Peritoneal dialysis (PD) is the preferred dialysis modality in children. Its major drawback is the limited technique survival due to infections and progressive ultrafiltration failure. Conventional PD solutions exert marked acute and chronic toxicity to local tissues. Prolonged exposure is associated with severe histopathological alterations including vasculopathy, neoangiogenesis, submesothelial fibrosis and a gradual loss of the mesothelial cell layer. Recently, more biocompatible PD solutions containing reduced amounts of toxic glucose degradation products (GDPs) and buffered at neutral pH have been introduced into clinical practice. These solutions contain lactate, bicarbonate or a combination of both as buffer substance. Increasing evidence from clinical trials in adults and children suggests that the new PD fluids may allow for better long-term preservation of peritoneal morphology and function. However, the relative importance of the buffer in neutral-pH, low-GDP fluids is still unclear. In vitro, lactate is cytotoxic and vasoactive at the concentrations used in PD fluids. The BIOKID trial is designed to clarify the clinical significance of the buffer choice in biocompatible PD fluids.The objective of the study is to test the hypothesis that bicarbonate based PD solutions may allow for a better preservation of peritoneal transport characteristics in children than solutions containing lactate buffer. Secondary objectives are to assess any impact of the buffer system on acid-base status, peritoneal tissue integrity and the incidence and severity of peritonitis.® solution for a period of 10 months. Patients will be monitored by monthly physical and laboratory examinations. Peritoneal equilibration tests, 24-h dialysate and urine collections will be performed 4 times. Peritoneal biopsies will be obtained on occasion of intraabdominal surgery. Changes in small solute transport rates, markers of peritoneal tissue turnover in the effluent, acid-base status and peritonitis rates and severity will be analyzed.After a run-in period of 2 months during which a targeted cohort of 60 patients is treated with a conventional, lactate buffered, acidic, GDP containing PD fluid, patients will be stratified according to residual renal function and type of phosphate binding medication and randomized to receive either the lactate-containing Balance solution or the bicarbonate-buffered Bicavera Peritoneal dialysis (PD) is the preferred dialysis modality in children. Advantages of PD over hemodialysis relevant to pediatric patients include its compatibility with a normal lifestyle and full psychosocial integration, the continuous mode of blood purification without dysequilibrium conditions, the absence of vascular access issues and the avoidance of puncture pain. However, the major drawback of PD is its limited technique survival. Almost fifty percent of adult as well as pediatric PD patients must switch to hemodialysis within 4 to 5 years of treatment ,2. While® (Fresenius), a purely bicarbonate-buffered biocompatible PD solution, with that of a conventional acidic, lactate buffered solution by a three-month crossover trial in children on automated PD [® treatment, which was readily reversible when patients returned to conventional solution. This effect was also observed with lactate- or lactate/bicarbonate-buffered biocompatible PD solutions [® was used. Two studies observed a slightly lower initial increase of the functional peritoneal surface area during a single PD dwell with pH-neutral compared to acidic solutions compatible with reduced peritoneal capillary recruitment; this trend was significant in one study [® than with lactate buffered conventional fluid despite identical content of base equivalents.In recent years, a new generation of more biocompatible PD fluids has been introduced into clinical practice. The separation of alkaline and acidic fluid compartments in pluri-chamber bags permits to sterilize glucose at very low pH with greatly reduced GDP formation and yet produce pH-neutral final dialysis solutions, using lactate and/or bicarbonate as a buffer. We recently compared the safety and efficacy of Bicaveramated PD . We obseolutions ,15, and olutions ,16 we obne study -19. FiscWhile these results are encouraging with respect to the long term preservation of the peritoneal membrane and strongly favour the primary use of low-GDP, neutral-pH biocompatible PD fluids, the relative importance of the buffer system is still unclear. In vitro data suggest that lactate per se may compromise local cell functions independently of pH by affecting the cellular redox state and reducing cellular energy sources ,20-22. BThe European Pediatric Peritoneal Dialysis Study Group (EPPS) plans a prospective, randomized study with administration of pH neutral, low-GDP PD solutions containing either lactate or bicarbonate buffer over a period of 10 months.primary objective is to evaluate the effect of lactate vs. bicarbonate buffer on peritoneal transport capacity in children. The hypothesis to be tested is that bicarbonate based PD solutions may allow for a significantly better preservation of peritoneal transport characteristics (D/PCrea) in children compared to a solution containing lactate buffer. Secondary objectives will be to assess differential effects of lactate and bicarbonate buffered PD fluids on acid-base status, surrogate parameters of peritoneal biocompatibility and local and systemic carbonyl stress, peritoneal morphology, the incidence and severity of peritonitis, statural growth and nutritional status. Moreover, this study will be used to assess genetic determinants of the peritoneal transporter status and the evolution of peritoneal morphology over time.The 2) and the type of phosphate binder therapy , since these variables may affect the overall efficacy of metabolic acidosis control. Following stratification, subjects will be randomized centrally to receive either the lactate-containing Balance solution or the bicarbonate buffered Bicavera® solution for a period of 10 months. Both during the run-in period and during the intervention phase, patients will be monitored by monthly clinical and laboratory examinations, including capillary blood gas analyses. In addition, peritoneal equilibration tests (PETs), 24-hour dialysate and urine collections and intraabdominal pressure assessments will be performed at time of randomization  and after 3, 6 and 10 months of treatment (with the study solutions). Also, peritoneal biopsies will be performed on occasion of intraabdominal sugery or laparoscopy prior to start and after termination of the study .This is a multicenter open-labelled, controlled, randomized clinical trial, designed to test the effects of the buffer substance in biocompatible PD fluids on peritoneal small solute transport capacity. All subjects will undergo a 2-month run-in period, in which they receive conventional lactate buffered, acidic, GDP containing PD fluid. During this period, patient eligibility for the trial will be verified and the dialysis dose will be optimized if necessary to ensure appropriate PD adequacy. At the end of this period, the patients will be stratified according to residual renal function , peritoneal neoangiogenesis (VEGF), fibrotic activity (TGF-β) and local inflammation (IL-6). With the same intention, the evolution of peritoneal histomorphology will be assessed in all patients available for sequential biopsies. Moreover, possible differential effects of lactate and bicarbonate buffer on the control of metabolic acidosis will be assessed by monthly blood gas analyses. Finally, the incidence and clinical course of peritonitis will be recorded as a possible indirect marker of local peritoneal macrophage function.2 body surface area, 4) the most recent episode of PD-associated peritonitis, if any, occurred more than 3 weeks ago, 5) signed informed consent by parent/guardian, with a subject aged > 7 years also signing an age-appropriate assent form.Criteria for inclusion in the study are 1) patients above 1 month and less than 19 years of age, 2) end-stage renal disease with manual or automated continuous peritoneal dialysis as maintenance treatment modality, 3) a fill volume approximately of 1100 ml/1.73 mCriteria for exclusion from the study are 1) reduced efficiency of peritoneal dialysis due to anatomic anomalies or intraperitoneal adhesions, 2) uncontrolled hyperphosphatemia, 3) severe pulmonary, cardiac, hepatic or systemic disease including any kind of malignancy, and 4) current or recent (within 30 days) exposure to any investigational drug.Reasons for permanently discontinuing the study medication are 1) renal transplantation, 2) switch to hemodialysis due to PD technique failure, 3) patient/parent withdrawal of consent of participate, 4) patient moving out of the area to a location with no participating center within reasonable distance, and 5) a severe adverse event.study fluids is given in Table ® and Balance will be available in three different glucose concentrations to meet individual ultrafiltration requirements. The fluids will be administered at a dose of approximately 1,100 ml/m2 body surface area per dwell. Both in patients on CAPD and CCPD, the number of cycles and dwell times can be varied according to clinical needs. The dose of dialysis will be tailored individually in order to ascertain a minimum total weekly Kt/VUrea of ≥ 2.0.The composition of the concomitant medication during the run-in period and the study period will be documented in the case report form with respect to type, dosage and mode of delivery. In case of peritonitis , treatment will be given intraperitoneally according to international pediatric guidelines [Any kind of idelines  using ceBicarbonate supplementation will be discontinued at start of the run-in period and only re-instituted if blood bicarbonate levels drop below 17 mmol/l despite sufficient dialysis efficacy. The recommended dosage is 0.5 mmol/kg/day divided into 3 doses.adverse event is defined as any untoward medical occurence in a patient who takes the study medication. It does not necessarily have a causal relationship with this treatment. This may be an unfavourable and unintended sign, symptom or disease, which is observed after exposure to the study medication, whether or not considered related to the treatment. Moreover, the participating investigators will report all treatment-emergent adverse events that are observed on the online adverse event form. This applies regardless of the clinical significance or the assessment of study drug causality. In this trial, such adverse events may include inflow pain, severe changes of the state of hydration, abnormal electrolyte and glucose blood levels, peritonitis, abdominal hernia, and allergic reactions.An severe adverse event or reaction is any untoward medical occurrence that a) results in death, b) is life-threatening, c) requires inpatient hospitalization or prolonges an existing hospitalization, or d) results in persistent or significant disability/incapacity.A Any serious adverse event, whether or not considered related to the study medication, and any unexpected drug reactions with significant hazard to the patient population will be reported to the responsible safety assessor at Fresenius Medical Care by phone or by fax within 24 hours following first knowledge of the event. Alternatively the clinical monitor may be informed. This information will be forwarded to and evaluated by the safety monitoring committee, and reports of serious adverse reactions will be disseminated to all participating centers for submission to their respective institutional review boards. Fresenius Medical Care is responsible for passing on the information to relevant supervisory authorities.Data acquisition will be entirely through the internet. The case report form menus will be used to record the following: 1) baseline clinical patient information, 2) physical and biochemical examination variables, 3) study and concurrent medications, and 4) adverse events.Periodic computerized audit reports will be run to monitor data quality and completeness. The data base is stored on a server drive that is backed up to tape daily by Tel-A-Vision, Media Networking GmbH.In order to insure confidentiality, data from each patient will be recorded in the computer data base with a unique contributing center code, study code, sequence number and patient initials. Patient names are never entered online or forwarded in any other form to the coordinating office.Cr from the time of randomization to the conclusion of the 10-month study period. In a previous trial we demonstrated a 6% increase of D/PCr in children on lactate-buffered PD fluid in contrast to a 4% decrease in D/PCr using bicarbonate buffered fluid within 3 months of exposure, resulting in a statistically significant 10% difference in the evolution of peritoneal creatinine transport rate [Cr at least 7 ± 10% can be expected when Balance and Bicavera® are applied for 10 months. To detect this difference with a sensitivity of 80% and an error probability of 5%, at least 15 patients per randomization group will be required. Assuming a 50% drop-out rate due to renal transplantation and other reasons in the course of the study, 60 patients will have to be enrolled.The primary study outcome is the change in 4h-D/Port rate . AssuminA computer based randomization protocol will be generated and applied centrally at the end of the run-in period. Baseline comparability between the two treatment groups will be evaluated with respect to entry criteria. Chi-square and t-tests will be used to assess differences between the two groups on the baseline variables. Any variables that are found to be discrepant between the two groups and that are related to the outcome variables will be treated as co-variates in later analyses.Cr ratios, two strategies will be employed:In order to evaluate the patients' change in D/P1. Repeated measure ANOVA will be performed on those patients who complete the 10-month observation period on the study medications.Crea ratio during the 10-month period. All patients started on study medication will be available for this analytical approach.2. The Kaplan-Meier method will be used to estimate the time in which patients are likely to display a ≥ 7.5 % increase in the D/PThe same strategies will be used to analyze secondary outcome variables.All publications will be authored by members of the scientific advisory committee. Co-authors will have contributed to the design, analysis, execution and actual reporting of the study.Steering committee: C.P. Schmitt, F. Schaefer, K.E. Bonzel, K. RönnholmScientific advisory committee: M. Almeida, K. Arbeiter, G. Ardissino, K.E. Bonzel, A. Edefonti, M. Fischbach, K. Haluany, J. Misselwitz, Markus J. Kemper, K. Rönnholm, F. Schaefer, C.P. Schmitt, S. WygodaSafety monitoring committee: V. Schwenger, U. Querfeld, G. OffnerWe report the protocol of a randomized clinical trial designed to test the effect of the buffer type on the evolution of peritoneal tissue integrity and transport function in children treated with 'biocompatible', i.e. neutral-pH, low-GDP PD solutions. The study utilizes the availability of two novel biocompatible PD solutions manufactured by the same company which differ selectively in the buffer employed, namely either pure lactate or pure bicarbonate. The comparative administration of these solutions will provide information on differences in peritoneal cell viability, tissue morphology, local host defense and solute transfer capacity potentially inferred by cytotoxic and/or vasocative effects of lactate administered to the abdominal cavity in unphysiological concentrations.This investigator-initiated trial was designed exclusively by the members of the EPPS scientific advisory committee. None of the investigators have any financial relationship with the manufacturer of the study medication. Financial support is received from Fresenius Medical Care to cover coordination costs and investigator meetings.The pre-publication history for this paper can be accessed here:


This report describes a large international chocolate-associated Salmonella outbreak originating from Germany.Salmonella (S.) Oranienburg isolates were subtyped by the use of pulsed-field gel electrophoresis (PFGE).We conducted epidemiologic investigations including a case-control study, and food safety investigations. S. Oranienburg notifications was registered in Germany. Simultaneously, an increase in S. Oranienburg infections was noted in other European countries in the Enter-net surveillance network. In a multistate matched case-control study in Germany, daily consumption of chocolate , having shopped at a large chain of discount grocery stores , and consumption of chocolate purchased there  were associated with illness. Subsequently, two brands from the same company, one exclusively produced for that chain, tested positive for S. Oranienburg. In two other European countries and in Canada chocolate from company A was ascertained that also contained S. Oranienburg. Isolates from humans and from chocolates had indistinguishable PFGE profiles. No source or point of contamination was identified. Epidemiological identification of chocolate as a vehicle of infections required two months, and was facilitated by proxy measures.From 1 October 2001 through 24 March 2002, an estimated excess of 439 Salmonella-containing products. Particularly in diffuse outbreak-settings, clear associations with surrogates of exposure should suffice to trigger public health action. Networks such as Enter-net have become invaluable for facilitating rapid and appropriate management of international outbreaks.Despite the use of improved production technologies, the chocolate industry continues to carry a small risk of manufacturing  Salmonella spp. is a substantive cause of human gastroenteritis in many parts of the world [Salmonella reports  received at the federal level by the Robert Koch-Institut (RKI) accounted for 31% of all notifications for the 54 notifiable conditions [Salmonella enterica subspecies enterica serotype Enteritidis (S. Enteritidis) is the predominating serotype followed by S. Typhimurium. They represented 65% and 23% of the reported cases of non-typhoidal salmonelloses with known serotype in 2001. Thus, the remaining ~250 serotypes reported to the RKI in that year, including S. Oranienburg, accounted for only 12%.Non-typhoidal he world . In Germnditions . SalmoneSalmonella and Other Enteric Pathogens (NRC) in Hamburg noted an unusual increase in the number of S. Oranienburg isolates received in October. At that time, no increase was noticeable in the national database for statutorily reportable infectious diseases; 50 S. Oranienburg notifications (median: 1 per week) had been registered for 2001. On November 19, the NRC in Wernigerode informed the RKI that it had received a S. Oranienburg isolate in September. The isolate was submitted by a private laboratory for serotyping and had come with the additional source information "confectionery sample". Upon inquiry, a large German chocolate manufacturer (company A), which produced a broad variety of chocolates and products made thereof, called the RKI on November 27, and confirmed that it had sent in the confectionery sample. According to company A, the positive sample originated from an in-house control of a chocolate product and the pertaining batch, due to be exported to the United States, was completely destroyed and not distributed. Notwithstanding, the number of statutory S. Oranienburg notifications had sharply increased and continued to rise. This report describes the epidemiologic, food safety, and microbiological investigations of this outbreak.In mid-October 2001, the National Reference Center for S. Oranienburg infections about chocolate consumption in the seven days before disease onset, and also to send any remaining chocolate to a food safety laboratory.A standard exploratory questionnaire was distributed on 20 November 2001 via state health departments to all local health departments to aid the collection of data on food and environmental exposure from cases. In addition, local health departments were asked to immediately interview patients with newly reported A request was distributed to participants of the Enter-net surveillance network  on DecemS. Oranienburg isolates from patients and from the in-house chocolate control were found to be indistinguishable by pulsed-field gel electrophoresis (PFGE). On the same day, a multistate case-control study was initiated and coordinated by RKI to test the hypothesis that at least one product from company A was associated with S. Oranienburg-infections. As we were denied a product list from company A, we resorted to the company's web-site and included in our food history evaluation all the products listed there. Some products from company A, e.g., bars of chocolate (brand A), were exclusively sold at a large chain of discount grocery stores (chain X). We found that the majority of chocolates sold at chain X were produced by company A. Therefore, for the analysis we constructed a variable for chocolate(s) purchased at chain X ("chain-X-chocolate") as a proxy for chocolate-products from company A because most patients could remember the flavor of the purchased chocolate, but seldom the brand name.On December 3, while exploration of patients were ongoing and results inconclusive, S. Oranienburg in other countries [S. Oranienburg infection to a public health department before December 6. Case-patients were excluded from the analysis, if they could have been secondary, i.e., if they reported to having had contact with a person with diarrhea in the seven days prior to symptom onset. Cases were selected from the national reportable database by simple random sampling; in Lower Saxony an attempt to interview all case-patients was launched. Case selection was done irrespective of whether patients also had been interviewed with an exploratory questionnaire. At least one age and telephone exchange-matched control subject was selected for each case-patient by sequentially adding 2 to each case-patients' telephone number. Control subjects were eligible if they were in the same age-group as their matched case-patient , had no gastrointestinal symptoms after 1 October 2001, and had not traveled abroad in the seven days prior to the onset of symptoms of the matched case. Telephone interviews were conducted by state health departments, local health departments, and the RKI. Data were analyzed with Epi Info V6.04c .The hypothesis-testing questionnaire collected data on the consumption of chocolates, and some other foods, particularly those previously associated with outbreaks of ountries -5. Food-Salmonella positive chocolate leftovers and five chocolates from grocery stores using the most probable number technique [The local food safety authority inspected company A's production facility and took samples from already packaged ("in-house") chocolates, and from ingredients from its suppliers. Beginning December 11, a nationwide chocolate sampling of German chocolates in grocery stores was initiated by the Federal Ministry of Consumer Protection, Food and Agriculture, and was assisted by the Federal Institute for Risk Assessment . On December 18, when a chocolate leftover from brand A tested positive, the investigations were tailored to German chocolates from company A. The BfR examined quantitatively four echnique .S. Oranienburg isolated from stool specimens were sent to the NRC from laboratories in Germany and, on Enter-net request, from other countries. Furthermore, isolates from chocolates were submitted from state or private food laboratories in Germany as well as from Canada and the Czech Republic. PFGE-analysis was carried out according to Prager et al [For comparison by the use of PFGE, er et al .S. Oranienburg up to reporting week 42, but 462 reports in the following 23 weeks , 240 (52%) patients were female. There was no difference in the gender distribution within the single 10-year age-bands (P = .51). All 16 states of Germany reported S. Oranienburg cases during the outbreak period, with the highest incidence in the state of Schleswig-Holstein  bordering on Denmark. In total, 206 of the 440 German counties were affected with a median of one report and a maximum of 16 from the city of Hamburg during the outbreak period.In 2001, the RKI received 50 reports of S. Oranienburg.Sixty exploratory questionnaires were received from eight states by the end of 2001. Forty-three (88%) of 49 patients with information on chocolate consumption had a symptom onset after 1 October 2001. Of the 34 who gave information as to where they bought the chocolate, 21 (62%) explicitly reported chain X. Some reported exclusively having eaten chocolate bars from brand A, among them a two-year-old child. On 18 December 2001, two months after the initial outbreak alert, a leftover consumed reportedly by this child in the seven days before symptom onset tested positive for S. Oranienburg had been reported in Denmark from October 18 through December 10, compared with only two cases in 2001 before October 18. None of the clustered cases were travel-related [S. Oranienburg problem, independently suspected German chocolate bought in chain X as the source of the Danish outbreak. Chocolate was the only food item that all patients reported eating. The majority stated purchasing chocolate in chain X, which, although German, operates internationally [S. Oranienburg infections was reported from other countries such as Austria, Belgium, Finland, Sweden, The Netherlands  after disease onset in case-patients. Twelve case-control pairs were excluded from chocolate-specific analysis, nine because the case-patients could have been secondary, one due to illness in September, and two where the control subjects could not remember whether they had eaten chocolate. Of the 48 cases and 50 controls that were analyzed, 24 (50%) case-patients and 32 (67%) control subjects were female, 22 (46%) case-patients were younger than 10 years. Ten (21%) of the case-patients reported to have suffered from bloody diarrhea and 14 (29%) were hospitalized  of 381 chocolates that were tested and reported to BfR during the outbreak period. S. Oranienburg was isolated from two different brands of company A; all positive chocolates were produced during the same week in August 2001. Estimates of the number of Salmonella in the tested chocolates ranged between 1.1 and 2.8 per gram.The local food safety authority in Germany did not identify hygienic deficiencies at the production facility. Samples obtained in the beginning of December 2001 from in-house chocolates (n = 12), as well as from cocoa (n = 3) and cocoa powder (n = 7) from a supplier of company A tested negative. This applied also to German chocolates sampled in grocery stores until 18 December (on that day a leftover tested positive). Overall, S. Oranienburg isolates from human cases of gastroenteritis originating in Germany (n = 52), Austria (n = 19), Belgium (n = 8), Canada (n = 6), Denmark (n = 4), The Netherlands (n = 4), Sweden (n = 4), and the Czech Republic (n = 1). Furthermore, 15 chocolate isolates were sent to the NRC for PFGE-analysis from Germany (n = 12), Canada (n = 2), and the Czech Republic (n = 1). They came from an in-house sample, from leftovers of chocolates consumed by patients in their incubation period, and from chocolates sampled in grocery stores in Germany. The PFGE profiles of S. Oranienburg isolates from patients with symptom onset after 1 October 2001 (outbreak period) in Germany and in the other countries mentioned above, except Canada, were indistinguishable  in the week prior to symptom onset, but not in the seven days before the interview. Case-patients were more likely than control subjects to report eating chocolate daily, likely indicating an increased probability of having been exposed to contaminated chocolate. Furthermore, patient isolates from the outbreak period shared a PFGE profile with isolates from chocolates but differed from isolates of patients who became sporadically diseased with S. Oranienburg before the outbreak. In addition, the food histories and microbiological results from S. Oranienburg patients in several other countries pointed to the same source [We describe an international outbreak of e source ,10.Salmonella infections after consumption of contaminated chocolate, although rare, have been known since the 1960's [Salmonella have been recovered from chocolates in these outbreaks, suggesting a very low infectious dose. Estimates of the number of S. Oranienburg cells per gram in this outbreak ranged from 1.1–2.8. However, we cannot exclude that the bacteria were unevenly distributed in the chocolate(products) and that those parts carrying many viable cells were not tested quantitatively. In chocolate, the low moisture (water activity aw: 0.4–0.5) and high sugar content does not favor bacterial growth, but significantly increases thermal resistance [Salmonella against the acidic conditions of the stomach [e 1960's . Common e 1960's -17  can carry Salmonella spp., the low water activity and high fat content in chocolate increases thermal resistance so that temperatures reached during chocolate production  do not  a small number of Salmonella may be sufficient to cause disease, even with low-level contamination, chocolate can affect large number of persons (often children) scattered over a wide area, and thus, has the potential to cause serious public health consequences.It is noteworthy that the case-control study did not identify further products as risk factors. This applied also to the second contaminated brand of company A, which was included in the recall. The small proportion of study cases (25%) mentioning having eaten chain-X-chocolate lends support to the hypothesis of more contaminated brands (even from other manufacturers), which could be one explanation for the continuing case-occurrence. However, inaccuracies due to lack of brand awareness may have played a particular role in this outbreak, and the time-delay between disease onset and interview (median: 37 days) may have contributed to an inaccurate recall of cases and their guardians. Furthermore, cases with a disease onset in 2002 may have occurred as a result of a diminished impact of the public warning due to the Christmas season. For example, chocolate gifts received or given for Christmas may not have been thoroughly enough checked for best-before dates stated in the public warning.Identification of vehicles in foodborne outbreaks can become difficult if the exposure is common. Consumption of a wide variety of German chocolates was reported by all case-patients (and 88% of explored patients), but also from 86% of the control subjects in the week prior to onset of illness. When groups are (nearly) universally exposed or a more specific hypothesis cannot be tested, often the best one can do is to establish a "dose-response-relationship" , i.e., uS. Eastbourne outbreak in Canada/USA in 1973/74, 286 environmental samples and 98 chocolate samples from the production-line were examined. No in-line chocolate sample tested positive and overall only 6 (1.6%) samples were positive  were obtained. In a An Enter-net urgent inquiry was sent after the first results of molecular subtyping suggested a link between human cases and chocolate from company A. Until then, investigators in Germany and Denmark had worked independently unaware that the outbreak extended outside of their respective countries. An earlier inquiry, ideally as early as an outbreak was suspected by the investigating countries (or as an increase was noted in the Enter-net database), may have speeded up hypothesis generating, and thus, may have helped in earlier identification of the vehicle, thereby preventing illnesses.Finally, a public warning or recall of company A products did not occur before a brand A leftover tested positive although the confluence of information – the results of the case-control study, the Danish investigations, and the subtyping comparison between human isolates and the in-house sample – had already pointed to company A products as the source of the outbreak. Yet, no specific product or lot had been identified at the time. For this reason, a recall or a public warning were considered excessive responses by the German food safety authority. However, relying on microbiological confirmation in leftovers, if available for testing, is disputable  and is dangerous in unopened food packages because critical time can elapse before a positive culture in food is obtained . TherefoSalmonella-containing products. For the future, awareness among German food safety authorities must be heightened for the need to base public health action not exclusively on laboratory confirmation in food, and to conduct timely and comprehensive source investigations to enhance food safety in the long-run. The international scale of this outbreak shows how easy it is to distribute a contaminated product across many countries. This underlines the necessity of mechanisms for international surveillance and information dissemination such as Enter-net to ensure that international outbreaks can be dealt with rapidly and in an appropriate manner. Similar networks should be set up or, if existing, should be connected (possibly overseen by WHO), to allow rapid communications to other parts of the world when it is clear that a contaminated product is distributed internationally.To our knowledge, this is the largest reported chocolate-associated outbreak, the seriousness being emphasized by the hospitalizations (29%) and self-reported bloody diarrhea (21%) of the study cases. Despite the use of improved production technologies, the chocolate industry continues to carry a small risk of manufacturing The author(s) declare that they have no competing interests.Salmonella in chocolate. EW coordinated food safety investigations in this outbreak. AE conducted the Canadian part of this outbreak investigation. AS conducted the Finnish part of this outbreak investigation. YA conducted the Swedish part of this outbreak investigation. MHK was instrumental in the design of the case-control study. AA coordinated the German part of this outbreak investigation, broadened the scope of this outbreak by prompting an urgent Enter-net inquiry, and helped in designing the case-control study and drafting the manuscript.DW was the principal investigator of the German part of this outbreak; he carried out the statistical analysis of the case-control study, and drafted the manuscript. JD and FF were responsible for the outbreak investigation including the case-control study for the state ("Bundesland") of Lower Saxony. UvT was responsible for the outbreak investigation including the case-control study for the state ("Bundesland") of Northrhine-Westfalia. GF was responsible for the outbreak investigation including the case-control study for the state ("Bundesland") of Hamburg. SE conducted the Danish part of this outbreak investigation. AMH was responsible for the outbreak investigation including the case-control study for the state ("Bundesland") of Hesse. PR detected the outbreak and conducted microbiological investigations. RP and HT conducted the PFGE-analysis. ISTF coordinated the Enter-net inquiries and investigations. SB conducted interviews in the case-control study, designed the database and helped in the analysis. EB conducted quantitative analysis of All authors participated in revising the manuscript.The pre-publication history for this paper can be accessed here:


Epidemiological studies on the potential role of surgery in Creutzfeldt-Jakob Disease transmission have disclosed associations with history of specific surgical interventions or reported negative results.Within the context of a case-control study designed to address surgical risk of sporadic Creutzfeldt-Jakob Disease in Nordic European countries (EUROSURGYCJD Project), a strategy was adopted to categorise reported surgical procedures in terms of potential risk of Creutzfeldt-Jakob Disease acquisition. We took into account elements of biological plausibility, either clinically or experimentally demonstrated, such as tissue infectivity, PrP expression content or successful route of infection.We propose a classification of exposed tissues and anatomic structures, drawn up on the basis of their specific putative role as entry site for prion transmission through contact with surgical instruments that are not fully decontaminated.This classification can serve as a reference, both in our study and in further epidemiological research, for categorisation of surgical procedures in terms of risk level of Creutzfeldt-Jakob Disease acquisition. Case-control research on the association between surgery and sporadic Creutzfeldt-Jakob Disease (CJD) encompasses six studies and one meta-analysis -8, whichIn this section, we summarily describe the on-going study, review reports that possibly shed light on the biological plausibility of surgery-related CJD transmission, and propose principles for re-classification of surgical procedures.The on-going case-control study, entitled "Surgery and risk of Creutzfeldt-Jakob Disease" (EUROSURGYCJD), constitutes a Concerted Action funded by the EU Research Commission, contract QLG3-CT-2002-81223. The main objective of this study is to quantify a putative excess risk of CJD associated with surgery. A secondary objective is to establish a basis for the design of preventive strategies. The most relevant methodological characteristics are: case-control design; exposure measurement prior to disease onset, registered as codes for surgical procedures; matched 5:1, randomly chosen population controls and random sample of population controls. The population base is the resident population in Denmark, Finland and Sweden, covered by the respective hospital in-patient registers. Cases are individuals with diagnoses corresponding to ICD-9 codes 046.1 and 331.5 and ICD-10 code A81.0 at death or at hospital discharge for the period 1987–2002, identified from the respective national hospital in-patient registers and corresponding national surveillance units. A questionnaire will be mailed to the heads of the registered hospital department or surveillance unit, and a copy of the medical record will be obtained for diagnosis validation. Approximately 300 patients will fulfil criteria for definite or probable sporadic CJD, and constitute the study cases. Population controls are: 1) 5 × 1 controls (approximately 1500), matched to the corresponding case by age, sex, county of residence of the case ; and 2) a 20/million sample of the 1987–2002 resident population aged >40 years, randomly selected from the corresponding national population registers.Individual person-numbers will be used for each resident case or control. Diagnoses and surgical procedures at hospital discharge of the corresponding CJD case at any registered time before date of death will be obtained from the three national hospital discharge registers in Sweden, Denmark and Finland. Perusal of surgical records might be undertaken for selected associations in order to understand transmission mechanisms and interpret results. Open-care surgery or dentistry will not be studied. Surgical procedures coded in registers as per national or NOMESCO classifications will be re-classified in accordance with putative levels of transmission risk based on scientific evidence/plausibility.The quality of CJD diagnoses will be assessed by a review of medical records. The accuracy of surgical history given by the registers will be assessed by comparison with that of a sample of controls and surrogate respondents obtained by interview.Centralised data analyses will be conducted by the Spanish team. In specific instances, risk due to blood transfusion, whether or not performed during surgical procedures, might also be studied.Surgery may be a pathway for patient-to-patient transmission of sporadic Creutzfeldt-Jakob Disease (CJD). In many invasive surgical procedures, non-disposable surgical instruments come in contact with tissues that are known to be infective in CJD patients. These same instruments may retain a considerable level of infectivity after routine sterilisation, and in successive patients can come into contact with tissues that may act as entry sites for CJD transmission. Among the almost 300 recorded cases of iatrogenic transmission of CJD, 5 cases have been attributed to surgical instruments employed in neurosurgical procedures, whilst 2 additional cases were caused by the use of a contaminated intracerebral EEG electrode . To dateIn the above-mentioned studies -7, surgiSc) is a conformational isoform of PrPC, a normal host protein present in neurons and other cell types. In sporadic and familial transmissible spongiform encephalopathies (TSEs), "spontaneous" conversion of PrPC into PrPSc is the key pathogenic event, followed by the accumulation, deposition and further conversion of PrPSc in tissues, together with its propagation along specific neural pathways. In the case of transmitted TSEs -when these are not due to direct inoculation into the CNS- a peripheral phase of neuroinvasion by PrPSc is followed by a subsequent phase of prion replication and propagation along the peripheral nervous system, with final access to the central nervous system [Sc in mucosae-associated lymphoid tissue. For the purpose of classifying tissues susceptible to prion inoculation, the following considerations can be derived from this pathogenic model: i) a tissue can act as entry site for prion transmission if it normally expresses PrPC; ii) the level of PrPSc expression of an infected tissue correlates positively with the risk of prion acquisition by that tissue; and, iii) all tissues involved in the propagation chain of infection from peripheral tissues to the central nervous system can act as entry sites for prion transmission.According to the "protein only" hypothesis , pathoges system . In scraSc by Western blot. This three-level classification correlates quite closely with the distribution and levels of PrPC expression in normal nervous and non-nervous tissues in mammals.[Sc detection have been obtained exclusively in animal TSEs and/or vCJD. This is the case of the small bowel, large bowel (including enteric nerve plexuses), adrenal tissue, pancreas and bone marrow.The recently published WHO classification of tissue infectivity in TSEs , though  mammals. The WHO C under normal conditions. This is the case of anterior ophthalmic tissues, skeletal muscle, peritoneum, and subcutaneous tissue rich in sensitive nerve fibres. These anatomical structures have therefore been independently added to our classification as putative routes of entry, with a lower level of risk compared to the high level represented by the central nervous system, sensitive ganglia and posterior eye tissues. The fact that PrPSc has been recently found in 1/4 skeletal muscle samples of sCJD cases[Further relevant data for tissue classification derive from iatrogenic CJD cases and from experimental transmission of prion diseases to animals. In roughly half of iCJD cases the entry site has been the CNS or the eye , whilst in the other half, injection of pituitary hormones means that a peripheral route of entry has to be assumed . ExperimCJD cases promptedA final classification of entry sites for putative surgical transmission of CJD contains tissues, including all those showing positive results for sporadic and familial CJD in the WHO classification , with miWe propose a list intended to be used to generate attributes of single, well-defined surgical procedures and criteria for their classification in terms of putative risk level of transmission. The two main attributes will be: 1) use of non-disposable surgical instruments; and, 2) exposure during surgery of tissues included in the preceding list. High- and lower-risk surgical procedures will be defined by exposure of tissue corresponding to the respective risk level during surgery. In addition, the lowest risk level is represented by those surgical procedures where disposable surgical instruments are not employed or where no listed tissue or anatomical structure is exposed to surgical instruments.A categorisation of surgical procedures based on the above attributes is inevitably prone to some degree of subjectivity, something that should be minimised by adequate methodological assessment. However, this drawback is more than offset by the possible benefits of identifying specific surgical procedures that pose a significant risk of CJD transmission, in terms of increased study power and control of misclassification of exposure by the removal of surgical procedures, which are probably irrelevant for CJD transmission, from gross anatomical classifications of surgery. We are also aware of the fact that whereas the same surgical instruments are commonly employed in an homogeneous group of procedures in some countries, as is the case of Nordic countries, the same instruments may circulate through a much wider range of procedures and putative risk levels in other countries. Final risk for disease transmission in each surgical procedure combines postulated risk related to tissues exposed in that procedure with the highest risk level of tissues to which instruments have been previously exposed. Accordingly, results should always be interpreted in the light of a known or assumed pattern of instrument circulation between surgical procedure groups. Finally, it is worth stressing that the aim of the approach presented here is exclusively to produce a useful tool for epidemiological research in CJD transmission. Under the present state of knowledge, no consequences for the possible adoption of any practical recommendation concerning surgery or further preventive measures are to be drawn from this approach.The author(s) declare that they have no competing interests.AR assumed the basic task of reviewing literature, proposing tissues and structures, and drafting the first manuscript version. JPC indicated the subject domain, suggested differences between disease transmission and disease acquisition as seen from experimental and observational epidemiological research, generated first paragraphs relating to epidemiological aspects. KM suggested changes in epidemiological aspects. ÅS provided some criticisms. MC gave diverse comments, particularly on biological plausibility. HL clarified the need for methodological refinement in future work. All authors read and accepted the final version.The pre-publication history for this paper can be accessed here:


In the many descriptive studies on prescribed psychotropic drug use by community-dwelling older persons, several sociodemographic and other factors associated with drug use receive inconsistent support.Empirical reports with data on at least benzodiazepine or antidepressant drug use in samples of older persons published between 1990 and 2001 (n = 32) were identified from major databases and analyzed to determine which factors are most frequently associated with psychotropic drug use in multivariate analyses. Methodological aspects were also examined.Most reports used probability samples of users and non-users and employed cross-sectional designs. Among variables considered in 5 or more reports, race, proximity to health centers, medical consultations, sleep complaints, and health perception were virtually always associated to drug use. Gender, mental health, and physical health status were associated in about two-thirds of reports. Associations with age, marital status, medication coverage, socioeconomic status, and social support were usually not observed.The large variety of methods to operationalize drug use, mental health status, and social support probably affected the magnitude of observed relationships. Employing longitudinal designs and distinguishing short-term from long-term use, focusing on samples of drug users exclusively, defining drug use and drug classes more uniformly, and utilizing measures of psychological well-being rather than only of distress, might clarify the nature of observed associations and the direction of causality. Few studies tested specific hypotheses. Most studies focused on individual characteristics of respondents, neglecting the potential contribution of health care professionals to the phenomenon of psychotropic drug use among seniors. The use of prescribed psychotropic drugs by older persons has been a subject of interest for several decades ,2. PsychThe prevalence of psychotropic drug use among community-dwelling older persons  varies from about 20% to 48% -5. More Since aging