, the number of Roma births was much smaller than that of non-Roma births, and the unbalanced structure of the sample might have reduced the statistical power. However, given the overall size of the study, the statistical power was sufficient to demonstrate, in Roma vs. non-Roma comparisons, an odds ratio of 1.20 or higher at 95% confidence level. The probability of the beta error is therefore low.In the research on ethnic differences in health in general, an important questions has been debated for some time, namely what are the reasons for such differences . For difMaternal education made by far the largest single contribution to explaining the poor birth outcomes in Roma mothers. This is not surprising, because there were huge differences in educational attainment between Roma and non-Roma mothers in this study table , and becMaternal size, particularly height, partly reflects socioeconomic conditions in earlier life . ReproduThe author(s) declare that they have no competing interests.MB analysed the data and drafted the paper. JD and RJS designed and coordinated the study and commented on the drafts of the paper. IS contributed to the data collection and data management and commented on the drafts of the paper.The pre-publication history for this paper can be accessed here: