To determine the frequency of near-miss  and the nature of near-miss events, and comparatively analysed near-miss morbidities and maternal deaths among pregnant women managed over a 3-year period in a Nigerian tertiary centre.Retrospective facility-based review of cases of near-miss and maternal death which occurred between 1 January 2002 and 31 December 2004. Near-miss case definition was based on validated disease-specific criteria, comprising of five diagnostic categories: haemorrhage, hypertensive disorders in pregnancy, dystocia, infection and anaemia. The near-miss morbidities were compared with maternal deaths with respect to demographic features and disease profiles. Mortality indices were determined for various disease processes to appreciate the standard of care provided for life-threatening obstetric conditions. The maternal death to near-miss ratios for the three years were compared to assess the trend in the quality of obstetric care.There were 1501 deliveries, 211 near-miss cases and 44 maternal deaths. The total near-miss events were 242 with a decreasing trend from 2002 to 2004. Demographic features of cases of near-miss and maternal death were comparable. Besides infectious morbidity, the categories of complications responsible for near-misses and maternal deaths followed the same order of decreasing frequency. Hypertensive disorders in pregnancy and haemorrhage were responsible for 61.1% of near-miss cases and 50.0% of maternal deaths. More women died after developing severe morbidity due to uterine rupture and infection, with mortality indices of 37.5% and 28.6%, respectively. Early pregnancy complications and antepartum haemorrhage had the lowest mortality indices. Majority of the cases of near-miss (82.5%) and maternal death (88.6%) were unbooked for antenatal care and delivery in this hospital. Maternal mortality ratio for the period was 2931.4 per 100,000 deliveries. The overall maternal death to near-miss ratio was 1: 4.8 and this remained relatively constant over the 3-year period.The quality of care received by critically ill obstetric patients in this centre is suboptimal with no evident changes between 2002 and 2004. Reduction of the present maternal mortality ratio may best be achieved by developing evidence-based protocols and improving the resources for managing severe morbidities due to hypertension and haemorrhage especially in critically ill unbooked patients. Tertiary care hospitals in Nigeria could also benefit from evaluation of their standard of obstetric care by including near-miss investigations in their maternal death enquiries. For many years, evaluation of maternal healthcare services aimed at improving the quality of obstetric care has traditionally relied on enquiries into maternal deaths. More recently, review of cases at the very severe end of the maternal morbidity spectrum, described as "near-miss" (those who nearly died), has been found to be a useful complement to investigation of maternal mortality ,2. RevieAt Olabisi Onabanjo University Teaching Hospital, Sagamu, a state-owned referral centre in southwest Nigeria, maternal mortality ratio is close to 2000 per 100,000 deliveries . The majIn order to provide an insight into the quality of maternal care provided in our institution, we embarked on a retrospective study to determine the frequency of near-miss  and the nature of near-miss events, and comparatively analysed near-miss morbidities and maternal deaths among pregnant women managed in this centre over a 3-year period. The review is expected to serve as a complementary method for auditing the quality of maternal healthcare in this institution.The study was conducted at the obstetric unit of Olabisi Onabanjo University Teaching Hospital (OOUTH), Sagamu, a publicly funded tertiary care institution, which serves as the major referral centre for other public and private hospitals within Ogun State, in southwest Nigeria. In addition to providing emergency obstetric services to women referred from other centres, the hospital also provides antenatal care and delivery services for both unreferred low and high-risk pregnant women from Sagamu community and neighbouring towns. The centre provides emergency obstetric and gynaecological care 24 hours a day. Although patients are expected to pay for their services, in emergency situations, they are managed within the means of existing resources before funds are made available. Nine consultant obstetricians and an average of 15 registrars and 30 midwives ran the three obstetric units of the hospital during the reviewed period. The hospital provides blood transfusion services from limited stock and relatives of patients are requested to donate or pay for blood when needed. Each unit of blood costs between N1500-N2000 (approximately £6–10) during the reviewed period. The only intensive care unit (ICU) of the hospital is within the main surgical theatre though patients requiring critical care are admitted from other units after paying a certain fee. Proliferation of many private hospitals and traditional birth homes within Ogun State in recent past has limited the total number of deliveries but has relatively increased the frequency of complicated pregnancies and deliveries managed in the obstetric unit. An average of 40–45 deliveries are conducted per month out of which 10–15 are unbooked.Near-miss events are defined as acute obstetric complications that immediately threaten a woman's survival but do not result in her death either by chance or because of hospital care she receives during pregnancy, labour or within 6 weeks after termination of pregnancy or delivery  while a Life-threatening obstetric conditions refer to maternal complications severe enough to cause near-miss morbidity and maternal death while "critically ill obstetric patients" are women who suffered life-threatening obstetric conditions . Maternal death is defined according to the tenth revision of International Classification of Diseases (ICD-10) by the World Health Organization .Near-miss cases were retrospectively identified among women with pregnancy-related complications admitted into the obstetric units of the hospital between 1 January 2002 and 31 December 2004. Using the provisional and final diagnoses documented in the admission-discharge register of the hospital, case files of women whose diagnoses met the above pre-defined criteria as well as those with the possibility of being associated with severe acute maternal complications were retrieved for scrutiny by the Near-miss Audit Committee comprising three consultant obstetricians and three specialist registrars. Overall, 520 cases were retrieved for scrutiny. For each case of near miss, data were collected on demographic characteristics including gestational age at the time of sustaining the near-miss morbidity, nature of obstetric complication(s) responsible, presence of organ-system dysfunction/failure, ICU admission, timing of near-miss event with respect to admission, fetal outcome in those associated with labour and length of hospital stay. Information on maternal deaths and deliveries conducted during the reviewed period were obtained from the labour/delivery registers and case files from the Medical Records Department. For each case of maternal death, data were collected on the demographic characteristics including gestational age at the time of death and the underlying cause of death.Data were entered into a computer database using Microsoft Excel spreadsheet and statistical analysis was performed with Epi Info 2002 software . Results2 or Fisher's exact test when appropriate while continuous variables were compared with the Student's t-test. Differences between data were considered statistically significant when p<0.05.Categorical variables were compared with the χDuring the reviewed period, there were 1501 deliveries, 211 near-miss cases and 44 maternal deaths. As shown in Table A total of 242 near-miss events were identified among the near-miss cases with frequencies decreasing from 95 in 2002 to 65 in 2004  with an overall prevalence of 140.6 per 1000 deliveries. Critically ill obstetric patients constituted 17.0% of all women who delivered during the reviewed period. The frequency of critically ill obstetric patients also decreased significantly between 2002 and 2004 (p = 0.002). Maternal mortality ratio for the 3-year period was 2931.4 per 100,000 deliveries. Though there were fewer deaths in 2004, there was no significant difference between the maternal mortality ratios of 2002 and 2004 (p = 0.236). The overall maternal death to near-miss ratio was 1: 4.8 with no significant difference in this relationship between the years of study. Overall, 17.3% of critically ill obstetric patients died during the 3-year period. Majority (80.6%) of the near-miss cases were referred from other facilities namely traditional birth attendant homes, primary and secondary healthcare units and private hospitals within Ogun State and beyond. Most near-miss cases already had near-miss morbidity upon arrival at OOUTH, Sagamu while only 15.6% of them became near-miss after admission to the hospital. The proportion of near-miss events occurring after admission varied between diagnostic categories; haemorrhage (23.3%), hypertensive disorders (15.8%), dystocia (8.5%), infections (10.0%) and anaemia (11.5%).Table Only 9 (4.3%) of the near-miss cases were managed in the ICU while organ-system dysfunction/failure were recorded in 19 (9.0%) of them. The nature of organ-system dysfunction/failure and the associated obstetric factors among the near-miss cases are shown in Table The need to assess the quality of obstetric care in any centre is paramount to understanding the improvement resulting from investment in its maternity services. Up till now, evaluation of obstetric performance in many Nigerian hospitals is limited to investigations of maternal deaths, an indicator that is vulnerable to many flaws in this environment. To the best of our knowledge, ours is the first review in this country that quantitatively examined the quality of obstetric care using alternative indices.The study shows that severe acute maternal morbidities (near-miss) occur in a considerable percentage of women managed in this obstetric unit. Life-threatening obstetric conditions, including those that resulted in deaths complicated up to 17% of all deliveries during the reviewed period. This implies that obstetricians in this centre were confronted with life-saving emergency situations in almost 1 out of every 6 women who utilised their obstetric services. While the prevalence of our near-miss cases shows some degree of consistency with the reports from other teaching hospitals in West Africa ,12. ThisOne of the advantages of the criteria used for our case definition is that it mirrors the major causes of maternal mortality and therefore readily permits comparison that allows assessment of the standard of care with respect to common causes of maternal deaths. As logically expected, there were no major differences in the underlying pathology for near-miss morbidities and maternal deaths indicating that near-miss review can be a useful surrogate of maternal death analysis in this centre. Similar to the findings in many previous studies ,11,15, hThe importance of including near-miss investigations in maternal death audits is demonstrated by this review. Comparison of the disease processes responsible for near-miss and maternal deaths shows that infection, with a mortality index of 28.6%, constituted a significant threat to the survival of affected patients though it was the least frequent cause of life-threatening obstetric conditions. Similarly, it became clear that uterine rupture received the poorest form of care even though it accounted for 5.7% of life-threatening obstetric conditions. The level of care provided for pregnancies complicated by eclampsia also deserves special attention. According to the mortality index, approximately one-fifth of critically ill eclamptic patients died in this centre. Though eclampsia is a known major cause of maternal death worldwide, the poor standard of care for women with eclampsia in our unit may be related to the existing management policy for hypertensive disorders in pregnancy. Up till now, magnesium sulphate, which has been shown to reduce eclampsia-related risk of maternal mortality ,18, is yThe management of haemorrhage due to abortion during the reviewed period is commendable as none of such cases caused near-miss morbidity or maternal mortality. Though this may be related to the frequent training of members of staff in manual vacuum aspiration and incorporation of postabortal care into the existing management protocol of abortion in the last five years, it is possible that affected women did not present at the hospital either because they did not survive or because of fear of legal prosecution in cases of criminal abortion. Of the various types of life-threatening obstetric haemorrhage, postpartum haemorrhage constituted the greatest danger to affected women while early pregnancy haemorrhagic complications and antepartum haemorrhage were less risky. This implies that efforts need to be focussed on improving the protocols and resources for combating postpartum haemorrhage, while maintaining and improving the existing preventive measures and treatment strategies for early pregnancy complications and antepartum haemorrhage.As shown in this study, the lack of proper antenatal care is a major determinant of adverse maternal outcome. Majority of the women with near-miss morbidity arrived at the hospital in critical condition having being referred from both modern and traditional maternity facilities. Though some authors suggest that near-miss upon arrival at the hospital should not be used to assess the quality of care at the admitting facility , we beliIt is unlikely that the overall substandard level of care in this centre is due to a higher prevalence of life-threatening complications compared to other centres. This is because with the recorded delivery rate, the prevalence of critically ill obstetric patients translates to an average of 7 of such patients being managed per month (255/36 months) and a maternal death to near-miss ratio of 1: 5 is unjustifiable with the existing human resources. Though this level of care could be attributed to other extraneous factors ranging from cost of obstetric services, mismanagement at the sources of referral to lapses in the referral chain, it is the duty of a referral hospital to maintain a good standard of care if the utilisation of obstetric services among the population is to be encouraged. In spite of the decreasing trend in the frequency of near-miss cases over the 3 years, the similarity in the death to near-miss ratios indicates that there was no significant improvement in the level of care over these years. Therefore, the significant fall in the prevalence of near-miss cases is probably a reflection of recent governmental efforts to improve obstetric services at the primary and secondary healthcare units, which are the main sources of near-miss cases managed at the teaching hospital.Some important issues concerning definitions in near-miss studies were also illustrated in this investigation. It appears that identification of cases based on ICU admission or organ-system failure/dysfunction as used in some studies may underestimate the frequency of severe maternal morbidities in our setting since they occurred in only 4.3% and 9.0% of all near-miss cases, respectively. Though data collection is easy, a major disadvantage of using ICU admission as the criteria for case selection is that it is dependent on factors such as availability, capacity and location of ICU and institutional guidelines for ICU admission . TherefoA major limitation of this study is its retrospective nature. Besides the possibility of underestimating the near miss-cases as a result of incomplete documentation in case files, the methodology also discouraged assessment of substandard care with respect to the health workers or health administration and patient-orientated missed opportunities. Evaluation of the circumstances surrounding near-misses and maternal deaths would shed light on avoidable factors and therefore enable more focussed remedial actions. This aspect needs to be considered in subsequent near-miss investigations in this institution.In summary, our review shows that besides the 44 women who died due to pregnancy-related complications, there were 211 additional women who received critical care during the same period supporting the view that near-miss appraisal provides a larger sample to assess the threat to maternal life. The overall maternal death to near-miss ratio, however, indicates that a significant proportion of critically ill women died, suggesting a suboptimal level of care for life-threatening complications. Since there were little differences in the underlying disease processes causing near-miss and maternal mortality, evaluation of the circumstances surrounding near-miss cases could act as a proxy for maternal death in this centre. Efforts geared towards improvement in the management of near-miss morbidities would definitely go a long way in reducing the present maternal mortality ratio. From the findings of this review, attempts to reduce maternal deaths may best be achieved by developing evidence-based protocols for the management of severe hypertension and haemorrhage especially for critically ill referred patients. In addition, considerable efforts should be made to improve maternal care for infrequent but important life-threatening obstetric conditions such as uterine rupture and infection. Necessary facilities should be made available and training of personnel and emergency drills should be frequently conducted to combat the identified disease processes that received suboptimal care. Although this study did not specifically address avoidable factors, it has nevertheless raised awareness of the deficiencies in the management of serious maternal illnesses. It is apparent from this review that tertiary institutions in Nigeria could also benefit from evaluation of their quality of obstetric care by including near-miss investigations in their maternal death enquiries.The author(s) declare that they have no competing interests.OOT conceived and designed the study. OOT drafted the manuscript while AOS and AOO critically revised it for intellectual contents. OOT, AOS and AOO were members of the committee that collected the data. OOT and OJD analysed and interpreted the data.


A substance use screening instrument was used to determine factors predictive of drinking during pregnancy. Alcohol consumption during pregnancy can lead to negative birth outcomes.The participants  for the study were sampled from pregnant women attending prenatal clinics in Montana, South Dakota, and North Dakota. Clinic sites for the administration of the screening instrument were selected in each state, based on geographic and known population characteristics. Univariate and multivariate statistical procedures were used to determine factors predictive of drinking during pregnancy.Women who drank tended to: be single, be between 21–25 years old, have had fewer children, have had abortions, and be unemployed. Demographic factors that were protective of drinking when pregnant were married and full-time housewife status. Other variables associated with maternal alcohol use were: past sexual abuse, current or past physical abuse, tobacco use, other drug use, lived with substance users, and had mates who were substance users. Other contributing factors for alcohol use included: feeling sad, believing that drinking any amount of alcohol while pregnant was acceptable, had been in treatment, could use treatment now, and were able to hold four or more drinks.Because drinking rates were high and factors correlated with drinking are known, alcohol screening for this population is essential. Alcohol is the most commonly used teratogen in the western world . Of all Screening for alcohol use among pregnant women is becoming increasingly important in view of new studies that show that even low levels of prenatal alcohol exposure can have deleterious impacts on the fetus . Even thIt is estimated that about 60 percent of adult American women drink at least occasionally . Most woEstimates on the rate of pregnant women drinking ranged from 13.2 percent to over 50 percent -16. The Women who have had a previous child with Fetal Alcohol Spectrum Disorders (FASD) are at high risk for drinking during subsequent pregnancies . AlcoholThe Prenatal Questionnaire (PNQ) was adapted from the Self-Administered Questionnaire (SAQ) developed within the Indian Health Service in 1997  to meet Drinking on the PNQ was assessed in two ways: 1) by asking the amount and frequency of drinking during this pregnancy; and, 2) by comparing time of last drink with normal menstrual cycle as per the validation of the SAQ . PhysicaMedical clinics providing prenatal care were selected to participate in the study based on sampling procedures and willingness to participate in the survey. The sampling design for each state was stratified, based on geographic area or population densities and types . Clinics were randomly selected within these stratifications. Clinic personnel collected the completed questionnaires and returned them to the Center for Disabilities at the University of South Dakota.Women accessing prenatal care were asked to complete the PNQ anonymously by nurses or receptionists at their first prenatal care visit. All the women completing the surveys were pregnant, although it was not known if the pregnancies were planned. If the pregnant persons decided to participate, they were given packets containing general information on the study and contact information in the event that they would like more information, along with the PNQ, and an unsealed envelope. The women were instructed to read the general information sheet and instructions, complete the PNQ, seal the completed PNQ in the envelope, and return it to the nurses or receptionists. The pregnant women were given small incentive gift certificates upon finishing the questionnaires. Since participation was voluntary and 99 sites participated, it was not possible to assess exact response or refusal rates, although state supervisors estimated that more than 90 percent of the prenatal patients participated. IRB approval for the project was obtained from the University of North Dakota, the University of South Dakota, Montana State University, and the Indian Health Service Area Office in Aberdeen, South Dakota.sd = 5.8) years with age ranging from 14 to 47. Women completing the PNQ averaged 13.4 (sd = 2.5) years of education. The women had a mean of 1.1 (sd = 1.1) children with responses ranging from zero to fifteen. The survey participants reported an average of 1.7 (sd = 1.7) pregnancies, which was consistent across states. Of those responding, 8.6 percent had a previous abortion and 24.6 percent reported a miscarriage from a prior pregnancy.The information presented in this study was based on 4,828 questionnaires, collected at the first prenatal visit. Most (58.5%) of the respondents were in their first trimester, some (26.2%) in the second, and a few (15.2%) in their third trimester. The surveys were collected from sites in North Dakota , South Dakota , and Montana . The average age of the pregnant women completing the PNQ was 26.7  of the respondents were 'White,' and 8.9 percent were Native Americans Table . The totNearly all who responded to the health question felt that they had 'Good', 'Very Good' or 'Excellent' health. Almost one-half (45.1%) of those completing the survey indicated that their health was 'Very Good' and 3.0 percent reported their health status as 'Fair' or 'Poor.' About one-fifth (18.9%) reported at least some feelings of discouragement and hopelessness in the last month. Most of the respondents from each state reported that in the last month they did not have feelings of sadness, hopelessness, discouragement, or had so many problems that they wondered if everything was worthwhile.The significance of factors predictive of drinking was determined by univariate and multivariate factors with chi square and logistic procedures, respectively. Univariate statistics were used to determine the total number of significant factors, and multivariate procedures were used to determine a smaller set of questions that retain predictive validity. Probability values equal to or less than .05 were considered statistically significant. Probabilities were adjusted, as noted, to accommodate multiple comparisons.t = -5.03, p = .001) and fewer children  than the comparison (non-drinking) group.Based on all persons in the sample , some demographic factors were found statistically significantly related to drinking status, although group differences were modest and have limited clinical utility. The drinkers had more abortions  related to drinking classification. In examining the percent drinking by income category, it was noted that those with low  income and high income  had the highest drinking rates. Also, survey respondents who were younger (ages 21–25) were more likely to drink than were all other age groups . Unemployment  was another demographic factor predictive of drinking status.Income was significantly , full-time housewife status , and employed . Married women had the lowest drinking rate  of the marital status categories, and the single women had the highest  rate, suggesting that marriage is a protective factor for maternal substance use and being single a risk factor. Sexual abuse  and physical abuse in the past year  were significant risk factors. Amount of alcohol consumption was another category of risk factors. Women, who believed any amount of alcohol was safe for pregnant women to drink  or felt that they could hold more than four drinks , had elevated risk levels.Factors found to be protective of drinking included: married  and tobacco  were related to drinking or risk status. Additionally, being around others who used substances was correlated with risk status. Partners or mates using substances  and persons in household drinking or using drugs  were two factors related to drinking when pregnant. If partner or mate substance use was viewed as a problem by the pregnant women, the drinking risk was increased .The concurrent and past use of other drugs , could use treatment at present time , and had previous participation in substance abuse treatment programs .Other factors found to be predictive of drinking status were: being sad or discouraged in the last month (Nagelkerke R Square = .13) of the predictability of the binary dependent measure, indicating that there are many other psychological, social, or demographic factors that are related to substance use during pregnancy.Logistic regression was used to assess the significance of the dichotomous demographic and social-psychological related risk factors in predicting drinking and to establish a smaller number of questions, using a backward stepwise procedure . Significant factors were determined for blocks  of related questions. The significant factors for each block were used in the final regression analysis phase. With this procedure, only factors that added predictive information were included in the final regression model. In the final logistic regression model, eleven factors Table  were retThe final factors in the logistic regression model were: previous abortion, full-time housewife, physical abuse, perception of how many drinks a person can hold, need to cut down on drinking, mate was user of alcohol, used drugs before this pregnancy, believed that some alcohol use while pregnant was acceptable, and had experienced difficulty remembering events after drinking.This study examined risk factors for maternal drinking, using a prenatal questionnaire that included substance-screening questions with a large sample of pregnant women. The samples were systematically drawn from medical clinics from three states with large geographic  areas, along with some urban sites. Pregnant women were invited to complete the questionnaire anonymously during the first prenatal visit. The study results indicate that there are a number of risk factors present. The identification of the risk factors is paramount in targeting high-risk women for appropriate intervention programs.Marital status was related to risk status. Consistent with other studies ,16, beinPhysical and sexual abuses were identified as risk factors for maternal alcohol use. These findings are consistent with other research ,14,19,21A general area with potential opportunity for the amelioration of risk factors is the amount of alcohol that individuals reported drinking. Pregnant women, indicating any daily alcohol use , were at risk for maternal alcohol use. Nearly one-half (47.6%) of those believing that any amount of daily drinking was acceptable were found to be drinking. Additionally, many (38.0%) survey participants who felt they are able to hold 4 or more drinks were drinking during this pregnancy. Education and brief intervention programs that stress zero drinking, while pregnant, and limiting the number of drinks per occasion, while non-pregnant, could result in reduced drinking behavior and better birth outcomes.This article did not discuss the overall drinking rate, which was higher than many reported results, because the topic will be addressed in another paper. Refusal rates at the clinics were unknown, because participants self-selected themselves and the state project directors did not have direct oversight of the clinics or the patients. The participants should have been asked if the pregnancy was planned. Physical and sexual abuse questions were asked as general questions without much specificity. A validation of a short version of the PNQ is currently being conducted by the FAS Consortium.Knowing the risk factors for women who will likely use alcohol during pregnancy is vitally important to health care providers so that intervention procedures can be targeted for the appropriate persons. The use of an instrument like the PNQ is essential in screening women at prenatal clinics so that the immediate attention can be given to women who are drinking. One of the goals of the regression analysis was to establish fewer questions while maintaining predictive validity.The screening instrument should be administered as early as possible in the pregnancy to maximize the timing at which counseling or other intervention could be implemented. Once the extent and severity of alcohol use or misuse has been determined, the Institute of Medicine recommends that the clients be treated or managed with brief intervention by trained personnel . A numbePregnancy offers a unique opportunity to positively impact women's lives, resulting in the reduction of harmful substances such as alcohol, cigarettes, and other drugs. There is evidence that pregnancies provide increased motivation to reduce or eliminate unhealthy habits such as smoking and drinking .Prevention programs for pregnant women who are drinking should consider providing a range of services such as, transportation, brief intervention, counseling, social support, prenatal classes, parenting and family functioning classes, and mental health services. A promising intervention program that targets multiple domains was developed for pregnant women by other programs included in this Center for Substance Abuse Prevention (CSAP) grant . ProgramThe author(s) declare that they have no competing interests.GL and RL developed the design of the study and analysis and interpretation of data.RL and JS were involved in the acquisition of the data.All authors were involved in drafting the manuscript and have given final approval of the version to be published.


More than 80 eHealth experts from 20 different countries and four continents attended an international workshop in Heidelberg/Germany to agree on an international scientific collaboration in the field of ehealth, to work on a metadata structure for ehealth providers and to discuss trustmark concept and other ways to enhance trust, implement eHealth ethics and improve the quality of health information on the Internet.List of attendees, in alphabetical order:Lucas M. Bachmann  Carl R. Blesius , Markus Blume , Carl J. Brandt , Dan Brickley , Alejandro Cacherosky , Ken Campell , Richard Cleland , Phil Cross , Elenice de Castro , Guy de Roy , Tony Delamothe , Martin D. Denz , Persephone Doupi , Joan Dzenowagis , Christer Edling , Gunther Eysenbach , Gerard Freriks , Franz Frühwald , Lisa Gray , Pelle Gustafsson , Gerhard Heine , Katrin Hörner , Robert Hsiung , Jostein Ingulfsen , Thomas Isenberg , Edward Jacob , Alex R. Jadad , Jacobo Kelber , Hugo Kitzinger , Inge Kokot , Hans-Joachim Koubenec , Michel Labrecque , Kristian Lampe , Stephane Lejeune , Leonard B. Lerer , Odile Leroy , Nicolas Lienert , Pål Lindström , Sándor Lipp , Leena Lodenius , Antti Malmivaara , Miquel Angela Mayer Pujadas , Peter Mills , Cesar Molinero , Marc Muret , Wolfgang Nagel , Tim Nater , Joerg Nitzsche , Debra O´Connor , Gert Purkert , Ramon Sarrias Ramis , Christine Reuter , Ahmad Risk , Carl Bénédict Roth , Sebastian Schmid , Christiane Schmitz , Luk Schoonbaert , Frank Schuler , Ulrich Schwanke , Sasha Shepperd , Myra Sidrassi , Chris Sigouin , Chris Silagy , Denise Silber , Martin Sonderegger , Anke Steckelberg , Frederik Tautz , Nicolas P. Terry , Christian Thomeczek , Wouter Tukker, , Gerard H. van der Zanden , Georg von Below , Frank von Danwitz , C.-Peter Waegemann , Thomas Wetter , Petra Wilson, , Margaret A. Winker , Jeremy Wyatt , Gabriel Yihune


To estimate the prevalence of hazardous drinking and its socio-economic distribution among Russian men.Participants were an age-stratified, population-based random sample of men aged 25–54 years living in Izhevsk, a city in the Urals, Russia. Interviewers administered questionnaires to cohabiting proxy respondents about behavioural indicators of hazardous drinking derived from frequency of hangover, frequency of drinking beverage spirits, episodes in the last year of extended periods of drunkenness during which the participant withdraws from normal life (zapoi), consumption of alcoholic substances not intended to be drunk (surrogates) and socio-economic position. Logistic regression was used to examine associations between socio-economic position and indicators of hazardous drinking in the past year.Of 1750 men, 79% drank spirits and 8% drank surrogates at least sometimes in the past year; 25% drank spirits and 4% drank surrogates at least weekly and 10% had had an episode of zapoi in the past year. After adjustment for other socio-economic factors, education was strongly associated with indicators of hazardous drinking. Men with the lowest level of education compared to the highest level of education had an odds ratio of surrogate drinking of 7.7 (95% CI 3.2–18.5), of zapoi of 5.2 (2.3–11.8) and of frequent hangover of 3.7 (1.8–7.4). These indicators of hazardous drinking were also independently strongly associated with being unemployed (versus employed) and with levels of household wealth/amenities. Associations of all these variables with daily consumption of beverage spirits were weaker.Using a novel range of indicator variables of hazardous drinking, this paper shows that the prevalence of these behaviours is high among working-age men in this Russian city. Moreover, these hazardous behaviours show very clear socio-economic patterns, with particularly high prevalence among those who have had the least education and are not in employment. In contrast, more conventional measures of heavy drinking, based on frequency of consumption of beverage spirits, are less prevalent and show much weaker associations with socio-economic position. Russia is one of the very few industrialized countries in the world where life expectancy has been declining . In 2003Data on alcohol consumption in Russia, particularly for the past decade, are considered unreliable , as therA number of surveys , 18–26 hThe term ‘hazardous drinking’ is being used here to describe a range of extreme alcohol-related behaviours. This paper seeks to investigate the relationship between four such behaviours and selected socio-economic factors. Developing our understanding of the prevalence and socio-economic distribution of these behaviours is a prerequisite for developing contextually appropriate interventions.We have analysed data from a population sample of men aged 25–54 years recruited as controls in a case–control study of premature male mortality conducted in Izhevsk, Russia. This is a typical, medium-sized Russian industrial town, population 650 000, located on the western side of the Ural mountains. The study began in December 2003 following an earlier prototype investigation . Cases wBetween 18 December 2003 and 16 November 2005, 3078 potential controls were selected. Members of a team of 25 trained interviewers visited each address. Participant addresses from the electoral roll were verified at the city's address bureau and those found were visited up to three times in order to locate respondents, with the following results: the address did not exist or was not listed for 404 individuals; for 76 men there was no answer at the door; 157 men lived alone and were therefore excluded; in 45 households, no suitable proxy respondent was found or the man had died. Of the remaining 2396 eligible households, 646 proxies refused or were not available. However, 1750 successful proxy interviews were obtained, representing a response rate of 60% of those approached where the proxy was not known to have died or to be living alone. Eighty-five per cent of interviews were with the spouse, 9% with a parent and 2% or less with other proxy types.Proxies in each household were identified for interview according to a protocol specifying order of preference . The questionnaire was developed following a systematic review of the literature on the validity of proxy informants, and employed a five-stage piloting programme and eight iterations in Russian, with back-translations into English to ensure accurate translation.The study collected information about hazardous drinking over the previous year, in addition to usual questions about frequency and amount of beverage alcohols . Two questions investigated frequency of consumption of surrogate alcohols: ‘Please indicate how often alcoholic substances not intended to be drunk were usually drunk?’ ; ‘On which day of the week were alcoholic substances not intended to be drunk usually drunk?’ . Responses to the following questions were also obtained: ‘How often does he have a hangover?’; ‘Has he had one or more episodes of zapoi in the past year/month/week?’. Questions about alcoholic beverage consumption included frequency and usual amount consumed of beer, wine and spirits. Selected socio-economic information was collected, including education level, employment status, household car ownership and whether or not the household had central heating. Hazardous drinking was defined as any of the following in the past year: having drunk surrogates; having been on zapoi; having frequent hangovers (once per month or more); having drunk spirits daily.In addition to interviewing proxies for controls we also interviewed the controls themselves. However, we have analysed the information obtained from proxy informants, as we believe that this is less affected by the tendency for under-reporting than self-reported alcohol consumption . In our A selection of variables relating to specific aspects of socio-economic status was selected in order to explore the complex pathways between these and hazardous drinking behaviours. These were education level attained , whether the man was in employment  and an amenity index described by presence/absence of household central heating and/or car ownership. For these variables there is ‘almost perfect’  agreemenSocio-economic conditions may in themselves be causal determinants of hazardous drinking. However, hazardous drinking may also affect socio-economic circumstances. Of the variables we have selected, education is the least likely to be influenced by current or recent drinking habits . However, a low education level may plausibly be a marker or driver of a tendency to drink more hazardously. Car ownership was not particularly common among households in Izhevsk (44%), and is a useful variable to identify households with above-average income. Central heating is usually provided centrally in Russia, a country whose winter temperatures fall well below freezing, and the absence of central heating indicates a very poor housing standard. A combination of these two variables helps to differentiate the socio-economic position of men which may, plausibly, be linked to hazardous drinking behaviours. Finally, being in employment may be a particularly important factor in hazardous drinking: hazardous drinking may lead to job loss, although it is also possible that unemployment may lead to hazardous drinking. This, in turn, may lower the probability of re-employment. These complexities need to borne in mind when interpreting our analyses, although the cross-sectional data we have collected are unable, alone, to disentangle the direction of causality between hazardous drinking and socio-economic characteristics.The prevalence of hazardous drinking in this population was determined. Logistic regression was used to obtain odds ratios for the selected hazardous drinking behaviours with respect to the three socio-economic variables identified above , each of which were introduced into the models as categorical variables. The crude effect of each socio-economic factor was obtained for each type of hazardous drinking behaviour, and the effect of adjustment for each and both of the other socio-economic factors was examined in order to evaluate independent effects. Subsets of complete data were used in the examination of the effect of socio-economic factors on each separate type of hazardous drinking behaviour, in order to facilitate legitimate comparison of effects. All associations were adjusted for age. Distribution tables were directly standardized according to the age and marital status of the Izhevsk population  derived The analyses described above were replicated using self-reported data, in order to confirm that the use of proxy data is justified. Overall associations between exposures and drinking behaviours were similar, although strength sometimes differed.This study provides the first assessment of the prevalence of a range of indicators of hazardous drinking in working-age men and their relationship to socio-economic factors in a Russian city at the present time.More than 21% of men display behaviours associated with hazardous drinking. Russia has a traditional alcohol profile, with wine consumption not particularly widespread. Conversely, frequent beer consumption is widespread, consistent with evidence of the growth in beer consumption in Russia , encouraWhat are the pathways by which these socio-economic factors influence hazardous drinking behaviours? Education level as a determinant of all hazardous drinking is not unanticipated: it is well documented that this component of socio-economic status is related inversely to alcohol consumption levels . More stThe inconsistent pattern of the socio-economic determinants of daily spirits consumption may be explained partly by the possibility that those who can afford to drink spirits every day are unlikely to be in the lowest socio-economic groups. Although, overall, drinking spirits is widespread compared with the other three hazardous drinking behaviours, the small group of men who drink spirits daily are perhaps in an unsustainable situation, on the brink of entering, rather than already caught within, a downward socio-economic spiral which would explain the lack of an association with the amenity index. Indeed, it appears that those who can afford to do so choose to drink spirits. It is the least fortunate in society who are forced to turn to surrogate alcohols. The absence of an effect of the lowest level of education on spirits consumption may be explained partly by those with low education being less likely to drink spirits regularly, due to economic obstacles. Furthermore, among the small number of men reported to be unemployed due to ill health, none drank spirits daily. This suggests that those men who had become unemployed as a consequence of the health effects of alcoholism were no longer able to afford to drink spirits.One possible way of looking at the inter-relationship of the various socio-economic factors with hazardous drinking that we have considered is presented schematically in samogon (home-brew) or surrogate alcohols beyond consumption frequency, all of which would have been useful in developing a clearer understanding of drinking behaviours. These data are based on men living with at least one other person, so findings are not generalizable to the whole population. Nevertheless, hazardous drinking prevalence is probably higher among those living alone, so effect measures err on the side of underestimation. Our use of proxies is unusual. However, as we have discussed above, we believe that proxy-reported data provide a picture of associations between socio-economic exposures and indicators of hazardous drinking at least as good as, if not better than, that obtained from self-reports.These data have a number of limitations. We did not collect information on biomarkers of hazardous drinking, on consumption of In summary, this paper provides the first in-depth analysis of hazardous drinking behaviours and their socio-economic correlates among working-age Russian men, going beyond earlier surveys of frequency and amount of beverage alcohol consumption. This shows a much higher prevalence, and a far stronger relationship with socio-economic factors, of surrogate drinking, zapoi and frequent hangover than with daily or almost/daily consumption of spirits. This suggests that conventional approaches to assessing hazardous drinking, at least in the Russian context, should not be restricted to collecting information on the frequency and amount of consumption of beer, wine and spirits. The strong and robust association of employment status with hazardous drinking underlines that alcohol is not only a major public health issue but is likely to have a major negative effect on the development of the Russian economy.


B. malayi microfilariae in mice.Diethylcarbamazine (DEC) has been used for many years in the treatment of human lymphatic filariasis. Its mode of action is not well understood, but it is known to interact with the arachidonic acid pathway. Here we have investigated the contribution of the nitric oxide and cyclooxygenase (COX) pathways to the activity of DEC against B. malayi microfilariae were injected intravenously into mice and parasitaemia was measured 24 hours later. DEC was then administered to BALB/c mice with and without pre-treatment with indomethacin or dexamethasone and the parasitaemia monitored. To investigate a role for inducible nitric oxide in DEC's activity, DEC and ivermectin were administered to microfilaraemic iNOS-/- mice and their background strain (129/SV). Western blot analysis was used to determine any effect of DEC on the production of COX and inducible nitric-oxide synthase (iNOS) proteins.in vivo. Furthermore, experiments showed that treatment with DEC results in a reduction in the amount of COX-1 protein in peritoneal exudate cells. Additionally, in iNOS-/- mice infected with B. malayi microfilariae, DEC showed no activity, whereas the efficacy of another antifilarial drug, ivermectin, was unaffected.DEC administered alone to BALB/c mice resulted in a rapid and profound reduction in circulating microfilariae within five minutes of treatment. Microfilarial levels began to recover after 24 hours and returned to near pre-treatment levels two weeks later, suggesting that the sequestration of microfilariae occurs independently of parasite killing. Pre-treatment of animals with dexamethasone or indomethacin reduced DEC's efficacy by almost 90% or 56%, respectively, supporting a role for the arachidonic acid and cyclooxygenase pathways in vivo and show that in addition to its effects on the 5-lipoxygenase pathway, it targets the cyclooxygenase pathway and COX-1. Moreover, we show for the first time that inducible nitric oxide is essential for the rapid sequestration of microfilariae by DEC.These results confirm the important role of the arachidonic acid metabolic pathway in DEC's mechanism of action  Wuchereria bancrofti, Brugia malayi and B. timori) since 1947 and it continues to play an important role, being one of the drugs used in the Global Programme for the Elimination of Lymphatic Filariasis [in vivo and the lack of significant activity in vitro. In vivo, the response is rapid: within a few minutes of treatment, peripheral blood microfilariae counts drop dramatically [in vitro activity indicates that DEC probably requires some host factor for its activity, and previous work has highlighted the role of the innate immune system and leucocytes independent of T cells and complement in the activity of DEC [Diethylcarbamazine citrate (DEC) has been used in the treatment and control of lymphatic filariasis  pathway products prostaglandin (PG) E2, prostacyclin (PGI2) and thromboxane A2 but has no effect on platelet prostanoid production [in vivo and so we have used a mouse model to identify the host factors responsible for the rapid efficacy of DEC.DEC also has anti-inflammatory properties, as a result of its interference with arachidonic acid metabolism . The prooduction . In addioduction -11. Neve2 and iNOS/COX which is generally stimulatory but may also be inhibitory [in vivo.The arachidonic acid pathway includes lipoxygenase and cyclooxygenase enzymes. The COX pathway has similarities with the nitric oxide (NO) pathway, since both have constitutive and inducible isoforms of their enzymes and are key regulators of inflammatory responses ,13. The hibitory ,15. TherBrugia malayi were obtained from TRS Laboratories , suspended in RPMI 1640 with 5% FCS, and 300000 parasites in a volume of 200 μl were injected intravenously into mice. Systemic parasitaemia was allowed to equilibrate for 24 hours, then heparinised blood samples were taken by tail bleeding and parasitaemia was measured. Mice were allocated into age- and size-matched groups and treated as described below. All animals were kept in the Biological Services Unit of the University of Liverpool in accordance with Home Office regulations and were fed and watered ad libitum. BALB/c mice were kept under standard conditions, and the 129/SV and targeted knockout of the iNOS gene  strains in filter-top cages.Microfilariae of B. malayi microfilariae were treated with a single, oral dose of DEC 100 mg/kg [Three BALB/c mice infected with 00 mg/kg   or vehicle were administered orally to three female iNOS-/- mice or their background strain, 129/SV. Mice were tail-bled at regular intervals post-treatment for evaluation of parasitaemia. To test the efficacy of another anti-filarial drug, ivermectin, in these mice, ivermectin phosphate (1 mg/kg in 1% DMSO) was administered by i.p. injection. This experiment was repeated three times.The requirement for inducible NO in DEC's efficacy was determined in iNOS-/- mice were injected i.p. with 10 mg/kg DEC in endotoxin-free water or 100 μl of endotoxin-free water (three mice in each group). After 30 minutes, peritoneal exudate cells were collected in sterile PBS with 1 g/L glucose, 1% bovine serum albumin and 1 U/ml heparin. The cells were pelleted and lysed in 1 ml TRI reagent  then protein extracted according to the supplied protocol.Male 129/SV and iNOSFor Western blot analysis, 10 μg of each protein were separated on a 7.5 % denaturing SDS polyacrylamide gel and blotted on to 0.45 μM pore size PVDF membrane . After blocking overnight at 4°C in block buffer (1% casein in PBS/0.1% Tween) and washing in PBS/0.1% Tween, membranes were incubated for 1 hour in rabbit anti-mouse COX-1, COX-2 or iNOS polyclonal IgG  diluted to 1 in 5000 in block buffer. The anti-COX antibodies showed no cross-reactivity with the opposite isoform, whilst the anti-iNOS antibody showed only 5% cross-reactivity against nNOS and none against eNOS. Membranes were then washed and incubated for 1 hour in goat anti-rabbit IgG conjugated to horse radish peroxidase  diluted to between 1 in 20000 and 1 in 100000, depending on the primary antibody, followed by further washing. The electrochemiluminescent reagent SuperSignal West  was used to visualise the bands on X-ray films.t-test. P values of < 0.05 were considered to be significant.Parasitaemia data were expressed as mean percentage of pretreatment microfilariae or as a percentage of untreated control microfilaraemias per 100 μl of blood and were analysed by the two-tailed Student's In BALB/c mice treated with DEC alone, microfilaraemia levels were reduced by five minutes with a sustained reduction for at least 60 minutes post-treatment Fig. . However-/- mice, in which microfilaraemia was maintained at pre-treatment levels for at least 2 hours . In contrast, ivermectin was effective in both 129/SV and iNOS-/- mice .Thirty minutes after administration of endotoxin-free water to 129/SV and iNOSX-1 Fig. . Interesin vivo action. The involvement of two interacting pathways, the cyclooxygenase and inducible nitric oxide pathways, were shown to mediate the activity of DEC in vivo.Here we have used a murine model to elucidate the processes within the mammalian host that contribute to DEC's rapid B. malayi-infected mice led to sustained reductions in circulating microfilariae for at least 30 days [Treatment of mice with DEC resulted in a rapid reduction in microfilaraemia. This reduction, however, was transient and microfilaraemia began to recover 24 hours after treatment, with almost full restoration to pre-treatment levels two weeks after treatment. This has been previously observed in other models ,17 and s 30 days .in vivo is by the loss of COX-1 protein within 30 minutes of administration.Our results confirm previous findings showing that an important target for DEC is the arachidonic acid metabolic pathway. Inhibition at the first stage in the pathway by dexamethasone, which inhibits phospholipase A2, almost completely abolished the activity of DEC, whereas inhibition of the cyclooxygenase enzymes COX-1 and COX-2 by indomethacin reduced its efficacy by 56%, indicating that in addition to its well documented inhibition of the 5-lipoxygenase pathway , DEC actin vivo activity of DEC. Previously we have shown that B. malayi microfilariae are susceptible to nitric oxide in vitro [in vitro (not shown) or in vivo, in agreement with Rajan et al. [-/- mice. Several studies have shown that NO and iNOS interact with COX enzymes to cause an increase in enzymatic activity [The lack of activity of DEC in mice deficient in iNOS identifies a novel enzyme system involved in the in vitro . Howevern et al. , who didactivity  and consactivity -25, althactivity . One expactivity . Althougactivity ,28. Furtactivity -31 and hactivity ; it woulin vivo.Our findings could help expand our understanding of the mechanisms involved in the cellular processes leading to sequestration and the subsequent killing of parasites. In addition to the elevation of granulocyte adherence, platelets have also been shown to bind to and kill microfilariae . In view2, PGI2 and PGD2 [2 [S-transferase of O. volvulus synthesizes PGD2 from PGH2 [in vivo or that if they do, they are not involved in DEC-mediated sequestration. Further studies that involve inhibition of the key parasite enzymes would be required to determine the role of parasite-derived prostanoids in DEC activity. Recent studies have reported a direct activity of DEC against Wuchereria bancrofti microfilariae that results in exsheathment, organelle damage and cytolysis [in vitro and in vivo and suggest that DEC may have a direct effect on worms in addition to its interaction with host-derived pathways as reported here.Filarial parasites also produce and release prostanoids, including PGEand PGD2 -41, whicand PGD2 , vasodiland PGD2 . Signifi PGD2 [2 . In cont PGD2 [2 , but therom PGH2 . It is nytolysis , which oMuch remains to be discovered of the mode of action of DEC. What mechanisms lead to parasite killing following sequestration in the central vasculature; and how does this relate to the paradoxical appearance of microfilariae in the peripheral circulation following the 'DEC provocative test'? What is the role of host immunity and effects on adult worms in the long-term efficacy of DEC? This model should be a powerful tool to address these questions and others to further unravel the mysteries of this elusive drug.in vivo. Along with its well-documented activity on the lipoxygenase pathway, DEC administered in vivo reduced the amount of the host's COX-1. Further elucidation of DEC's mechanism of action with this murine model could provide a clearer understanding of the interaction of the nitric oxide and cyclooxygenase pathways and the cellular and molecular events at the site of sequestration.Inducible nitric oxide synthase and the cyclooxygenase pathway were found to be essential for DEC's activity 2, prostacyclin; NO, nitric oxide; iNOS, inducible nitric-oxide synthase.DEC, diethylcarbamazine citrate; COX, cyclooxygenase; i.p., intra-peritoneal; PG, prostaglandin; PGIThe author(s) declare that they have no competing interests.in vivo experiments, performed the Western blot detection, analysed and interpreted the results, conducted statistical analysis and wrote the manuscript. LDP collected the parasitaemia data and assisted with the in vivo experiments. MJT conceived the study, performed the in vivo experiments, interpreted the results and advised on the manuscript. All authors read and approved the final manuscript.HFM assisted with the