increases the likelihood of drug accumulation and intoxication, older persons are particularly vulnerable to adverse effects from psychotropic drugs . NotableAlthough more psychotropic drug users are found among older persons than any other age group, the prevalence of mental disorders appears to be lower among older than younger adults. This has been shown for major depression, anxiety disorders and sleep disorders ,22-30. OThe inappropriate prescription of psychotropic drugs may account partially for the discrepancy between low levels of distress and high levels of drug use among older persons. Inappropriate prescriptions include questionable drug combinations (such as two benzodiazepines), excessive treatment duration, and drugs contraindicated for use by older people . Authors estimate that one-fifth to one-half of psychotropic drug prescriptions to the elderly are "inappropriate" ,16,31,32These findings suggest that older persons' psychological well-being is not the principal determinant of their psychotropic drug use. In the present article, we review recent empirical studies in order to identify other factors that may account for psychotropic drug use among older persons. A large body of work bears on this age group and their use of psychotropic and other drugs ,34. EarlMedLine, Cumulative Index to Nursing & Allied Health Literature, Psychlit, Eric and Sociological Abstracts for the years 1990 to 2001. Various keywords were used. Selected reports had to: (1)constitute either a peer-reviewed journal article or a government publication published in English or French; (2) present specific retrievable empirical results concerning older persons, regardless of other age groups studied  and Canada (28%), followed by France (12.5%), Sweden (9.5%), and 3% each (one report) from Australia, Austria, Ireland, the Netherlands, Spain, and the United Kingdom (Table 1 see ). Of 26 Most reports  presented multivariate data analyses, usually multivariate logistic regression, where the independent contribution of various variables to the variance in psychotropic drug use could be ascertained while controlling for the contribution of other variables. Although variables with statistically significant associations (p < .05) to drug use that remained in the regression equation were often considered "predictors," strictly speaking only an association is demonstrated in this fashion, and the direction of causality can rarely be established. This is especially so when a theoretical model is not specified prior to the data analysis, as was the case in the vast majority of reports. The eight remaining studies conducted bivariate analyses solely, and most examined three or less variables.In the following review, associations of sociodemographic factors and life conditions with psychotropic drug use are examined first. A factor was deemed well supported by the review studies when 70% of the results from all studies that considered this factor were statistically significant and pointed in the same direction. Second, methodological and conceptual issues relevant to the study of psychotropic drug use among the elderly, and salient in the reviewed studies, are discussed.Weighted average prevalence rates of psychotropic drug use were estimated from all reports having collected data from probability samples or entire populations (n = 22). In longitudinal studies, data from the last year of the study were used. Average prevalence of any psychotropic drug use from 9 studies was 29.0% (range 11.8% – 42.5%). For drugs identified in the reports as benzodiazepines, minor tranquilizers, anxiolytics, or sedative-hypnotics, the average prevalence in 13 studies was 21.5% (range 6% – 43.8%). In 11 studies with data on antidepressants, the average prevalence was 6.9% (range 2.3% – 14%). Finally, for neuroleptics, it was 3.1% .Older people are more likely than any other age group to use any type of medication . HoweverOver the past three decades, numerous hypotheses have been proposed to explain the higher prevalence of psychotropic drug use among women than men: women are more inclined to reveal their emotional problems to their doctor,36,52-55In this review, 73% of the relevant studies support the established finding that women are more likely to use psychotropic drugs than men. In two studies, the relationship with gender holds only among those aged between 65 and 74 years, and in a third, the results are opposite. However, the studies shed little light on reasons for this disparity.Only two studies identified as a secondary objective to look at the gender issue in relation to psychotropic drug use ,49. A feThe role of culture, ethnicity, and race has received little attention so far in the literature on older persons' psychotropic drug use. Explaining cultural, ethnic, or racial disparities in use of health services is a complex endeavor, requiring analysis of predisposing, structural, access, and other variables in interaction -78. In tInterpretations of the race-specific findings from these six studies focused mostly on professional-and individual-level determinants. Brown et al.  suggesteIt has been suggested that older widows would be more likely to use psychotropic drugs because of the distress of bereavement . Eleven Living in deprived environments and having an unskilled occupation, low income and little formal education are variables associated with psychological distress among adults, and it might be assumed that the same would hold among older people. However, the studies reviewed fail to support this association. Socioeconomic status (SES) is typically operationalized by education, income, and occupation. As Table 2 see  shows, While the importance of SES as a predisposing or mediating influence on drug use might be more established in general population studies, it may be less relevant in the older age group because of a lower rate of psychological distress and greater access to income security plans and retirement pensions that prevent extreme poverty.In the United States and until recently in Canada, older persons benefited from Medicare or provincial health insurance plans without medication coverage. Insurance coverage has been shown to influence psychotropic drug use by the elderly . Five stNo study examined meso-level variables related to SES, such as census-tract or neighborhood poverty, except proximity to health centers. The use of health services, including medications, may be increased by proximity to such services . Close oStressful events may increase people's likelihood of using psychotropic drugs. Only three studies examined this relationship, each reporting a different result: a positive association , a negatA recent qualitative synthesis of the literature concludes that the pathway to psychotropic drug use among older people typically includes the presence of organic disease   found a significant association between the presence or the number of physical illnesses and psychotropic drug use. In their conceptual model, Gustaffson et al.  suggest Four of six studies (60%) examining the relationship between psychotropic drug use and use of other medications found a significantly positive association, but the direction of causality remains unclear.Health perception–the self-evaluation of one own's health–has been shown to be more strongly associated with psychotropic drug use than actual diagnosis of disease . Some reIn this review, seven of eight studies (87.5%) examining the association between health perception and drug use found a positive relationship. However, two thirds of the reviewed studies were cross-sectional, preventing conclusions about cause-effect relationship, and typically more than 80% of the psychotropic drugs used by their subjects were benzodiazepines. This raises the possibility that some subjects had poor health perception as a result of benzodiazepine consumption. Iatrogenic effects of long term benzodiazepine use may worsen health and functional capacity, hence health perception ,91. The It has previously been proposed that low social support is associated with psychotropic drug use among older people ,93. In 1Either social support is a minor strand in the tapestry of psychotropic drug use, or the concept of social support may be inadequately operationalized by standard scales. These may need to measure, beyond frequency of social contacts and residential status, subjective judgments of loneliness and of opportunities for social intimacy. Whereas a summed scale score indicating "social isolation" was not associated with benzodiazepine use in one study , in bothThe association between a diagnosis or rating of mental disorder or psychological distress and the use of psychotropic drugs is evidently anticipated. In 18 studies, 22 tests of this association were carried out, and it was significant in 17 (77%). An intriguing observation is that two of the four studies that failed to support the association included only the antidepressant drug class ,71. WhilDSM-III-R criteria [In the general population, Ohayon and Caulet  have clecriteria , is assoThe number of annual visits to a doctor's office has an obvious influence on the number of prescriptions since it has been shown that up to 75% of visits by older people end up with a prescription ,97. All Among the 16 factors identified in this review of 32 empirical reports, only the variables of language and stressful events were examined in less than five different studies. Gender, age, and mental health status were most frequently examined. The variables of race, medical consultations, proximity to health centers, sleep complaints and health perception are significantly associated with drug use in all or almost all studies incorporating them. Gender and mental health status are associated with drug use in over 70% of studies, while physical illness and number of medications are associated in slightly over half of relevant studies. However, significant associations with age, marital status, socioeconomic status, and social support are observed in only 27% to 36% of studies in which these factors are examined.Conflicting results could be explained partially by methodological and conceptual characteristics of many of the studies reviewed. The following discussion focuses on study design, sample, concept definitions and measurements , as well as distinction between short-and long-term psychotropic drug use. Table 1 see  lists tDescriptive methods (100%) using cross-sectional data (62%) predominate in this body of recent reports of psychotropic drug use in the elderly. Cross-sectional data are vulnerable to sample bias, especially when respondents are not randomly selected, as was the case in 9 of 30 (30%) studies. Given the greater costs involved, the proportion of longitudinal research (38%) seems respectable. Possibly because of cost factors, these studies examined fewer variables in relation to psychotropic drug use. However, besides highlighting the phenomenon of long-term use of psychotropic drugs by the elderly , they prVirtually all samples (29 in the 30 distinct studies) were composed of older consumers and non-consumers of psychotropic drugs. Comparisons between these two groups allow researchers to identify what differentiates users from non-users of psychotropic drugs. However, one notices from this review that researchers do not always succeed. One possible reason may be that short-and long-term users are combined in one group. Indeed, in almost every study it appears that investigators are comparing long-term users with non users. About 20% to 30% of community-dwelling older persons use psychotropic drugs , with ovThus, if most psychotropic drug use among the elderly transforms into long-term use, the process of transformation itself requires more observation and explanation, again by means of longitudinal research. Immediate problems leading to the first prescription of a psychotropic drug, such as psychological distress or insomnia, might have little relevance among long-term users. Possibly, drug dependence has developed among some long-term users and sustains long-term consumption . The sixIt also appears that over the past decade, the use of mixed samples