Studies on the effects of (-)-hydroxycitric acid (HCA) in humans are controversial. As differences in the HCA preparations may contribute to this apparent discrepancy, the aim of the current study is to compare different HCA-containing preparations in adult Wistar rats.The effects of 3 different HCA-containing preparations  on food intake and body weight were studied in adult male Wistar rats. The efficacy was tested under 2 different experimental conditions: 1) after a single dose administration and 2) during repeated administration for 4 subsequent days.Regulator and Citrin K significantly reduced food intake in both experimental setups, while Super CitriMax HCA-600-SXS was less effective. When administered for 4 subsequent days Regulator and Citrin K diminished body weight gain.Regulator and Citrin K were shown to be potent inhibitors of food intake in rats, whereas Super CitriMax HCA-600-SXS showed only small and more inconsistent effects. The striking differences in efficacy between these 3 preparations indicate that low doses of a relatively low-effective HCA preparation may have contributed to the lack of efficacy as found in several human studies. However, studies on the effects of HCA in humans are controversial. Four placebo-controlled studies support the efficacy of HCA in man. In these studies, HCA administration led to increased loss of body weight and appetite reduction ,2, decreSeveral factors may contribute to these inconclusive results of the human studies on the efficacy of HCA. First, the doses used in the human studies are highly variable, typically ranging from 5 – 40 mg/kg HCA per day whereas in one trial a dose as high as 250 mg/kg was used . Second,To obtain some insight into the difference in efficacy of commercially available HCA preparations, we studied the effects of three different HCA preparations on voluntary food intake and body weight in conscious rats. The product names of these preparations were: Regulator, Citrin K and Super CitriMax HCA-600-SXS (abbreviated as CitriMax), respectively.ad libitum unless mentioned otherwise.All experimental protocols were approved by the Animal Experiments Ethical Committee DEC-Consult, Bilthoven, the Netherlands. Male Wistar rats  aged 3 months and weighing 290–320 gram at arrival were used. The rats were kept at 20 ± 1°C, with lights on from 23.00 h (ZT 0.00) until 11.00 h (ZT 12.00), and with water and RMH-B standard lab chow, containing (w/w) 24% protein, 52% carbohydrates and 6% fat  The rats received a permanent silicone cannula  in the stomach under Isoflurane/oxygen/nitrogen oxide anesthesia according to the method described by Strubbe et al. . This waGarcinia cambogia, which contains 50% HCA , with potassium as its primary mineral (28 g/100 g) and (3) Super CitriMax HCA-600-SXS (abbreviated as CitriMax), an extract of Garcinia cambogia, which contains 60% HCA , containing K+ (15 g/100 g) and Ca2+ (11 g/100 g). To test whether the effects are specific to HCA, its structural analogue (4) tri-potassium citrate  was used for comparison.The following preparations were used: (1) Regulator, a synthetic produced product, which contains 97% of a tri-potassium salt of HCA , (2) Citrin K, an extract of At a concentration of 75 mg HCA/ml demineralized water, the osmotic values of all preparations were 0.545 mOsm/l for Regulator, 0.507 mOsm/l for Citrin K, 0.265 mOsm/l for CitriMax and 0.490 mOsm/l for an equimolar solution of tri-potassium citrate in demineralized water.Two types of experiments were performed to study the potential differences in efficacy between the different HCA preparations. The first series of experiments focused on the effect of one single administration of each preparation on food and water intake for the following 46 hrs in a 4 days placebo-controlled crossover experiment. In the second series of experiments, HCA was given twice a day for 4 days to study effects of repeated doses of the component on food and water intake. In both studies, rats were housed individually in cages in which food and water intake was monitored online .4 groups of 6 animals were used; within each group 2 single experiments were done. Each single experiment lasted for 4 days (96 hours). On day 1, food was removed 2 hours before dark onset (ZT 10.00). At ZT 11.30 randomly assigned rats received either a single bolus of the test component  or a single bolus of isovolumic amount of water alone through the gastric cannula. At ZT 12.00 food was returned, and food and drink intake were monitored at 1, 2, 3, 4, 5, 6, 12, 24 and 46 hrs after administration. This period of 46 hrs was a washout period at the same time. On day 3 the protocol of day 1 was repeated. The rats that received the component on day 1 now receive vehicle and vice versa. Body weight was registered daily. In this way each dose of each HCA preparation was tested with regard to it's own vehicle treatment in a crossover experiment.Each HCA preparation was tested, in a group of 6 animals, at two doses corresponding to 150 and 300 mg HCA/kg body weight. Thus, three groups of 6 animals were used to test Regulator at doses of 155 and 310 mg/kg, Citrin K at 300 and 600 mg/kg and CitriMax at 250 and 500 mg/kg, respectively. In the fourth group of 6 animals tri-potassium citrate, first, was tested at a dose of 475 mg per kg body weight (corresponding to the molarity of 300 mg/kg HCA) in comparison with vehicle treatment. Second, tri-potassium citrate (475 mg/kg) was tested in comparison with Regulator (310 mg/kg).To study the effects of long-term administration of the different HCA preparations, HCA or vehicle was administered intragastric twice daily for 4 subsequent days (at ZT 11.30 and ZT 17.00). Body weight and food intake were monitored during the 4 days of ig HCA-administration and the 3 days thereafter at ZT 10.00.For logistic reasons, the long term studies were performed in two subsequent series of experiments. In the first set of experiments  vehicle, Regulator and CitriMax and in the second set  vehicle, Regulator and Citrin K were tested. All tested doses corresponded to the dose of 300 mg HCA/kg body weight.In the single administration experiments, food intake were analyzed for the crossover experiments by a four-way ANOVA test with the factors, group of treatment order, animals within group, period and type of vehicle treatment, all per HCA preparation. First, the difference between time period and beginning was analyzed to test the possibility of a carryover effect. Because of the absence of a carryover effect, the type of vehicle treatment effects can be tested in the crossover experiment.To compare the food intake results of the different HCA preparations in the single administration experiments, the delta (= difference) between treatment and vehicle on t = 24 hrs was calculated. To make comparisons between the HCA preparations, these deltas were analyzed using a two independent sample t-test with equal variances.In the single administration experiments, bodyweight and water intake were also analyzed for the crossover experiments by a four-way ANOVA test, per HCA preparation.In the repeated-administration experiments, the effects of HCA treatment on food intake, water intake and body weight were analyzed by a one-way ANOVA test. P values less than 0.05 were regarded significant. Data are presented as mean ± SEM.Cumulative food intake was significantly reduced after intragastric administration of 310 mg/kg Regulator figure . CitriMaTo enable comparison between the effects of the different HCA treatments, the difference between 24 hrs cumulative food intake after component treatment and after vehicle treatment was calculated for each HCA source .The effects of repeated administration of the high doses of the three preparations on food intake were comparable to the data of the single bolus experiments. Both Regulator and Citrin K significantly reduced cumulative food intake at days 1–4, whereas CitriMax did not reduce food intake figure  and 6. TRegulator resulted in a significantly lower gain of body weight compared to vehicle at day 2 and 4. Citrin K significantly reduced gain of body weight compared to vehicle at day 1, 2 and 4 (data not shown).This study shows that three commercially available HCA preparations exert striking differences in efficacy in inhibiting voluntary food intake in rats. Regulator and Citrin K were potent suppressants of food intake, both after a single bolus and after repeated administration, whereas CitriMax exerted much smaller effects on food intake. Accordingly, repeated administration of Regulator and Citrin K, but not CitriMax, reduced gain of body weight. Many of the peer-reviewed human studies on HCA, which report a lack of efficacy, used a CitriMax preparation as their source ,10,12 atThe results of the current study are in line with earlier observations that HCA reduces food intake in rats -22. MostThe cause of the differences in efficacy between the various HCA preparations remains speculative. In this study, it cannot simply be explained by differences in the relative HCA content of the used preparations. Regulator (97% pure for HCA) was equally effective as Citrin K (50% pure for HCA). Citrin K was more effective than CitriMax (60% pure for HCA). It cannot be excluded that the 40% non-HCA content of CitriMax contains component(s) that interfered with the suppressive effect of HCA on food intake. Alternatively, the extraction method may have resulted in an increased formation of (-)-HCA lactones, which are less potent inhibitors of the citrate cleavage enzyme .It has been suggested that minerals play an important role in regulating the stability, bio-availability or solubility of HCA. In contrast to the two other more effective HCA sources, CitriMax has relatively a high calcium and relatively a low potassium content. Regulator and Citrin K contain negligible amounts of calcium and a relatively high content of potassium. If, as has been suggested, calcium reduces solubility and hinders bio-availability ,24, the The osmolarity of the CitriMax solution was considerably lower than the osmolarity of the more effective Regulator and Citrin K solutions. It has been suggested that osmolarity plays an important role in the regulation of satiety. Ingestion of hypertonic solutions decreased subsequent food intake in pigs . In humaIt should be noted, however, that a decrease in food intake as a result of induction of malaise or discomfort by any of the used HCA sources cannot be excluded. Still, previous studies on the occurrence of conditioned taste aversion after HCA administration concluded that the food intake reducing effects of HCA cannot be solely explained by the induction of discomfort . AccordiIn summary, this study shows that different commercially available HCA preparations show differences in their potency: Regulator and Citrin K are potent inhibitors of food intake in rats, whereas similar doses of CitriMax hardly showed any effect on food intake. As most of the (ineffective) human studies used low dose CitriMax preparations, the present study may indicate that low doses of a relatively low-effective HCA preparation may have contributed to the lack of efficacy in several human studies.The author(s) declare that they have no competing interests.JL: has made substantial contributions to conception and design, acquisition, analysis and interpretation of data and drafted the manuscript.PW: has made substantial contributions to conception and design, acquisition, analysis and interpretation of data and has been involved in revising the article critically.AS: has made substantial contributions to conception and design and has been involved in revising the article critically.AN: has made substantial contributions to conception and design, has been involved in drafting the article and gave final approval of the version to be published.All authors read and approved the final manuscript.


The burden of shigellosis is greatest in resource-poor countries. Although this diarrheal disease has been thought to cause considerable morbidity and mortality in excess of 1,000,000 deaths globally per year, little recent data are available to guide intervention strategies in Asia. We conducted a prospective, population-based study in six Asian countries to gain a better understanding of the current disease burden, clinical manifestations, and microbiology of shigellosis in Asia.Shigella was isolated from 2,927 (5%) of 56,958 diarrhoea episodes detected between 2000 and 2004. The overall incidence of treated shigellosis was 2.1 episodes per 1,000 residents per year in all ages and 13.2/1,000/y in children under 60 months old. Shigellosis incidence increased after age 40 years. S. flexneri was the most frequently isolated Shigella species  in all sites except in Thailand, where S. sonnei was most frequently detected (124/146 [85%]). S. flexneri serotypes were highly heterogeneous in their distribution from site to site, and even from year to year. PCR detected ipaH, the gene encoding invasion plasmid antigen H in 33% of a sample of culture-negative stool specimens. The majority of S. flexneri isolates in each site were resistant to amoxicillin and cotrimoxazole. Ciprofloxacin-resistant S. flexneri isolates were identified in China (18/305 [6%]), Pakistan (8/242 [3%]), and Vietnam (5/282 [2%]).Over 600,000 persons of all ages residing in Bangladesh, China, Pakistan, Indonesia, Vietnam, and Thailand were included in the surveillance. Shigella strains. The heterogeneous distribution of Shigella species and serotypes suggest that multivalent or cross-protective Shigella vaccines will be needed to prevent shigellosis in Asia.Shigella appears to be more ubiquitous in Asian impoverished populations than previously thought, and antibiotic-resistant strains of different species and serotypes have emerged. Focusing on prevention of shigellosis could exert an immediate benefit first by substantially reducing the overall diarrhoea burden in the region and second by preventing the spread of panresistant  Shigella appears to be more ubiquitous in Asian impoverished populations than previously thought, and antibiotic-resistant strains have emerged.A prospective, population-based study in six Asian countries showed that Shigella, a group of rod-shaped bacteria closely related to those that normally live in the human intestine, is known to cause severe diarrhea in both developed and developing countries, but the global impact of Shigella infection (shigellosis) has not been well characterized. Shigella exists in more than 40 different varieties, an increasing number of cases have been found to be resistant to available antibiotics, and no vaccine is licensed except one oral vaccine in China.Infections that cause diarrhea are a major public health problem in developing countries and other places where resources are scarce, particularly in young children. Although deaths from diarrhea have decreased considerably in recent decades, diarrheal illnesses continue to cause some 2.5 million deaths each year. The best information available on the impact of shigellosis has been based on historical estimates, which are subject to inaccuracy. More recent studies suggest that the older reports may have underestimated the impact of shigellosis. The authors of this study wanted to obtain more accurate, current estimates of the impact of shigellosis in developing countries.Shigella does not necessarily provide protection against other types. Therefore, in order to develop an effective vaccine, researchers would need to know which types of Shigella are causing illness in affected parts of the world. Accordingly, the authors of this study also wanted to investigate the specific types of Shigella  involved in cases of diarrhea.In addition, immunity to one type of Shigella. When Shigella was identified, the bacteria was serotyped and tested for resistance to antibiotics. Because standard culture methods do not always detect Shigella when it is present, as a double-check, the researchers also tested some of the specimens for a type of DNA  that serves as a molecular “footprint” of Shigella. Patients received treatment according to national guidelines.The researchers set up surveillance projects for diarrhea in six developing countries throughout Asia: at three rural or semirural sites  and three urban slum sites . They conducted information campaigns in each area to encourage residents to visit a participating clinic if they or their children developed diarrhea. Patients presenting with diarrhea were enrolled in the study and their medical findings were documented on standardized report forms. Stool or rectal swab specimens were obtained (with patient consent) and sent to laboratories to test for The study involved approximately 600,000 participants over 1–3 years, and detected approximately 60,000 cases of diarrhea. Shigella was found in 5% of diarrhea episodes, meaning that two new cases of shigellosis occurred per 1,000 people  per year. Rates were higher in children and in people over age 40. Among children less than 5 years old, there were 13 new cases per 1,000 children per year. Rates of shigellosis were higher in the Bangladesh site than in the China, Pakistan, and Indonesia sites, which in turn had higher rates than the Vietnam and Thailand sites.In contrast to prior studies, no deaths were detected following episodes of shigellosis, and less than one-third of cases of shigellosis were associated with bloody diarrhea (dysentery).Shigella detected at all sites were resistant to two or more antibiotics. Testing for the ipaH gene was able to identify Shigella in half of patients with bloody diarrhea whose routine stool cultures did not reveal Shigella.The distribution of serotypes was found to differ from one site to another and within a given site over time. A high percentage of This study found that shigellosis occurs in these Asian sites at a rate approximately 100 times higher than in industrialized countries. The finding that shigellosis frequently occurs in the absence of bloody stool means that government data collections using dysentery as part of the case definition can be expected to miss the majority of shigellosis cases. Also, the increased rate of shigellosis above age 40 shows that older people share significantly in the burden (and most likely the transmission) of shigellosis.Shigella-associated diarrhea calls into question the priority that this disease should receive in global vaccine development efforts, especially given the technological challenges posed by the complex and variable distribution of serotypes. Nonetheless, the emergence of multidrug-resistant strains clearly remains a threat, and raises the perennial issue of improved sanitation, rather than new antibiotics, as a long-term solution to the plethora of water-borne illnesses that disproportionately affect developing countries.The generally benign clinical course of http://dx.doi.org/10.1371/journal.pmed.0030353.Please access these Web sites via the online version of this summary at World Health Organization topic page on diarrheaCenters for Disease Control and Prevention: ShigellosisWikipedia entry on Shigella (note: Wikipedia is a free Internet encyclopedia that anyone can edit) Shigella strains. The recently reported emergence of ciprofloxacin resistance further narrows the choice of effective antimicrobials  of 305), Pakistan (8 [3%] of 242), and Vietnam (5 [2%] of 282). Of the 1,653 ampicillin-resistant and the 1,490 cotrimoxazole-resistant S. flexneri isolates, 1,322 were cross-resistant to ampicillin and cotrimoxazole. Eighteen isolates were resistant to all four tested antimicrobials.A high percentage of ll sites . The higShigella culture-positive specimens, ipaH was detected in 385 (90%). In 1,124 culture-negative patients who reported dysentery, 564 (50%) had ipaH in the stool, in contrast to 673 of 1767 (38%) patients with nonbloody diarrhoea (p = 0.0001). The highest percentage of culture-negative, ipaH-positive specimens was detected in the two countries with the highest shigellosis incidence, China , and Bangladesh . In Thailand, one of the sites with the lowest shigellosis incidence rate, ipaH was detected in 14%  of stool samples  of stool samples.Of 427  samples . In VietIpaH detection was lowest in children under age 6 mo, peaked between the second and tenth year of life, after which the percentage of ipaH-positive specimens declined until age 40 y, at which time the percentage of positive specimens increased again  of patients reported medical events during follow-up. Persistent diarrhea was seen in 18% of patients following shigellosis episodes; however, the clinical importance of these persistent episodes is not clear. Earlier reports from the Asian region have stressed the potential severity and poor outcome of shigellosis episodes –40. Seveggestion . Third, S. flexneri isolates in China are resistant to ciprofloxacin. The emergence of multidrug-resistant Shigella isolates could reverse the benign course of shigellosis episodes observed in this study.The over-the-counter sale of antibiotics without prescription enjoys popularity in all our study sites and may be responsible for the emergence of antibiotic resistance. The project confirmed that ampicillin and cotrimoxazole no longer have a place in the treatment of shigellosis. Nalidixic acid was recommended by the WHO as the first-line treatment against shigellosis until 2004, when it was replaced by ciprofloxacin . CompletShigella strains. Safe water supplies and adequate sanitation combined with improved hygiene are likely to reduce the shigellosis burden in the future. Steady economic growth is likely to overcome the barriers currently obstructing improvements in infrastructure for underserved populations. But such progress can take decades and will provide little relief to unstable and mobile populations. In this context a safe and affordable vaccine to protect against shigellosis would be a welcome public health tool. Several Shigella vaccine candidates are under development [The prevention of shigellosis could exert an immediate benefit by substantially reducing the diarrhea burden in the region and by preventing the spread of panresistant elopment –10. Our elopment –13 and celopment .Shigella strains in six Asian countries. The Shigella species believed to be dominant are S. flexneri in resource-poor countries and S. sonnei in industrialized nations. Consistent with previous reports [S. flexneri was most frequently isolated in the study sites in the five resource-poor countries , whereas in Thailand, which is rapidly becoming industrialized, S. sonnei was the most common species. Surprisingly, S. boydii, which had been thought to be relatively rare, was responsible for nearly one-quarter of shigellosis episodes at the Bangladesh site. Relatively few S. dysenteriae were detected during this surveillance project. Amongst the S. flexneri isolates were a surprisingly wide range of serotypes that varied across the Asian sites. The large variety in Shigella species and serotypes may explain the unusual age distribution of this enteric disease: Patients may remain susceptible to serotypes to which they have not been exposed earlier. The finding that S. sonnei is more frequently isolated in younger than in older children and S. flexneri is more frequently isolated from older than from younger shigellosis patients may be evidence for the steady replacement of Shigella strains with increasing age.We found an unexpectedly complex landscape of circulating  reports , S. flexS. flexneri serotypes vary geographically, they vary temporally. We found statistically significant shifts in S. flexneri serotypes between observation years at each of the three sites where a comparison was possible. Temporal shifts in Shigella serotypes have been reported previously in Kolkata, India [Shigella species and serotypes. An alternative approach would be to search for an antigen common to all Shigella species and serotypes. A vaccine that could elicit immunity against such a common antigen may be a promising future strategy to control shigellosis.Not only do a, India  but not a, India . Such shIn conclusion, shigellosis is a frequent cause of diarrhea in the more impoverished areas of Asia. Although there were few medical complications associated with shigellosis, control of this disease could reduce of the overall diarrhea burden globally. The development of a vaccine protective against shigellosis is a highly desirable public health goal, but the development of such a vaccine is complicated by the variation in species and serogroups between sites, years, and age groups.Alternative Language Abstract S1(1.2 MB PDF)Click here for additional data file.http://www.ncbi.nlm.nih.gov) accession number of the gene discussed in this paper is ipaH (M32063).The GenBank (


Falls are a major source of morbidity and mortality among older adults. Unfortunately, self-report is, to a large degree, the gold-standard method for characterizing and quantifying fall frequency. A number of studies have demonstrated that near falls predict falls and that near falls may occur more frequently than falls. These studies suggest that near falls might be an appropriate fall risk measure. However, to date, such investigations have also relied on self-report. The purpose of the present study was to develop a method for automatic detection of near falls, potentially a sensitive, objectivemarker of fall risk and to demonstrate the ability to detect near falls using this approach.15 healthy subjects wore a tri-axial accelerometer on the pelvis as they walked on a treadmill under different conditions. Near falls were induced by placing obstacles on the treadmill and were defined using observational analysis. Acceleration-derived parameters were examined as potential indicators of near falls, alone and in various combinations. 21 near falls were observed and compared to 668 "non-near falls" segments, consisting of normal and abnormal  gait. The best single method was based on the maximum peak-to-peak vertical acceleration derivative, with detection rates better than 85% sensitivity and specificity.These findings suggest that tri-axial accelerometers may be used to successfully distinguish near falls from other gait patterns observed in the gait laboratory and may have the potential for improving the objective evaluation of fall risk, perhaps both in the lab and in at home-settings. In Juned States . Much efd States -6, but tDifferent techniques have been developed to automatically identify falls and related measures with varying degrees of success using sensors embedded in the home environment or body-fixed sensors -9. Body-We hypothesized that methods based on body-fixed sensors could, however, be adapted to identify missteps or near falls, potentially enhancing the utility of an approach for assessing fall risk. Missteps and near falls are used here synonymously as a stumble or loss of balance that would result in a fall if sufficient recovery mechanisms were not activated . AutomatYoung adults  and older adults  participated in this study. Subjects in both groups were healthy and had no gait disturbances. Subjects were excluded if they had any disability likely to impair gait or balance, cognitive decline, or dementia . The research carried out on humans was in compliance with the Helsinki Declaration and the study protocol was approved by Human Studies Committee of the Tel Aviv Sourasky Medical Center. All subjects provided informed written consent.® MiniMod portable tri-axial accelerometer  was worn on the lower back to measure the vertical, anterior-posterior and medio-lateral accelerations . All gait intervals were divided into 5 second, non-overlapping segments. The normal gait segments were compared to the "near fall" segments. Acceleration-axis calibration was performed, as described previously , in ordeFor each 5 second gait segment, the signal vector magnitude (SVM),and the Normalized Signal Magnitude Area (SMA),where x,y,z are the 3 axes of acceleration, were determined  and threFor each gait parameter, the best threshold for distinguishing between normal gait segments  and near falls was determined by plotting a range of possible thresholds using a Receiver Operating Characteristic curve, ROC, and choosing the threshold with the best specificity and sensitivity values, i.e., the ones closest to the  point. The algorithm performance was examined for each parameter separately and for two or three parameter combinations. For the multiple parameter combinations, we checked detection performance when all parameters were above a certain threshold, i.e., the "and" state, and when at least one parameter was above a certain threshold, i.e., the "or" state. Performance was expressed by means of sensitivity and specificity.Overall, we observed 592 normal segments, 21 near falls, 18 stops, 30 step-overs (stepping over obstacles), and 28 kicks. All of the acceleration derived measures showed higher values during a near fall  and in aging . Normal balance responses may have been altered and restricted by the treadmill setup . In this initial study, we focused on the identification of near falls, but made no attempt at differentiating between the loss of balance and the recovery. Theoretically, these are two distinct processes. In this work, we aimed to identify the "stumble" or near fall. It is, however, possible that some of the recovery phase may have been identified, although most of the derived parameters that had good success in identifying these events are, at least intuitively, more likely related to the loss of balance than to the recovery process. Further work is also needed to verify that the developed algorithms are successful at identifying near falls in normal and free walking environments. There are some subtle differences between over-ground walking and treadmill walking and, as a result, the accelerometer signal is not identical in both conditions. However, even on a treadmill, the signals from all three axes have a form that is similar to over-ground walking, supporting the idea that over-ground near falls can also be detected using the algorithms described.Despite these and other limitations, the initial results reported here motivate continued work along these lines, provide a basis for future studies in both in the lab and at-home settings, and suggest that a tri-axial accelerometer can successfully identify near falls and may also have the potential for improving the objective evaluation of fall risk.A patent related to this work has been submitted.AW and IS designed the study and carried out the data collection and analysis. AW drafted the manuscript. NG assisted with the study design and manuscript revision. JMH assisted with study design, data analysis and manuscript revision. All authors read and approved the final manuscript.