of users and non-users of psychotropic drugs has provided little information about older consumers themselves. Although comparison is essential for understanding, perhaps more studies should target older drug users exclusively. For instance, we know of no study examining mental health outcomes of older psychotropic drugs users over time. One might deem it illogical if no studies had been conducted on the long-term effects of antihypertensive medication on blood pressure. Grad  made theThe concepts of mental health, psychological distress, depression, and social support are often studied in relation to psychotropic drug use, but operationalized differently across studies. For instance, in the body of studies here reviewed, mental or emotional state is generally measured by standardized, self-rated scales that focus on the manifestation or experience of various symptoms of psychological or bodily distress, or by structured diagnostic interviews aiming to identify mental disorders according to official diagnostic criteria. In all, at least 12 different instruments or scales, 4 different systems of diagnostic criteria , and 3 unstructured open questions were used in 18 studies to measure concepts identified as depression (12 studies), anxiety (6 studies), psychological distress, mental disorders, life events (3 studies each), psychiatric syndromes (2 studies each), and morale, nervous or emotional disorders, melancholy, nerves, emotional condition, dementia, and sleep problems (1 study each). This variability in concepts and instruments surely impacts the variability of observed relationships between drug use and mental health status , few investigators test specific hypotheses to account for the associations. For example, sparse work focuses on cultural factors that might explain drug use disparities between Whites and African-Americans. Similarly, with most drug users being long-term and most drug treatments for insomnia losing their effectiveness with long-term use, the strong association between sleep complaints and drug use needs thorough examination.One of the least studied aspects of the phenomena in the reviewed studies concerns the role of health care professionals. Physicians, nurses, and pharmacists all interact significantly with community-dwelling older persons, especially with those who take psychotropic medications. Only through a health care professional such as a physician and a pharmacist would the vast majority of older people obtain a psychotropic drug to relieve a sleep problem. Recently, the Internet and mail-order pharmacies without face-to-face interaction have facilitated individuals' access to prescription drugs. Each professional's role, as mentioned, is also likely to alter as the individual's phase of consumption transforms from short-to long-term. Researchers must face the challenge to incorporate variables related to health care professionals' attitudes and behaviors, as well as to new modes of distribution of psychotropic drugs to consumers, in their study of the phenomenon.Approximately one third of community-dwelling older persons use psychotropic medications. If the rate of psychiatric disorders among a population serves as a guideline, then obviously older persons' use of psychiatric drugs far outpaces these drugs' standard indications and has extended into areas where drugs have little documented effectiveness. Viewed in this light, the ubiquitous phenomenon of long-term psychotropic drug use should evoke concern and caution. The discipline of nursing can definitely contribute to the rational use of these agents among older people. As suggested in this review, researchers do not still fully grasp the dynamics of psychotropic drug use among this population and creative and rigorous research from several disciplines, and from interdisciplinary perspectives, is needed. However, nurses concerned by the problem of the overuse of medication and its adverse consequences can already implement and evaluate programs to educate older people and allied health care and social service professionals about the risks of psychotropic drugs and alternatives to drugs for the management of everyday anxiety, loneliness, depression, and especially insomnia. Nurses can also actively implement and evaluate drug withdrawal programs aimed at long-term users who have had difficulty in withdrawing, and especially at short-term users who might soon be trapped into dependency and thus long-term use. Conversely, diverse patterns of psychotropic drug use undoubtedly exist among older persons, and positive patterns of use, emanating from users' own experiences and discoveries, need to be documented and disseminated.None declared.PV and DC conducted the literature review and drafted the manuscript. SL and JC revised the literature review and subsequent drafts. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:Characteristics of 32 empirical reports on psychotropic drug use among community-dwelling older persons, 1990–2001. Reports on psychotropic drug use among community-dwelling older persons.Click here for fileFactors associated with psychotropic drug use among community-dwelling older persons in 32 empirical reports, 1990–2001. Factors associated with psychotropic drug use among community-dwelling older persons.Click here for file


There is a dearth of standardized studies examining exposure to environmental tobacco smoke (ETS) and its relationship to respiratory health among adults in developing countries.1 and FVC). Logistic and linear regression analyses were conducted to study the relation between ETS score and studied outcomes, whereby categorical (tertiles) and continuous scores were used respectively, to evaluate the association between ETS exposure and respiratory health, and explore the dose-response relationship of the association.In 2004, the Syrian Center for Tobacco Studies (SCTS) conducted a population-based survey using stratified cluster sampling to look at issues related to environmental health of adults aged 18–65 years in Aleppo . Exposure to ETS was assessed from multiple self-reported indices combined into a composite score (maximum 22), while outcomes included both self-report , and objective indices  and were included in the current analysis. The vast majority of study participants were exposed to ETS, whereby only 3.6% had ETS score levels ≤ 2. In general, there was a significant dose-response pattern in the relationship of ETS score with symptoms of asthma, hay fever, and bronchitis, but not with diagnoses of these outcomes. The magnitude of the effect was in the range of twofold increases in the frequency of symptoms reported in the high exposure group compared to the low exposure group. Severity of specific respiratory problems, as indicated by frequency of symptoms and health care utilization for respiratory problems, was not associated with ETS exposure. Exposure to ETS was associated with impaired lung function, indicative of airflow limitation, among women only.This study provides evidence for the alarming extent of exposure to ETS among adult non-smokers in Syria, and its dose-response relationship with respiratory symptoms of infectious and non-infectious nature. It calls for concerted efforts to increase awareness of this public health problem and to enforce regulations aimed at protecting non-smokers. The deleterious effects of exposure to ETS on the respiratory system of adults and children is well documented -4. ExposThe situation with exposure to ETS in developing countries is likely to be aggravated by the widespread of smoking, lack of restrictions regarding indoor smoking, overcrowded housing conditions, and failure of health services -15. CigaDespite these troubling facts, there is a dearth of research examining the relationship between ETS exposure and respiratory health in developing countries, with the few available studies limited by poor outcome definition, lack of systematic exposure assessment, and inadequate control of confounding ,22. A reThe target population consisted of adults 18–65 years of age residing in the greater city of Aleppo . Detailed description of the sampling design and procedures of the AHS is reported elsewhere and illustrated in Figure The survey was conducted between May-August 2004, and the protocol and the informed consent documents were approved by the Institutional Review Boards at the University of Memphis and SCTS.This interviewer-administered survey involved six, 2-person, mixed gender teams of surveyors equipped with notebook computers programmed to record questionnaire responses and measurements using a custom data entry program (Delphi programming language and SQL server DBMS). The questionnaire included 8 main sections; socio-demographics, general health and disability, chronic disease, respiratory health, household members' health, environmental health, smoking, and ETS exposure. For the assessment of respiratory health and risks, the questionnaire was developed based on relevant instruments , as well surveys done in Syria -35. NextData from self-reported non-smokers (both cigarettes and waterpipe), validated by breath CO levels ≤ 10 ppm Table  29-35].-35.29-35Past year recurrent cough and recurrent shortness of breath were defined as having 3 or more recognizable episodes of these symptoms. Those reporting recurrent cough or shortness of breath were asked to select, from a provided list, one or more options that best described their symptoms Table . Medicatst second (FEV1) and Forced Vital Capacity (FVC) were measured for all participants according to standard guidelines [Forced Expiratory Volume in the 1idelines . We usedidelines . We usedidelines   and the 95% confidence interval for the relation between ETS score and respiratory symptoms adjusting for age, sex, SES score, parental allergy, occupational exposure to other respiratory pollutants, and pack years (for ex-daily smokers). Linear regression analysis was used to assess the relationship between ETS score and lung function  adjusting for age, BMI, SES score, and occupational exposure to other respiratory irritants, as well as interaction terms of age with height and weight. This analysis was performed separately for men and women, since lung development and response to ETS has been shown to differ by gender [p for dose-response relationship. Because of the concern that ex-smokers may avoid ETS exposure and have respiratory problems , we repeated the analysis including only never smokers, but this did not affect the results considerably . All analyses were done by SPSS 11.Descriptive statistics were calculated for the overall study population and for measures of ETS exposure among non-smokers Tables ,2. Compoy gender ,28. In bFrom a total of 2038 valid survey responses , 1118 (27.1% men) satisfied the inclusion criteria for the exposure-symptoms analysis (Table p for dose response 0.004), past year recurrent shortness of breath , past year recurrent exertional shortness of breath that disappears after rest , past year recurrent shortness of breath almost all of the time . Additionally, several symptoms suggestive of asthma/allergy were related to ETS exposure, including past year recurrent wheezing/whistling in the chest , past year recurrent episodic dry cough accompanied by wheezing , past year recurrent episodic shortness of breath accompanied by wheezing , past year recurrent nocturnal cough not related to cold that wakes the subject up , and past year hay fever symptoms . Among symptoms suggestive of chronic bronchitis, ETS exposure was associated with recurrent shortness of breath accompanied by cough and phlegm . And finally, past year episodes of acute lower respiratory infection  were associated with exposure to ETS  . General respiratory symptoms associated with exposure to ETS were past year recurrent cough , medical care utilization for respiratory problems in general Table , as well1 , FVC , and %FEV1/FVC . Linear regression analysis between ETS exposure score and lung functions showed significant inverse associations with indices of airflow limitation (FEV1 and FEV1/FVC) only in women. Women in the middle category of ETS exposure had on average 88 ml deficit in FEV1 and 2% in FEV1/FVC in comparison to those in the low exposure category. This association did not show a dose-response relationship  among women only.This study shows that exposure to ETS is universal among non-smoking adults in Aleppo-Syria. This exposure is associated with respiratory complaints of both infectious and non-infectious etiology in a dose-response fashion, suggesting a causal relationship. Unlike data from developed countries, however, exposure to ETS was not related to increased severity of asthma or other respiratory conditions judged by symptoms frequency and medical care utilization because of respiratory problems. ETS exposure was associated with decrements in lung functions suggestive of airflow limitation  irritation for a quarter of nonsmokers. In comparison, less than a quarter of non-smokers in a national sample of 43,732 adults in the US report exposure to ETS . InteresIn general, this study shows stronger and dose-dependent relationships of ETS exposure with general respiratory symptoms (i.e. recurrent cough or shortness of breath) than with symptoms characteristic of specific respiratory problems . Arguably, general symptoms are more easily identifiable as well as shared among many respiratory problems. The magnitude of difference in self-reported asthma symptoms according to exposure level is generally in the range of a twofold increase. This effect magnitude is similar to that reported in adults from 16 European countries , but lower than that reported from the Swiss Study on Air Pollution and Lung Diseases in Adults (SAPALDIA) ,50. SimiLevel of exposure to ETS in our population was not associated with severity of asthma, sinusitis, or lower respiratory tract infection. In contrast, in a study of 349 adults with asthma in the US, Eisner and colleagues found that exposure to ETS at baseline was associated with more symptom severity and emergency/hospital admissions because of asthma at 18 month followup . Medical1, FVC, FEV1/FVC) in women but not men [1, and FEV1/FVC) in female but not male non-smokers. The reduction for the middle compared to low exposure category was in the magnitude of 88 ml for FEV1 and 2% for FEV1/FVC. Although other studies have reported similar gender-specific vulnerability of women [1 in the univariate analysis. It is possible that we are dealing in our setting with levels of exposure that exceed those occurring in western societies. Indeed, because of the low magnitude of the effect of ETS exposure on lung function, studies have relied on comparisons of exposed vs. non-exposed individuals to assess this relationship [Studies of the relation between exposure to ETS and lung function have generally shown a detrimental effect of such exposure. This effect, however, was not consistent and of low magnitude generally (50–100 ml) . For exa not men . Data fr not men . The eff not men . Our stuof women , it is itionship ,53-55. IThis study shows that exposure to ETS is rampant among adult non-smokers in Syria, where it is hard to escape it due to a high prevalence of smoking, household over-crowding, and lack of smoking restrictions. This exposure is leading to increased respiratory symptoms/disease of both infectious and non infectious etiologies, and is likely to have deleterious effects on respiratory function among women. In addition, the dose-response association found between exposure to ETS and respiratory symptoms point towards causal relationship. These results send a clear message to health advocates and policy makers about the spread and harmful effects of exposure to ETS in Syria and on the importance of collective efforts to educate both the public and authorities about this major health hazard and ways to effectively protect non-smokers from it. In addition to giving further support to the health hazards of ETS exposure, this study can provide guidance for future research on this issue in other developing countries.• AC- air condition• AHS- Aleppo Household Survey• ECRHS- European Community Respiratory Health Survey• ETS- environmental tobacco smoke1- forced expiratory volume in the 1st second• FEV• FVC- forced vital capacity• NHANES III- third National Health and Nutrition Examination Survey• OR- odds ratio• PC- personal computer.• ppm- part per million• PPS- probability proportionate to size• SAPALDIA Swiss Study on Air Pollution and Lung Diseases in Adults• SD-standard deviation• TV- televisionst draft of the manuscript. KD Ward, T Eissenberg, participated in the study design and co-authored the manuscript. S Rastam and F Mzayek participated in the data management, analysis, and co-authored the manuscript.W Maziak, designed the study, conducted the analysis and wrote the 1Appendix 1 : Composite scores for SES and ETS used in the study with the total score categorized around tertile cut off points.Click here for file


Viral promoters are used in mammalian expression vectors because they generally have strong activity in a wide variety of cells of differing tissues and species.The utility of the BLV LTR/promoter (BLVp) for use in mammalian expression vectors was investigated through direct comparison to the CMV promoter (CMVp). Promoter activity was measured using luciferase assays of cell lines from different tissues and species stably transduced with BLVp or CMVp driven luciferase vectors including D17, FLK, BL3.1 and primary bovine B cells. Cells were also modified through the addition of BLV Tax expression vectors and/or BLV infection as well as treatment with trichostatin A (TSA).Results indicate the BLV promoter, while having low basal activity compared to the CMV promoter, can be induced to high-levels of activity similar to the CMV promoter in all cells tested. Tax or BLV infection specifically enhanced BLVp activity with no effect on CMVp activity. In contrast, the non-specific activator, TSA, enhanced both BLVp and CMVp activity.Based on these data, we conclude the BLV promoter could be very useful for transgene expression in mammalian expression vectors. Viral promoters are commonly used as regulatory elements in gene therapy vectors due to their strong activity in various cell lines in vitro. Probably the most widely used promoter in mammalian expression systems is the human cytomegalovirus immediate-early gene (CMV) promoter. The CMV promoter induces high-level constitutive expression in a variety of mammalian cell lines . In manycis-acting elements in addition to the CAAT box, TATA box, and transcription start site , FLK s], BL3.1 7 cells were stained for 15 min at 6° – 12°C with 10 μg/100 μl total volume anti-IgM . After washing, 20 μl/100 μl total volume of MACS rat anti-mouse IgG2a+b microbeads were mixed with the cells and incubated for 15 min at 6° – 12°C. Cells were thoroughly washed, and magnetically separated. These IgM+ cells were considered primary B cells. Microfluorimetry using anti-IgM  indicated 90% purity. Stably transduced cell lines were generated after one week in selective media. Primary B cells were analyzed after one week in selective media since they began to die out after two weeks in culture.Primary bovine B cells were purified as follows. Peripheral blood mononuclear cells (PBMC) were isolated from heparinized cow blood through a ficoll density gradient as previously described . B cellsBam HI-Hind III fragment) to create the vector pLNBlv. The pLNBlv and pLNCX retrovector plasmids were modified to place the Gateway Rfa cassette  downstream of the internal promoters (BLV or CMV) in order to simplify further cloning, to create retrovector plasmids pLNBlv-G or pLNC-G. For enhanced protein expression, the WPRE element (from plasmid BluescriptII SK+ WPRE-B11 (a gift from Tom Hope–the same as bp 2717–3309 of Genbank Locus OHVHEPBA ACCESSION J04514) was cloned downstream of the Gateway Rfa cassette with standard cloning methods to create vectors pLNC-GW and pLNBlv-GW. The source for firefly luciferase encoding sequence was pGEM-luc (Promega). The luciferase coding sequence was subcloned into pENTR1A (Invitrogen) to engineer the Gateway entry vector pENTR1A/luc. The Luciferase gene was recombined into pLNC-GW or pLNBlv-GW using LR Clonase (Invitrogen) per manufacturer's instructions. The promoter-less luciferase expression control vector pLNW/luc was engineered by removing the BLV promoter (Bam HI digest) from pLNBlv/luc. BLV Tax (Genbank Locus AAF97920) was isolated by reverse transcription PCR from FLK cells and subcloned into pENTR1A (Invitrogen) to engineer the Gateway entry vector pENTR1A/Tax. The Tax gene was recombined into pLBC-GW where the neomycin resistance gene of pLNC-GW was replaced with the blasticidin resistance gene.The plasmid pBLV913 (a gift from David Derse), coding for an infectious molecular clone of BLV  was usedThroughout these studies we assayed expression vectors with and without the WPRE. WPRE enhanced transgene expression in all cell lines used, and in a promoter-independent fashion (about 2-fold greater for BLVp and CMVp in D17 cells). Subsequently, all data shown in this report are only with vectors containing WPRE.Retrovirus-mediated gene transfer was accomplished using the BD Retro-X System (BD Biosciences Clontech) following the manufacturer's suggested protocol. Briefly, 100 mm × 20 mm tissue culture dishes  were seeded with the packaging cell line GP2-293 at 70–90% confluency. Each dish of GP2-293 cells was co-transfected with 5 μg each of retroviral vector and the envelope glycoprotein expression vector pVSV-G using 15 μl/transfection of Lipofectamine 2000 (Invitrogen) cationic lipid reagent for 3 h in a total volume of 5 ml medium/dish. Subsequently, transfection medium was replaced with 10 ml growth medium, and the cells were incubated for 72 h. Retrovirus-containing supernatant was then harvested and passed through a 0.45 μm cellulose acetate filter, then concentrated by ultracentrifugation at 50,000 × g for 30 min at 4°C. Supernatant was carefully poured off and virus was resuspended in the residue (~200 μl) and frozen (-70°C) for future use. Cells for transduction were plated on 6-well tissue culture plates  at 50% confluency. Concentrated retrovirus (titer unknown) along with polybrene (8 μg/ml) were added to one ml/well cells (in a 6-well plate) and incubated overnight. Transduction medium was replaced with fresh growth medium, and the following day cells were split into appropriate selective medium. BLV was harvested from supernatant of FLK cells, concentrated, and used to transduce cells in a similar fashion.6 cells were aliquoted to 1.5 ml microcentrifuge tubes. Then, cells were pelleted at 300 × g for 10 min, washed once with PBS, and lysed with 200 μl reporter lysis buffer (Promega). Lysate was stored at -20°C until assayed. Lysate was thawed and pelleted (300 × g for 10 min), and luciferase was measured with the luminometer using 10 μl lysate/50 μl reagent for 10 s. Linear range was under 1 × 107 RLU.Luciferase assays (Promega) were performed using a single-tube luminometer (Pharmingen) to measure relative light units (RLU) on a linear scale. Cells to be assayed were counted using a hemacytometer, and 1 × 10Student's t-test was performed for statistical evaluation of the results. Results are expressed as the arithmetic mean with the variance of the mean (mean ± SE).Our studies utilized a commercially available retroviral system with its standard CMV promoter (CMVp) or replaced with the BLV promoter (BLVp). Figure cis elements that are dependent on BLV Tax for transgene expression [cis element that is B cell specific (PU.1/Spi-B). We therefore compared the strengths of BLV and CMV promoters in primary B cells and a BLV infected B cell line hypothesizing that BLVp expression would be comparable to CMVp activity. BLVp activity was still less than CMVp activity in primary B cells but by only about a 5-fold difference . Luciferase assays demonstrated that BLV promoter activity in infected D17 cells was about 10-fold greater than BLV promoter activity in non-infected D17 cells  has been shown to be the most efficient activator of BLV expression known to date . To detecis-acting elements and the dependence upon Tax using reporter vectors in mammalian cell lines has been published [Viral promoters are used in mammalian expression vectors because they can have strong activity in a wide variety of cells of differing tissues and species. Probably the most employed is the CMV promoter because of its proven high-level constitutive expression in a variety of mammalian cell lines ,25. Whilublished ,27,28. HSeveral attributes are important in developing a mammalian expression vector. Probably the most important attribute of a mammalian expression vector promoter is its ability to accomplish high-level transcriptional activity in a large variety of cell types of different tissues and species. Our studies showed that the BLV promoter could achieve similar high-level activity to the CMV promoter in cells expressing BLV Tax or infected with BLV. This comparatively high BLV promoter activity was demonstrated in D17 cells which we have found to be the highest expresser of CMV promoter driven transgenes of all cell lines tested in our laboratory. The CMV promoter activity was still about 5-fold greater than BLV promoter activity in the BLV infected D17 cells compared to the relatively equal activity of the CMV promoter versus BLV promoter in BLV infected FLK cells. However, FLK cells contain four copies of the BLV provirus  whereas cis-elements have demonstrated significant decreases in basal level activity, as with the mutation of the GRE site [A second important attribute of an inducible promoter apart from high-induced expression is low basal expression. Researchers have reported barely detectable BLV promoter Tax-independent activity through luciferase assays of COS-1, C8, and KU-1 cell transient transfections . Our resGRE site , signifiGRE site , or eithGRE site . Still, A third important attribute for an inducible promoter would be a sensitive modulated response to a specific inducer. Enhancement of the BLV promoter can occur independent of Tax by the addition of activating agents. Phorbol esters, phytohemaglutinin, and lipopolysaccharides have all been shown to enhance BLV promoter expression . Howeverfos. Clearly, there is great potential to magnify the desirable traits of the BLV promoter/Tax system for mammalian expression vectors and minimize undesirable traits.Nevertheless, the transactivating properties of BLV Tax are not limited to activation of the BLV promoter. Tax has been shown to upregulate Bcl-2 and increase nuclear NFkB activity . Tax expTo determine whether the BLV promoter could be a useful mammalian expression vector element, we compared its activity with the CMV immediate early promoter in dog osteosarcoma (D17), BLV-infected fetal lamb kidney (FLK), BLV-infected bovine B-lymphosarcoma (BL3.1), and primary bovine B-cells. Without concomitant Tax expression from a transgene or BLV infection, the BLV promoter activity was low compared to CMV promoter activity. In the presence of Tax or BLV expression, the BLV promoter activity became equally as active as the CMV promoter. The CMV promoter was not influenced by Tax or BLV. Tax overexpressed as a transgene in BLV infected cells resulted in BLV promoter expression greater than CMV promoter expression. The deacetylase inhibitor, trichostatin A was a potent upregulator of both BLV and CMV promoters. Our results indicate the BLV promoter has great potential use as an inducible promoter for mammalian expression vectors.None declared.JSH carried out cell culture work including transfection/transduction and luciferase assays, data preparation and analyses, and drafted the manuscript. KAE performed genetic engineering of vectors. LSK did preliminary work to establish study concepts. RDB and GAS participated in the design and coordination of the study. All authors read and approved the final manuscript.


This study was designed to examine the knowledge, attitude and beliefs about causes, manifestations and treatment of mental illness among adults in a rural community in northern Nigeria.A cross sectional study design was used. A pre-tested, semi-structured questionnaire was administered to 250 adults residing in Karfi village, northern Nigeria.The most common symptoms proffered by respondents as manifestations of mental illness included aggression/destructiveness (22.0%), loquaciousness (21.2%), eccentric behavior (16.1%) and wandering (13.3%). Drug misuse including alcohol, cannabis, and other street drugs was identified in 34.3% of the responses as a major cause of mental illness, followed by divine wrath/ God's will (19%), and magic/spirit possession (18.0%). About 46% of respondents preferred orthodox medical care for the mentally sick while 34% were more inclined to spiritual healing. Almost half of the respondents harbored negative feelings towards the mentally ill. Literate respondents were seven times more likely to exhibit positive feelings towards the mentally ill as compared to non-literate subjects .Our study demonstrates the need for community educational programs in Nigeria aimed at demystifying mental illness. A better understanding of mental disorders among the public would allay fear and mistrust about mentally ill persons in the community as well as lessen stigmatization towards such persons. Throughout the world, there is an increasing awareness of mental illness as a significant cause of morbidity . This awMental and behavioral disorders are common, affecting more than 25% of all people at some time during their lives . They arThe role of the community in the prevention and care of the mentally handicapped has now been widely acknowledged and is regarded as the most appropriate basis for the development of mental health programs. Several studies have shown that knowledge of public attitude to mental illness and its treatment is a vitally important prerequisite to the realization of successful community-based programs -6. The rPeople tend to have strong beliefs about the mentally ill, and many of these concepts are based on prevailing local systems of belief . In deveThe 1995 Nigeria National Mental Health Policy advocates the integration of mental health promotion, treatment and rehabilitation into primary health care services (PHC). However, this goal cannot be successfully achieved without an understanding of community attitudes towards mental illness. We therefore set out to ascertain the perceptions, attitudes and beliefs of adults regarding the causes, manifestations and treatment options of mental illness in a traditional Hausa community near Kano, Nigeria.The study population included 250 adults residing at Karfi village, about 15 kilometers from Kano city. This typical Hausa community has 11,314 inhabitants . MajoritA cross sectional descriptive studyA multistage sampling technique was adopted. In the first stage, four wards out of the seven in the village were randomly selected. After house numbering, 250 houses were selected from the four wards using a table of random numbers. Where more than one household was found in a house, one household was selected by balloting. Finally, one adult was selected at random from each household for the interview. A final sample size of 250 adults was therefore obtained.We adopted and modified a pre-existing semi-structured questionnaire  to evaluThe study instrument was validated using a pilot study of 10 randomly selected households in a nearby village with similar demographic characteristics (Kumbotso). Results of the pilot study were used to modify content and wording of the questionnaire. Previously trained medical undergraduates fluent in Hausa language administered the questionnaires to the sample population.® 6.0 statistical software package . Descriptive statistics were depicted using absolute numbers, simple percentages, range, and measures of central tendency  as appropriate. The Chi-square test was used to test the significance of associations between categorical groups. All tests of hypothesis were two-tailed with a type 1 error rate fixed at 5%.The data was analyzed using the Epi-InfoIn all, 250 respondents were interviewed with 167 males and 83 females giving a sex ratio of 2:1 in favor of males. Their ages ranged from 18 to 74 years. Majority (78.0%) of the respondents were aged between 25 and 60 years. The median age (± SD) for the respondents was 34.5 ± 4.6 years; 36.0 ± 2.3 years for males and 28.5 ± 1.6 years for females. The Hausa-Fulani ethnic group constituted 89% of respondents, and the rest were Yoruba 2.0%, Igbo 5.0% and other minority Nigerian tribes 4.0%. About 16.0% of respondents had primary education, 12.0% had secondary education, and 4.0% had tertiary (post-secondary school) education. Approximately 27.0% of the population sampled had no formal education. Nevertheless, 41.0% of all respondents had Quranic education. The majority of respondents (90.0%) were Muslims and the remaining 10.0% were Christians. About 10.0% were single, 80.0% were married, 6.0% were divorced and the remaining 4.0% were widowed. Forty eight per cent of the respondents were engaged in farming, 25.0% were full-time housewives, 20.0% were engaged in petty trading, 7.0% were students and the remaining 4.0% were civil servants. About 13 persons interviewed (5.2%) had a relative with mental illness, but because of the small sample size we did not separately analyze findings from this group of participants.The most common symptoms proffered by respondents as manifestations of mental illness Table  includedThe majority of respondents (46.0%) opted for orthodox medical care when asked about preferred source of treatment for the mentally ill. This was followed by spiritual healing (exorcism) 34.0%) and the use of traditional herbal medicines (18.0%)  . Our finding is also in contrast to Adebowale and Ogunlesi [Belief in demons as the cause of mental health problems is a well-known phenomenon in many cultures of the world  but in oOnly 1.0% of respondents admitted that financial distress or poverty was a possible cause of mental disorder. Such a low score in the face of the present adverse socio-economic conditions prevailing in Nigeria may be explained by the Hausa cultural cum religious belief in providence and patience in the face of adversity. Other factors have also been reported by investigators as being associated with perceived causes of mental illness among patients and their relatives. Srinivasan and Thara  found thThere was a higher score on the preference for modern medical care in treating psychiatric illness. Similar changes in attitude towards the modern scientific approach regarding mental disorders was documented by Alem et al  in theirFear and avoidance of the mentally sick was frequent among female respondents. Traditionally, men are expected to be outwardly brave and less submissive towards aggression. The high frequency of negative attitudes among our respondents may be due to the fact that the concept of the mentally sick has an unfavourable public image. It has been shown that people may evaluate mental illness negatively, reject and discriminate against mental patients, and base their views on traditional stereotypes ,10,16.et al. [et al. [et al. [Literacy was found to be significantly associated with positive attitude towards the mentally sick. Similar findings were reported by Madianos et al.  in Greec [et al.  in Ethio [et al. . Interes [et al. . Our res [et al.  that negThis study demonstrates the need for educational programs aimed at demystifying mental illness. A better understanding of mental disorders among the public would allay fear and mistrust about mentally ill persons in the community as well as lessen stigmatization towards such persons. Our findings may be of utility to health policy makers in the design of community mental health education programs and community mental health services in existing primary health centers in Nigeria.None declared.KM and IZ initiated the study, and participated in the field work. IZ and AIS did the preliminary analysis and wrote the draft manuscript. KM, AIS and IZ participated in the design of the study and performed the statistical analysis. KM, IZ, and AIS participated in its design and coordination. AMH, KM and IZ wrote the final version of the draft manuscript. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here: