The delivery of implantable cardioverter defibrillator (ICD) therapy is sophisticated and requires the programming of over 100 settings. Physicians tailor these settings with the intention of optimizing ICD therapeutic efficacy, but the usefulness of this approach has not been studied and is unknown. Empiric programming of settings such as anti-tachycardia pacing (ATP) has been demonstrated to be effective, but an empiric approach to programming all VT/VF detection and therapy settings has not been studied. A single standardized empiric programming regimen was developed based on key strategies with the intention of restricting shock delivery to circumstances when it is the only effective and appropriate therapy. The EMPIRIC trial is a worldwide, multi-center, prospective, one-to-one randomized comparison of empiric to physician tailored programming for VT/VF detection and therapy in a broad group of about 900 dual chamber ICD patients. The trial will provide a better understanding of how particular programming strategies impact the quantity of shocks delivered and facilitate optimization of complex ICD programming. Over the past decade ICD implantation has become increasingly straightforward, yet ICD programming and follow up has become more complex due to device feature and capability enhancements. While sophisticated algorithms provide high sensitivity and improved specificity of arrhythmia detection, allowing delivery of necessary effective therapy with minimization of inappropriate defibrillation shocks, detection and therapy of ventricular tachycardia (VT) / ventricular fibrillation (VF) still requires programming about 100 settings .Good programming choices are crucial as they relate to patient acceptance of ICD therapy. It has been found that patients who receive multiple shocks have greater difficulty adjusting to the ICD implant. These patients may become anxious or depressed, especially if a prior history of these ailments exists . ReducinTo date, there is no proven consensus on how to use information about the patient's complex diseases to program the ICD, and usually little is known about the patient's spontaneous VT rates, their risk of syncope, or therapies to effectively terminate spontaneous ventricular arrhythmias. Furthermore, ICD indications have dramatically changed within the last five years. Physicians may retain old programming habits even with enhanced devices or expanding patient indications, which may result in sub-optimal detection and therapy, such as unnecessary shocks for faster VT, supraventricular tachycardia (SVT), and non-sustained VT. Physicians often adjust many programmable settings that may benefit the patient. For example, physicians may prescribe patient-specific regimens for anti-tachycardia pacing (ATP) or shock energies based on lab testing. While one would expect this tailoring of programming to improve outcomes, it has never been studied.Empiric programming has been shown to be effective for subsets of ICD settings, including subsets of dual chamber detection and ATP therapies ,5-10. WhA proven optimal programming approach would be useful for simplifying therapy prescription, improving therapy outcomes, reducing inadvertent programming errors, and overall reducing shock-related morbidity. The EMPIRIC trial has been designed to evaluate a standardized empiric programming regimen by testing the hypothesis stated below. The EMPIRIC trial outcome will provide an understanding of how programming strategies impact defibrillation shock delivery in ICD therapy.This trial tests the hypothesis that the shock related morbidity of ICD therapy is similar whether patients are treated with a standardized empiric programming regimen for VT/VF detection and therapy or with a patient-specific physician tailored approach.Only sustained VT/VF that cannot be painlessly terminated should result in shock therapy and it is unusual for supraventricular arrhythmias (SVT) to require shock therapy. Shock morbidity is related to the number and frequency of shocks that patients receive and therefore morbidity is reduced if shocks are delivered only when necessary for effective arrhythmia termination. Thus, indices that address shock morbidity should reflect both the frequency and appropriateness of shocks for VT/VF and SVT.Shock morbidity is quantifiable by determination of the following:true VT/VF episodes that are shocked♦ proportion of true SVT episodes that are shocked♦ proportion of ♦ time to first shock (VT/VF or SVT)♦ time to first VT/VF shock♦ time to first SVT shockThese parameters are used to define the Empiric Trial's main objectives.and the proportion of shocked SVT episodes in a population whose ICDs are programmed using a standardized regimen for VT/VF detection and therapy, is either similar to or less than the same proportion in a similar population whose ICDs are programmed using a physician-tailored approach. This primary objective was chosen to independently evaluate the effects of programming on both appropriate and inappropriate ICD shocks (which are likely to have different implications for patient management). The advantage of this approach is that it focuses on frequency of shock delivery while also allowing an assessment of their appropriateness. However, this assessment could be confounded by a disproportionate number of SVT events in the two study groups. For example, an abundance of non-shocked SVT events in the physician-tailored arm, despite a greater incidence of inappropriate SVT shock therapies in that arm, nevertheless would result in the proportion of SVT episodes shocked being similar in the two arms. The analysis is also heavily dependent on the electrogram data stored in the ICDs. Given the electrogram storage capability of ICDs, differing rates of electrogram storage might occur between study arms or between VT/VF and SVT episodes that may skew the amount of data available for analysis. Therefore, the key secondary endpoint in this study is considered to be the time to delivery of first shock therapy in any given patient. This endpoint offers the advantage that it enables patient cross over to occur between the study arms without endpoint compromise and it is a clinically robust indicator of patient shock-related morbidity. Furthermore, its analysis is not influenced by the appropriateness or otherwise of a shock therapy and therefore cannot be confounded by differential occurrence of non-shocked SVT events in the study arms.The primary objective is to demonstrate that the proportion of shocked VT/VF episodes Other secondary endpoints will further evaluate the impact of the standardized programming regimen on patients by an assessment of detection performance, health care utilization, shock impact on device longevity, and "true VT/VF" episode durations.The EMPIRIC trial is a worldwide, multi-center, prospective, one-to-one randomized comparison of empiric to physician tailored programming. About 900 patients were enrolled worldwide at 52 centers from August 2002 to October 2003. Each patient will be followed for approximately one year.The inclusion criteria require patients to meet all of the following conditions:1. Indicated for an ICD according to internationally accepted criteria.2. Willing to sign informed consent or offer a legal representative who can provide consent.3. Achieved a 10 Joule safety margin at implant.Patients are excluded if they:1. Have permanent atrial fibrillation (AF).2. Had a previous ICD.3. Have a medical condition that precludes the testing required by the protocol or limited trial participation.4. Have a life expectancy less than one year.5. Are unable to complete follow-ups at the trial center.6. Are enrolled or participating in another clinical trial.Patients receiving a Marquis DR ICD are randomized to one of the two programming approaches after meeting a 10 J safety margin. In order to control for physician practice between the two treatment arms, randomization is stratified by treatment center. Further, since the incidence and prevalence of spontaneous VT/VF and SVT among primary prevention patients is not well known, randomization is also stratified by ICD indication (secondary vs. primary). A secondary indication includes patients with a history of spontaneous sustained VT/VF or syncope with suspected VT. A primary prevention indication includes all other patients.The physician tailored approach is based on the standard practice of each physician. All VT/VF programming may be tailored to the patient except that VT detection must be turned to 'On' or 'Monitor' to record episodes of slower VT.The empiric standardized regimen is based on various programming strategies to reduce shocks. In this arm, initial device settings are fixed . In order to protect protocol design integrity, reprogramming will be encouraged for non-justified programming deviations. In this manner the initial treatment strategies are tested using an intention-to-treat analysis with characterization of programming changes.The empiric arm standardized programming regimen is based on the following key strategies to reduce shocks.Multiple ATP attempts for VT≤ 200 bpm: Three sequences of ATP will be attempted for rhythms with ventricular rates ≤ 200 bpm. Empiric ATP has been shown to terminate ≥ 90% of VTs in the VT zone [•  VT zone -10. Furt VT zone . Three s VT zone . ATP wil VT zone ,12-14.ATP for VTs 201 – 250 bpm: One sequence of ATP will be delivered for fast VTs (FVT) using the FVT via VF zone, which maintains sensitivity to polymorphic VT (PVT) and VF and delivers ATP if the 8 beats prior to FVT detection are ≤ 250 bpm. Approximately 81% of ICD detected VF is monomorphic VT (MVT). MVT can be pace-terminated approximately 75% of the time with one sequence of ATP, without increased risk of syncope or acceleration [• leration ,7,15.Longer detection duration: The VF initial beats to detect will be set to 18 of 24. Shorter beats to detect are often programmed by physicians, but may increase the unnecessary shocks for non-sustained VT and for SVTs. At least 25% of ICD-detected VF is non-sustained VT/VF [• ed VT/VF -17.st VF and FVT Shock: High Output 1A 30 Joule energy will be used for the first VF and FVT shock. This will allow additional time for spontaneous conversions that frequently occur. A higher shock energy may also improve 1st shock success and therefore reduce the need for multiple shocks within an episode. The LESS study found no difference in 1st shock success with 31 J versus DFT++, however it analyzed all VT/VF faster than 200 bpm [st shocks is due to concerns about syncope. Several recent studies have shown very low syncope rates [•  200 bpm  ATP shoupe rates ,19 FurthEmpiric SVT Criteria: The PR logic criteria of AF/A. Flutter and Sinus Tach will be programmed 'On' in all patients. These criteria have been shown to have a relative VT/VF sensitivity of 100% and a positive predictive value to 88.4% [• to 88.4% .SVT Criteria applied to faster rates: The SVT limit and VF rate cut-off will be increased to 200 bpm in all patients to provide SVT discrimination at faster rates. Two of the top five reasons for inappropriate detections in the GEM DR Study (933 patients) were a ventricular rate during AF in VF zone and a SVT cycle length faster than programmed SVT limit [• Avoid detecting 1:1 SVTs with Long PRs as VT: 1:1 SVTs with long PR intervals accounted for 38% of inappropriate detections in the Gem DR (7271) Clinical Study [• al Study .Longer detection duration: VF initial beats to detect will be set to 18 of 24. Shorter beats to detect may result in more unnecessary shocks for SVTs or ventricular over-sensing.• ATP attempts: In addition to terminating ventricular arrhythmias without shocks, ATP should eliminate some inappropriate shocks when inappropriate detections occur by terminating SVTs or slowing conduction.• VT rate cut-off is one of the most important ICD settings because it can result in untreated symptomatic VT if set too fast, however it can result in unnecessary therapies for non-sustained VT, SVTs, or sensing issues, if set too slow. Reports have shown that some secondary prevention patients have significant symptoms for VTs outside treated zones [The ed zones . The VT both the proportion of shocked VT/VF episodes and the proportion of shocked SVT episodes are no more than 10 percentage points greater in the empiric arm than the physician tailored arm. The chosen margin 10 percent is considered clinically important.The primary endpoint is the proportion of true episodes that are shocked during the 12-month follow-up period. The standardized empiric programming regimen will be considered non-inferior to the physician tailored programming approach if It is assumed that 24% of patients will have at least one true VT/VF episode and 33% of patients will have at least one true SVT episode during the 12-month follow-up period. Based on unpublished data from other Medtronic trials, the within-patient correlation coefficient for multiple episodes is assumed to be 0.3. Assuming a similar distribution of episode counts per patient as observed in these previous trials and a shock rate of 30% and 14% for VT/VF and SVT episodes respectively, a total of 900 patients (450 in each arm) will give at least 80% power for the VT/VF hypothesis and 90% power for the SVT hypothesis, each tested at the significance level 0.05.The critical secondary endpoint, time to first shock therapy, will be analyzed using the Cox proportional hazards model for 1) any VT/VF or SVT, 2) true VT/VF only and 3) true SVT only. The empiric programming approach will be considered non-inferior if the upper confidence limit for the hazard ratio is less than 1.5.To better understand the changing ICD patient populations, we will investigate whether or not the proportion of appropriate and inappropriate shocks delivered is related to the following baseline characteristics: main indication for implant , left ventricular ejection fraction, CAD status, history of Atrial Tach/Atrial Fib/Atrial Flutter, NYHA classification, use of amiodarone, sotalol, or beta-blockers, and inducibility for VT/VF. In addition, to facilitate understanding of the optimal programmable settings for various patient sub-groups, we will consider the impact of programmable settings on outcomes. In particular, we will examine the "treated cut-off" (TC), which is the VT detection cut-off if VT detection is 'On' or the VF detection cut-off if VT detection is 'Off' or 'Monitor'. Outcomes in patients with a faster TC (physician tailored arm) will be compared to patients with slower TC (either physician tailored arm or empiric arm). Other programmable settings that will be investigated include the number of beats to detect VF and the number of ATP attempts based at various rates . The types of arrhythmias, median ventricular cycle length, and therapies delivered will also be characterized relative to the patient's conditions and programming. Furthermore, the incidence of slower VTs in patients without a history of spontaneous, sustained monomorphic VT will be characterized.The EMPIRIC trial is a worldwide, multi-center, prospective, one-to-one randomized comparison of shock- related morbidity in a population of about 900 ICD patients whose ICD therapy is determined either by a standardized programming regimen or by physician tailored programming of VT/VF detection and therapy. Shock-related morbidity is assessed by a primary objective that compares between study arms the proportion of VT/VF episodes that are shocked and the proportion of SVT episodes that are shocked, and by a key secondary endpoint that compares to time to first shock therapy.ICD patient populations have rapidly changed within the last five years but little has been published on optimal programming for the emerging patient subsets . Therefore a standardized regimen of parameters is used in this trial for all patient populations. Today's patient population is quite diverse, so a slightly more sophisticated programming approach may be necessary (e.g. change VT cut-off based on main ICD indication) or perhaps complex physician tailoring is critical to reducing shocks.The EMPIRIC trial will characterize the shock morbidity of a single empiric programming approach compared to patient-specific, physician tailored programming. Empiric programming may be an acceptable strategy if it achieves equivalence with physician tailored programming. The EMPIRIC trial results will also provide a better understanding of how particular programming strategies impact the frequency of shocks delivered and will facilitate a way to optimize complex ICD programming.1. Have you received reimbursements, fees, funding, or salary from an organization that may in any way gain or lose financially from the publication of this paper in the past five years, or is such an organization financing the article-processing charge for this article?Dr. Morgan: Yes, Medtronic has paid me honoraria.Dr. Sterns: Yes, I am a paid investigator in several Medtronic clinical trials and key investigator in the present trial. I understand that Medtronic is paying for the processing fee for this article.Dr. Wilkoff: Yes, Medtronic, Guidant, St. Jude MedicalHanson, Ousdigian, and Otterness: Yes, Employees of Medtronic.2. Have you held any stocks or shares in an organization that may in any way gain or lose financially from the publication of this paper?Dr. Morgan and Dr. Sterns and Dr. Wilkoff: NoHanson, Ousdigian, and Otterness: Yes, own Medtronic stock.3. Do you have any other financial competing interests?Dr. Morgan and Dr. Sterns and Dr. Wilkoff: and Hanson and Ousdigian and Otterness: No.4. Are there any non-financial competing interests you would like to declare in relation to this paper?Dr. Morgan and Dr. Sterns and Dr. Wilkoff: and Hanson and Ousdigian and Otterness: No.All 6 authors contributed to the study design and writing of this manuscript.


This was particularly disturbing in that we are in the midst of a growing epidemic of obesity and diabetes with very alarming figures and projections from all over the world. Any intervention that has the potential for helping curb this dangerous epidemic which claims thousands of lives every day should be looked at with a great deal of objectivity.Before beginning the review of this book, we had no particular opinion about the role of low carbohydrate diets in diabetes. In order to write a fair and unbiased review, we have done a rather extensive search on the subject. One of the most disturbing findings of our search is the amount of hostility towards low carbohydrate diets that is on the web and in the scientific literature. We found several sites that present no scientific arguments but are, rather, full of Letter on Corpulence Addressed to the Public [The low carbohydrate approach, in fact, is not new and was used in England more than a century ago, made popular by William Harvey , an ENT e Public , the firThe Atkins Diabetes Revolution  plan is The Atkins Diabetes Revolution book is an attempt by the authors to present the low carbohydrate diet as a preventive and treatment strategy for patients with type 2 diabetes and those with the metabolic syndrome, who are at high risk for developing diabetes and cardiovascular disease. In doing so, the book, which is very well written, and which clearly presents illustrative cases, explains very complex metabolic concept in a very easy to read and understandable format. The first nine chapters explain the different concepts involved in glucose and lipid metabolism and the interplay of the various cardiovascular risk factors that culminate in cardiovascular disease the number one killer of Americans today. Definitions of metabolic syndrome, pre-diabetes, body mass index, waist to hip ratio, central obesity and their relationship to diabetes, heart attacks and strokes, are eloquently presented with a great deal of accuracy yet in a simple format. Most impressive were the case presentations, especially that of reactive hypoglycemia and carbohydrate craving. This response is associated with hyperinsulinemia in the pre-diabetic phase and sometimes puzzles clinicians unless they know to look for it.The second section of the book is devoted to an in-depth discussion of the various macro and micronutrients and their role in diabetes and obesity. Concepts such as the glycemic index and glycemic load are very well illustrated. The last section consists of meal plans and menus of low carbohydrate diet that the book is advocating.1c, something that has been clearly shown to reduce microvascular disease in both type 1 and type 2 diabetes [The concept of low carbohydrate diet and glycemic control certainly has a pathophysiological merit. First, dietary carbohydrates are the principal source for the initial rise of glucose in the diabetic populations, who generally have a defect in the first phase insulin secretion that is responsible for handling the glucose load . There idiabetes ,8. Secondiabetes ,10. So, diabetes ,10. Alsodiabetes . This fadiabetes . This ladiabetes . The facdiabetes -15.In two recent randomized controlled trials published in the New England Journal of Medicine ,17, the 2subfractions [Despite the evidence from these randomized controlled trials, published in the prestigious New England Journal of Medicine, there is a significant amount of reluctance in the scientific community to acknowledge the beneficial effects of low carbohydrate diets. These studies, in fact, provide a striking example of this resistance. A commentary in the same issue of the New England Journal of Medicine  states tractions ,22.On the other hand, the American Diabetes Association, despite recommending the traditional low fat diet, has recently reduced the recommended carbohydrate contents in the diet, perhaps reflecting a trend towards a reduced carbohydrate diet to follow .Atkins Diabetes Revolution has a list price of $25.95 and is available at Amazon.com and presumably other sites for half that price. Possibly, a shorter and still more affordable version of the book would be helpful for diabetic patients, their families and for the general reader, to help identify their risk for the disease.Returning to the Atkins book, despite the fact that the book is very well referenced, certain statements such as "high carbohydrate diet leads to diabetes" are not well substantiated, unless of course such a diet leads to weight gain, which it may. Furthermore, the book does not devote a sufficient amount of space discussing the side effects associated with dieting in general and low carbohydrate diet in particular. This is of concern, since it leaves the reader with the impression that the low carbohydrate diet or dieting, in general, has no negative consequences. Nonetheless, the amount of information the book provides in a simple, yet accurate format will benefit patients with diabetes and their families as well as those who are at risk for developing diabetes and the metabolic syndrome. If, after reading this book, the reader is able to identify that he or she is at risk for diabetes and the metabolic syndrome and takes action that could potentially save his or her life the book will be a valuable contribution. Atkins Diabetes Revolution, however, is sufficiently convincing to make us believe that some form of low carbohydrate intervention is worth investigating and should be considered by practitioners. The highly negative un-scientific response of critics, if anything, encourages us in this direction.As clinicians, we would not be comfortable recommending any diet without first hand experience. The


Health disparities are a growing concern. Recently, we conducted a practice-based trial to help primary care physicians improve adherence with 21 quality indicators relevant to the primary and secondary prevention of cardiovascular disease and stroke. Although the primary concern in that study was whether patients in intervention practices outperformed those in control practices, we were also interested in determining whether minority patients were more, less, or just as likely to benefit from the intervention as non-minorities.Baseline (fourth quarter 2000) and follow-up (fourth quarter 2002) data were obtained from 3 intervention practices believed to have at least 10% minority representation. Two practices had a black (non-Hispanic) population sufficient for analysis, while the other had a sufficient Hispanic population. Within each practice, changes in the 21 indicators were compared between the minority patient population and the entire patient population. The proportion of measures in which minority patients exhibited greater improvement was calculated for each practice and for all 3 practices combined, and comparisons were made using non-parametric methods.For all black patients, the observed improvement in 50% of 22 eligible study indicators was better than that observed among all white patients in the same practices. The average changes in the study indicators observed among the black and white patients were not significantly different (p = 0.300) from one another. Likewise for all minority patients in all 3 practices combined, the observed improvement in 14 of 29 (43.3%) eligible study indicators was better than that observed among all white patients. The average changes in the study indicators among all minority patients were not significantly different from the changes observed among the white patients (p = 0.272).Among 3 intervention practices involved in a quality improvement project, there did not appear to be any significant disparity between minority and non-minority patients in the improvement in study indicators. In 2002, the Institute of Medicine (IOM) issued a report suggesting that minorities are more likely than non-minorities to receive a lower quality of healthcare . BecauseDisparities are particularly evident in the area of chronic diseases. Although blacks are more likely than whites to have blood pressure monitoring, cholesterol screening, and smoking counseling, coronary heart disease is more prevalent among blacks than among whites . Additioth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure outlines specific guidelines for preventing and managing hypertension, hyperlipidemia, and coronary heart disease [In hopes of improving health outcomes and prevention practices for all patients, much focus has recently been given towards the improvement in quality of healthcare. For example, the 7 disease . The 2nd disease . Other qRecently, there have also been a number of practice-based interventions aimed at improving the quality of healthcare for patients. For example, researchers have shown that a practice-based intervention  can enhance the quality of care for families of young children . AdditioWhat these earlier interventions have lacked, however, are analyses examining whether the interventions have improved the quality of care for all patients, regardless of ethnicity. Because these types of interventions are heavily dependent on physician and/or clinical staff interaction with patients, because ethnic minorities may have less trust in their healthcare providers , and becThe aim of this study was to examine whether or not a multi-method quality improvement (QI) intervention was equally successful among patients of different ethnicities. Some of the findings from this QI intervention have been previously published ,12, and The multi-method QI intervention added practice site visits (for academic detailing and QI facilitation) and network meetings (for sharing of best practices) to the approach of guideline dissemination and audit and feedback, employed in a less intensive intervention. Ten sites received the intensive multi-method QI intervention, and ten sites received the less intensive intervention. The study was conducted in a practice-based research network (PPRNet) among users of a common electronic medical record , which historically provided audit and feedback to its practice members.As a supplement to the original study, we were also interested in whether minority patients were more, less, or just as likely to benefit from the intervention as non-minorities. The study presented here focused on outcome and process measures for minorities within 3 primary care practices, all of which received the intensive intervention. These 3 practices  were selected because they each had a significant (i.e. > 10%) proportion of minority patients and had recorded patient ethnicity in their electronic medical record. Practice A is an urban internal medicine practice in the Midwestern U.S. with 5 healthcare providers. Practice B is a rural family medicine practice in the Northeastern U.S. with 8 healthcare providers. Practice C is an urban family medicine practice in the Southeastern U.S.A total of 21 study indicators  data sets on standard microcomputers for analyses.To determine practice performance on the study indicators, participating practices ran a computer program to extract patient activity during the previous quarter from their electronic medical record. To protect patient confidentiality, the extract program assigned an anonymous numerical identifier unique to each patient. The extract program obtained demographic information such as age, ethnicity, and gender, and diagnoses, medications, laboratory data, and vital signs. Text of consultation reports, progress notes, and discharge summaries were not extracted. The data were copied to diskettes and mailed to PPRNet or sent electronically via a secure server. In the PPRNet offices, data were bridged to standard data dictionaries and converted to SASIn each patient's electronic medical record, ethnicity was recorded as white, black/African American, American Indian/Alaskan native, Asian, native Hawaiian/other Pacific islander, and "some other ethnicity", while ethnicity was recorded as Hispanic/Latino and non-Hispanic/Latino, all in concordance with the 2000 U.S. Census ethnicity categories. Currently, these physician practices allow the patient to designate their ethnicity categorization. However, because this process for collecting ethnicity data began in the middle of our study, some ethnicity categorizations were made by the office staff within each of the practices. Ethnicity data was only available on approximately 42% of patients, due to the fact that the electronic medical record software program did not require physicians to enter patients' ethnicity data until its most recent version was released, which occurred during the study time frame. Improvements in process and outcome measures were compared between minority and non-minority patients. Minority was defined as any ethnic designation other than white non-Hispanic.Changes in the process and outcome measures were of primary interest in this study. Within each practice, these changes were compared between the minority patient population and the white patient population. Measures were deemed eligible for comparison if at least 10 minority patients were included in the rate calculations. For example, if practice A only had 8 minority patients with a diagnosis of having had myocardial infarction (MI), then the measure of the percentage of MI patients who had been prescribed a beta blocker could not be compared between the minority and white patient population. The proportion of eligible measures in which minority patients exhibited greater improvement was calculated for each practice and for all 3 practices combined. A Wilcoxon signed rank test  was used to test the hypotheses that minority patients exhibited changes similar to those of the non-minority patients. This study had approximately 80% power  to detect a 6.6 percentage point difference between average improvement in the study indicators among all minority and non-minority patients.Baseline characteristics of the patients from the 3 practices are listed in table In these 3 physician practices, all of which were in the intervention arm of a randomized trial aimed at improving primary and secondary prevention of cardiovascular disease and stroke, we found that results for minorities were relatively similar to the results experienced by the overall practice populations. Change from baseline was greater among minority patients than among white patients for 48.3% of the 29 eligible study indicators, and the average changes in the study indicators among all minority patients were not significantly different from the changes observed among the white patients.There are some limitations of this study which should be noted. As noted earlier, the ethnicity status was only available on 42% of patients within the practices of interest; thus the results may not truly represent what occurred in these practices overall during the study. Given the relatively small number of eligible indicators for comparisons across ethnicities, this statistical power to detect subtle differences was not optimal. Nevertheless, the overall findings suggest that any true differences in this intervention's effectiveness across ethnicities are small.These findings are encouraging, and they suggest that the quality improvement strategies that have been developed to date for physician practices that use electronic medical records have a similar impact on minorities and non-minorities. Future studies should continue to address whether the effectiveness of interventions such as ours is cross-cultural, and whether interventions tailored to be more culturally appropriate can improve the overall effectiveness of interventions.IOM: Institute of MedicineHIV: Human Immunodeficiency VirusAIDS: Acquired Immunodeficiency SyndromeQI: Quality ImprovementLDL: Low-Density LipoproteinMI: Myocardial InfarctionThe author(s) declare that they have no competing interests.PJN helped design the study, perform the analyses, and write the manuscript. SMO helped design the study, perform the site visits, and edit the manuscript. RGJ helped design the study, perform the analyses, and write the manuscript. LFR helped design the study, assisted with data acquisition, and edited the manuscript. LMD helped design the study, perform the site visits, and edit the manuscript. CF helped perform site visits and edit the manuscript. All authors read and approved the final manuscript.Study indicators as measured at baseline (B) and the end (E) of the study for all patients and minority patients within each of the 3 practices.Click here for file


The newly published strategic plan for developing an HIV vaccine is crucially important, say the PLoS Medicine editors, but it must be followed by clear milestones and a process for monitoring progress The new global plan is exciting, but now needs clear milestones In 1997, United States President Bill Clinton announced the challenge to develop an AIDS vaccine by 2007. Since 1997, the AIDS Vaccine Advocacy Coalition (AVAC) has published annual reports on the global status of the effort to meet Clinton's deadline. Last year's report, entitled “AIDS Vaccine Trials—Getting the Global House in Order,” officially ends the countdown. Saying that “we are on a long term mission,” AVAC concludes that there will not be a safe and efficient vaccine in 2007, and that we need to “focus on the long haul and set an agenda for sustained and sustainable action that stretches well beyond 2007.” It is not that there are no vaccine candidates in clinical trials, but there is little hope that any of the current candidates will turn out to be a cheap and safe vaccine that affords long-term protection.PLoS Medicine .Among notable developments over the past 12 months, the AVAC report highlights the Global HIV/AIDS Vaccine Enterprise as an effort to improve coordination within the AIDS vaccine field. The Enterprise was announced in June 2003 and now shares its scientific strategic plan with everyone affected by the AIDS pandemic—that is, all of us—by publishing it in In its plan the Enterprise presents itself as a global endeavor and emphasizes the need for integration and capacity building around the world. It is not “a discrete organization with a pool of money” but a “coordinating group of individual funding agencies that will support specific areas of research using their own mechanisms, according to their own practices and policies, and following the Enterprise's principles.” These principles include collaboration, standardization, and coordination among international researchers and agencies. The plan focuses on specific scientific roadblocks that need to be overcome, but also looks ahead and mentions the need to build capacity for product manufacturing and clinical trials, and to address regulatory issues.10.1371/journal.pmed.0020036), mentions the danger of “group think,” and the Enterprise must not fall into that trap.These are noble goals, and the fact that they are stipulated jointly by many of the leaders in the field will generate excitement and expectations, even though much of what is said has been said before. The plan stresses collaboration and coordination; there are clear benefits from a concerted effort. But might a level of competition, rather than collaboration, be healthy, and, if so, what level of competition would work best? The Enterprise members seem to have wrestled with that question. The plan mentions an “appropriate balance between productive competition and effective collaboration,” and suggests that certain incentives could be provided by “the funders with greatest flexibility.” As long as it remains unclear where scientific breakthroughs will come from, diversity and flexibility should be encouraged and not stifled. David Ho, in his Perspective on the plan  Moreover, provided it can be done, it is impossible to predict when the necessary scientific advances will happen. That said, without a list of specific projects, project leaders, and a time frame for achieving or at least evaluating specific goals, it will be impossible to define success and failure, review progress, and assure internal and external accountability.There is another reason why a best-guess timeline is essential: realistic expectations about an AIDS vaccine would stress the urgency of combating the AIDS pandemic over the next decade—and maybe longer—in the absence of an effective vaccine. The potential benefits of a vaccine cannot be overestimated, and its development has to be one top priority for the global scientific community. But its success cannot be taken for granted and will come too late for millions. Therefore, parallel efforts to prevent or reduce transmission and to treat infected individuals need to be accelerated now.The Enterprise's plan should be hailed as a crucially important outline for vaccine development, but the goodwill surrounding it won't last unless it is quickly followed up with a set of milestones, and a transparent process by which progress will be measured and course corrections implemented.


Id2 mutant animals are deficient in lobulo-alveolar development. This failure of development is believed to be due to a proliferation defect.During pregnancy, the mammary glands from Id2 expression is necessary for Wnt induced mammary hyperplasia, side branching, and cancer, by generating mice expressing a Wnt1 transgene in an Id2 mutant background.We have asked whether functional Id2. We also show that Wnt1 expression is able to cause mammary tumors in an Id2 mutant background.We show in this work that forced expression of Wnt1 in the mammary gland is capable of overcoming the block to proliferation caused by the absence of Id2 expression is not required for Wnt1 to induce mammary hyperplasia and mammary tumors.We conclude that functional  Basic helix-loop-helix (bHLH) transcription factors such as MyoD, E12, and E47 are key regulators of gene expression and control many differentiation events during development . These tId2, is expressed in glandular and ductal epithelium of the mouse mammary gland and has also been implicated in its development. Mammary glands of female mice that are homozygous mutant for Id2 have impaired lobulo-alveolar development [Id2 is regulated by Wnt-β catenin signaling [Id2 expression, thereby leading to cancer. We have asked therefore whether functional Id2 expression is necessary for Wnt induced mammary hyperplasia, side branching and cancer, by generating mice expressing a Wnt1 transgene in an Id2 mutant background.There are 4 mammalian Id genes, which show differences in their patterns of expression and function ,3. One oignaling ,6. It haId2 males and females on a 129/Sv background. Id2 genotyping was done by PCR  using primers Id2-S (5'-tctgagcttatgtcgaatgatagc-3'), Id-2AS (5'-cgtgttctcctggtgaaatggctg-3'), and neo 1 (5'-tcgtgctttacggtatcgccgctc-3").We used heterozygous Hemizygous transgenic MMTV-Wnt1 males on a mixed FVB/BL6/SJL background were obtained from Yi Li in the H.Varmus laboratory. Genotyping was done by PCR  using Wnt1 (5'-gaacttgcttctcttctcatagcc-3') and SV40 (5'-ccacacaggcatagagtgtctgc-3') primers that produce a 350 bp product in transgenic mice.4, dehydrated, cleared in xylene, and mounted in Permount.Five mammary glands per mouse were removed and fat and muscle were dissected away. The glands were flattened between two slides and flooded with Carnoy's fixative  and fixed overnight. They were then de-fatted in 3 changes of acetone, rehydrated, stained overnight in 0.2% carmine and 0.5%KSOId2 loss of function mutant mice [Id2 -/- or Wnt1 transgenic mothers, as these animals cannot feed their young [Id2 +/- females were crossed with MMTV-Wnt1 hemizygous transgenic males, producing 7 MMTV-Wnt1 Tg; Id2+/- males   and we cant mice ,8. Crossir young ,7. Id2 +Id2 -/- mice have an immunologic defect. Even with this care, 50% die before maturity [Id2 -/- mice were born in sub-Mendelian ratios, they were smaller than litter-mates, and several died of unknown causes.The subject animals were kept in mixed groups in autoclaved cages because maturity . Id2 -/-Id2 +/- and Id2 -/- females glands were similar to those of WT females [Id2 +/- and MMTV-Wnt1 Tg ; Id2 -/- mice had branching patterns resembling those of MMTV-Wnt1 Tg females at 3 months , the mechanism through which hyperplasia and side branching is promoted by Wnt1 expression in the virgin mammary gland is unknown. Our results demonstrate that Wnt1 is not operating solely through Id2 or that it is not operating through Id2 at all.The lack of pithelia . We showId2-/- mice [Id2-/- phenotype, suggesting that Wnt1 signaling is independent of both Cyclin D1 and Id2 in the mammary gland.Another known Wnt target with a similar loss of function phenotype is Cyclin D1 , a prote-/- mice , a resulId2, we conclude that functional Id2 expression is not required for Wnt1 to induce mammary hyperplasia and mammary tumors.By showing that forced expression of Wnt1 in the mammary gland is capable of overcoming the block to proliferation caused by the absence of The author(s) declare that they have no competing interests.SM and CR carried out the experiments. YY participated in the design of the study. SM and RN conceived of the study, participated in its design and coordination and wrote the manuscript. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:


The purpose of this study was to investigate the indications for and approach to hysterectomy at Kingston General Hospital (KGH), a teaching hospital affiliated with Queen's University at Kingston, Ontario. In particular, in light of current literature and government standards suggesting the superiority of vaginal versus abdominal approaches and a high number of concurrent oophorectomies, the aim was to examine the circumstances in which concurrent oophorectomies were performed and to compare abdominal and vaginal hysterectomy outcomes.A retrospective chart audit of 372 consecutive hysterectomies performed in 2001 was completed. Data regarding patient characteristics, process of care and outcomes were collected. Data were analyzed using descriptive statistics, t-tests and linear and logistic regression.Average age was 48.5 years, mean body mass index (BMI) was 28.6, the mean length of stay (LOS) was 5.2 days using an abdominal approach and 3.0 days using a vaginal approach without laparoscopy. 14% of hysterectomies were performed vaginally, 5.9% were laparoscopically assisted vaginal hysterectomies and the rest were abdominal hysterectomies. The most common indication was dysfunctional or abnormal uterine bleeding (37%). The average age of those that had an oophorectomy  was 50.8 years versus 44.3 years for those that did not (p < .05). Factors associated with LOS included surgical approach, age and the number of concurrent procedures.A significant reduction in LOS was found using the vaginal approach. Both the patient and the health care system may benefit from the tendency towards an increased use of vaginal hysterectomies. The audit process demonstrated the usefulness of an on-going review mechanism to examine trends associated with common surgical procedures. In Canada in 2001, 446 hysterectomies were performed per 100 000 women .In response to the consistent demand for this procedure, recent reports have identified hysterectomy as a key health care indicator used to measure and compare hospital performance. In particular, the Ontario Hospital Association has identified the ratio of vaginal (VH) to abdominal hysterectomy (AH) as a measure of hospital performance , with a Considerable attention has also been directed towards the high rate of concurrent oophorectomy  with this procedure. This rate is of particular concern in premenopausal women because of the early menopause that ensues.The purpose of this study was to compare abdominal and vaginal approaches to hysterectomy, investigate the rate of concurrent oophorectomy, and identify factors associated with length of surgery, LOS and approach, by auditing all hysterectomies performed over a one-year period at a university teaching hospital.The study involved all patients who underwent a hysterectomy in 2001 at Kingston General Hospital (KGH), a teaching hospital affiliated with Queen's University at Kingston, Ontario. The Queen's University Health Sciences and Affiliated Teaching Hospitals Research Ethics Board approved the study (OBGY-117-03). There were no exclusion criteria. Patients were identified by medical record tracking using ICD-9 codes and charts were reviewed to collect patient characteristics, length of stay, length of surgery, indication for surgery and approach. Readmissions, complications, infections and repeat laparotomies were also assessed.Menopause was defined as one year since the last menstrual period. Up to three indications for surgery were obtained from the chart, including those identified in clinic letters, admission sheets and operative reports. All indications were collected regardless of whether or not the post-operative diagnosis coincided with the preoperative diagnosis.VH included laparoscopically assisted vaginal hysterectomy (LAVH) and AH included VH converted to AH unless otherwise noted. Readmission was defined as a visit to the emergency room or an admission to the same hospital with a diagnosis that was related (readmission to another facility was unlikely as KGH is the only tertiary care facility in the region). Post-operative infections were defined as those that occurred within 30 days of surgery. A complication of excessive bleeding was defined as an intra-operative hemorrhage requiring transfusion or laparotomy, post-operative hematoma/seroma formation, or a significant post-operative vaginal bleed that required medical attention. All complications that occurred during the surgery or within 30 days of surgery were recorded, other than problems associated with removal of catheter, urinary retention, hypertension, hypotension, pain control, nausea and vomiting or headache. Any repeat laparotomy or unplanned laparotomy (other than for conversion of VH to AH) that occurred during the surgery or within 30 days of discharge was also noted.Follow up information was tracked using hospital chart and clinic note information from the six-week post-operative visit. All data were analyzed using SPSS statistical software . Between-group comparisons utilized two-sample t-tests and one-way analysis of variance (continuous data) and Chi-square analyses . Predictors of LOS and length of surgery were identified using linear regression, while predictors of surgical approach were identified using logistic regression. Variables were offered into the models on the basis of the strength of the bivariate associations with the outcomes (p < 0.20).Three hundred and seventy two women underwent a hysterectomy in 2001. The characteristics of these patients can be found in Table The majority of hysterectomies were AH (78%), 14% were VH, 5.9% were LAVH and 2.2% were VH converted to AH. Total hysterectomies accounted for 79.8% of hysterectomies, 16.1% were subtotal, and 4% were radical or modified radical hysterectomies. There were no significant differences between patients who had a subtotal and those that had a total hysterectomy for BMI, age, LOS, length of surgery, number of infections, or number of complications. The patients differed only in terms of parity, in that those who underwent a total hysterectomy had more children .A concurrent procedure was performed in 26.6% of patients. This included biopsies (10.5%), reparative surgery (5.9%), procedures to establish urinary continence (3.5%), appendectomies (1.9%), and surgery to manage intra-operative events (2.2%). Table Fifty-eight (15.6%) of the patients had a diagnosis of cancer pre-operatively, which rose to 76 (20.4%) post-operatively. The population with cancer was older, had higher BMIs, longer surgeries, and longer lengths of stay than those without cancer Table .Twenty-six patients visited the emergency room within 30 days of their discharge and an additional nineteen patients were readmitted to the hospital. Table Infections occurred in 15.3% of patients, including urinary tract infections (7.5%), incision site infections (5.6%) and pelvic infections (2.2%). Those who developed an infection had a higher mean BMI (p = 0.018), longer LOS (p = 0.018) and longer length of surgery (p = 0.036) than those who did not.Four percent of patients had a repeat laparotomy or unplanned laparotomy (not including those for conversion of VH to AH). Other complications occurred in 24.5% of patients, the most common being excessive bleeding (11.3%) and post-operative ileus (5.4%). Other complications involving the bladder, bowel, pulmonary function, cardiac function or drug reactions occurred in less than 2% of patients respectively.Table A comparison of the abdominal and vaginal approaches revealed no differences in terms of incidence of infection, readmission to the ER or hospital, incidence of excessive bleeding or complication rate.LAVH and VH converted to AH were excluded from all regression analyses as they represented subgroups that were clinically different than routine AH and VH. Table Logistic regression for approach of hysterectomy indicated that a patient was 1.1 times more likely to have an AH for each one-point increase in BMI (p = 0.003), 47.6 times more likely to have an AH if she had a concurrent unilateral or bilateral oophorectomy (p < 0.001) and 1.7 times more likely to have a VH with each additional child (p < 0.001).The majority of the patients were overweight  or obese . These numbers define a population whose obesity level is 21.8 percentage points above the national average and although there is no known average BMI for all hysterectomy patients in Canada for comparison, the high obesity rate at this centre may have contributed to the reliance on the abdominal approach. A patient was in fact eleven times more likely to have an AH for every 10-point increase in BMI. Although recent studies exclude BMI as a factor in determining the route of hysterectomy, it has been noted that obesity of the buttocks may interfere with the exposure necessary for a VH [The general trend in determining the route of hysterectomy has been to challenge the validity of the exclusionary criteria for VH, such as nulliparity, larger uterine size, previous cesarean delivery, and pelvic laparotomy. These are no longer considered to be strong contraindications to a vaginal approach -11. Yet The overall ratio of abdominal to vaginal  surgeries is 5.6:1 but when only considering those surgeries performed for indications other than cancer (cancer found pre or post operatively), the ratio reduces to 3.9:1. This is consistent with the fact that most malignant indications for surgery require an abdominal approach in order to ensure access to structures and to allow for staging procedures. Our data did not demonstrate a significant difference between AH and VH in terms of outcome variables such as the rate of infection or complication, however, the two day reduction in LOS for VH may have significant cost reduction potential ,13. In oThe merit of performing a concurrent oophorectomy during hysterectomy continues to be debated for women not at high risk of developing ovarian cancer. Estimates regarding the number of prophylactic oophorectomies needed to prevent one case of ovarian cancer range from 200  to 300 . BenefitThe limitations of this study include uneven distribution of patients in each treatment group and lack of randomization due to the nature of the retrospective chart review process. Furthermore, because the audit process relied entirely on chart documentation, information may have been missed or incorrect as a result of improper or absent documentation. The broad range of information collected also prevented the researchers from employing more rigorous definitions and verification of outcomes. The retrospective nature of the study precluded an evaluation of the decision making process leading to oophorectomy as well as the influence of pre-operative indications, uterine size, parity, previous c-section and concurrent oophorectomy on surgical approach. This would need to be addressed prospectively, by surveying the surgeons at the time that the decision was made.Both the patient and the health care system may benefit from the trend towards increased use of vaginal hysterectomies. However, the abdominal approach continues to dominate, likely related to patient size, surgeon preference and the need for adnexal surgery. The audit process proved to be an important method by which to assess trends associated with common surgical procedures. This study raises important questions about the relationship between patient characteristics, surgical approach and the indications for surgery, and a prospective approach, designed to address these questions more fully, is now indicated. Furthermore, in light of recent evidence  demonstrThe author(s) declare that they have no competing interests.AT performed data collection, participated in the study design and coordination and participated in drafting the manuscript. WH performed the statistical analysis and participated in drafting the manuscript. RHG conceived the study and participated in its design and coordination and participated in drafting the manuscript. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:


Trypanosoma evansi (T. evansi) RoTat 1.2 Variable Surface Glycoprotein (VSG), a primer pair was designed targeting the DNA region lacking homology to other known VSG genes. A total of 39 different trypanosome stocks were tested using the RoTat 1.2 based Polymerase Chain Reaction (PCR).Based on the recently sequenced gene coding for the T. evansi and in seven out of nine T. equiperdum strains tested. This product was not detected in the DNA from T. b. brucei, T. b. gambiense, T. b. rhodesiense, T. congolense, T. vivax and T. theileri parasites. The Rotat 1.2 PCR detects as few as 10 trypanosomes per reaction with purified DNA from blood samples, i.e. 50 trypanosomes/ml.This PCR yielded a 205 bp product in all T. evansi strains, except T. evansi type B, and is especially useful in dyskinetoplastic strains where kDNA based markers may fail to amplify. Furthermore, our data support previous suggestions that some T. evansi stocks have been previously misclassified as T. equiperdum.PCR amplification of the RoTat 1.2 VSG gene is a specific marker for  Trypanosoma evansi. T. evansi belongs to the subgenus Trypanozoon, together with T. equiperdum and T. brucei. The parasite can infect different host species and is mechanically transmitted by different biting flies such as Tabanidae and Stomoxys as well as by vampire bats such as Desmodus rotondus [T. evansi infections of cattle and buffaloes usually lead to a pronounced immunosuppression resulting in an increased susceptibility to other opportunistic diseases such as Pasteurella and anthrax [Surra is an animal disease occurring in Africa, Asia and Latin America, caused by rotondus . Camels  anthrax .T. evansi infection usually starts with clinical symptoms or the detection of antibodies to T. evansi. Conclusive evidence of T. evansi infection, however, relies on detection of the parasite in the blood or tissue fluids of infected animals. Unfortunately, parasitological techniques cannot always detect ongoing infections as the level of parasitaemia is often low and fluctuating, particularly during the chronic stage of the disease [Diagnosis of a  disease .Trypanozoon specific primers have been designed previously: TBR primers which target a 177 bp repeat [T. congolense and T. vivax infections exist as well [Trypanozoon subgenus still remains a challenging issue. For T. evansi infections, the only specific test available so far is based on the detection of a kinetoplast DNA sequence [T. evansi RoTat 5.1 [T. evansi parasites. Recently, Ventura et al. [T. evansi based on a Random Amplified Polymorphic DNA (RAPD) fragment. The taxon specificity of this PCR remains uncertain since it was only tested on nine T. evansi strains, one T. equiperdum, two T. b. gambiense and one T. b. rhodesiense. Following evidence that the variable epitope of RoTat 1.2 VSG is expressed by all T. evansi strains tested so far [T. evansi but not in T. brucei isolates [As an alternative to parasitological tests, DNA detection based on PCR has been proposed. p repeat , pMUTEC p repeat  and ORPHp repeat . Most ofp repeat , water bp repeat  or goatsp repeat . PCR tes as well . The devsequence ,13. HoweoTat 5.1  and E152oTat 5.1  casts dod so far , and thaT. evansi populations (lanes 3–8). Moreover, the same fragment was found in seven out of the nine T. equiperdum populations tested. The T. equiperdum BoTat 1.1 was PCR negative (lane 10), while the T. equiperdum OVI strain yielded a PCR product shorter than 205 bp (lane 11) probably due to mispriming. All other tested trypanosome populations, including six T. b. brucei, eight T. b. gambiense, five T. b. rhodesiense, two T. congolense, one T. vivax and one T. theileri, were negative. (lanes 18–40). As a negative control, a PCR-mix without template DNA was included (lane 2). Sequencing of the positive samples revealed that all amplicon were identical (data not shown). The weak band in OVI did not yield sufficient material to enable sequencing.The 39 different trypanosome stocks used in this study are listed in Table 1 see . They we5 trypanosomes down to 1 trypanosome per 200 μl sample) of RoTat 1.2 trypanosomes in mouse blood was prepared to determine the analytical sensitivity of the PCR. As shown in figure A tenfold dilution series  and two T. b. gambiense type II strains (ABBA and LIGO) tested positive in this PCR (data not shown).To evaluate the RoTat 1.2 diagnostic system alongside other published methods, we compared our method to the PCR-Te664 method as published by Ventura et al.  using thT. evansi from the other members of the Trypanozoon subgenus. The study is an extension of the initial observation that the RoTat 1.2 VSG gene only is found in T. evansi and not in T. brucei strains [T. evansi rather than the use of this VSG in diagnosis of Salivarian trypanosomes.This study was initiated to develop a specific PCR test that would be able to distinguish  strains . This stT.b. gambiense infections (sleeping sickness). In these studies, five different primers derived from VSG genes, AnTat 11.17, LiTat 1.3, 117, 2 K and U2 were used in PCR screening of different trypanosome populations, originating from distinct geographical locations [T.b. gambiense from T.b. brucei parasites from most foci of sleeping sickness in countries such as Nigeria, Cameroon, Côte d'Ivoire, R. P. Congo/Brazza. and Sudan. However, populations originating from the Moyo focus in North-west Uganda and from Cameroon were shown to be negative in AnTat 11.17 and in LiTat 1.3 (2 K) PCRs respectively. According to Bromidge et al. [T. brucei populations tested. In T. evansi, a similar phenomenon may occur in certain Kenyan isolates. A recent study by Ngaira et al. [T. evansi stocks in the Isiolo district in Kenya seem to lack the Rotat 1.2 VSG gene. It is believed that these stabilates belong to the T. evansi type B group. So far, this type of T. evansi has only been observed in this specific region in Kenya [T. evansi isolated elsewhere, are from the classical T. evansi type A group. Thus, we assume that, except for these few Kenyan strains belonging to the type B group, our PCR is specific for T. evansi.Previously, other research groups have used VSG genes as target sequences for PCR detection of ocations -20. AnTae et al. , this mia et al.  pointed in Kenya ,23. To oet al. [T. b. brucei, nor with T. b. gambiense type II was observed. However, regarding T. equiperdum, both PCR test positive for the same seven T. equiperdum strains and are both negative for the BoTat 1.1 and OVI strains. Since the RAPD fragment (AF397194) shares no homology with the Rotat 1.2 VSG gene (AF317914) and is not found within the expression site of trypanosomes, both sequences can be considered as independent molecular markers. Based on the observations with both markers, it appears that on the genomic level the Botat 1.1 and the OVI strains are different from the other T. equiperdum and T. evansi strains. The observed analytical sensitivity with the RoTat 1.2 PCR is comparable to what was reported for the Te664 PCR (25 cells per reaction) [Compared to the PCR-Te664 presented by Ventura et al. , the PCReaction) .T. equiperdum strains corresponds with the serological evidence that rabbits experimentally infected with these strains develop RoTat 1.2 specific lytic antibodies within 30 days post infection [T. evansi specific and that RoTat 1.2 PCR positive T. equiperdum strains are actually T. evansi and not T. equiperdum. Indeed, in a previous molecular characterization study using Random Amplified Polymorphic DNA (RAPD) and the Multiplex-endonuclease Genotyping Approach (MEGA) it appeared that the T. equiperdum collection is not as homogenous as previously believed and that the generally followed concept that T. equiperdum is very closely related to T. evansi and more distant from T. b. brucei, seems incorrect. From the cluster analysis on the available strains, it appeared that only two clusters can be identified: a homogeneous T. evansi/T. equiperdum cluster and a more heterogeneous T. b. brucei/T. equiperdum cluster [T. evansi/T. equiperdum cluster are all PCR RoTat 1.2 VSG positive while the strains found in the more heterogeneous T. b. brucei/T. equiperdum cluster, in casu BoTat 1.1 and OVI are PCR RoTat 1.2 VSG negative.The presence of a RoTat 1.2 specific DNA sequence in some nfection . In cont cluster . InteresT. evansi strains, except T. evansi type B, and is especially useful in dyskinetoplastic strains where kDNA based markers may fail to amplify. Furthermore, our data support previous suggestions that some T. evansi stocks have been previously misclassified as T. equiperdum.PCR amplification of the RoTat 1.2 VSG gene is a specific marker for T. equiperdum strains, BoTat 1.1, OVI and STIB 818 are well documented, i.e. known origin and host. The other six are putative T. equiperdum, based on publications or on their use as reference strains in different national dourine reference laboratories [A total of 39 different trypanosome populations were used in this study. They belong to 39 stocks and six species, isolated from a variety of host species at distinct geographical locations (Table 1 see ). Only tratories -30.in vitro in Cunningham's medium [2HPO4.2H20, 2 mM NaHPO4, 80 mM glucose, 100 mM sacharose, pH 8.0). Bloodstream form trypanosomes were expanded in mice and rats and were purified from the blood by di-ethyl-amino-ethyl (DEAE) chromatography [2HPO4.2H20, 2 mM NaHPO4, 80 mM glucose, 29 mM NaCl, pH 8.0). Trypanosome sediments were subsequently stored at -80°C.Procyclic trypanosome populations were grown s medium  and in ts medium . Pure prtography , followe7 cells) were resuspended in 200 μl of Phosphate Buffered Saline (PBS)  and the trypanosome DNA was extracted using the commercially available QIAamp DNA mini kit , resulting in pure DNA in 200 μl of TE buffer. The typical yield of DNA extracted from a 20 μl pellet was 150 ng/μl or 30 μg total DNA. The extracts obtained were diluted 200 times in water and divided into aliquots of 2 ml in microcentrifuge tubes for storage at -20°C.Twenty μl of trypanosome sediment  resulting in 200 μl of extracted DNA in Millipore water. Manipulation was performed according to the manufacturer's instructions.et al. [ann. 59°C and RoTat 1.2 Reverse ATT AGT GCT GCG TGT GTT CG, Tann. 59°C.Primers were derived from the RoTat 1.2 VSG sequence AF317914), recently cloned and sequenced by Urakawa 914, rece2 , 200 μM of each of the four dNTPs  and 0.8 μM of each primer .Twenty μl of extracted DNA were mixed with 30 μl of a PCR-mix containing: 1 U Taq DNA recombinant polymerase , PCR buffer , 2.5 mM MgCl® Trio-block thermocycler. Cycling conditions were as follows: denaturation for 4 min. at 94°C, followed by 40 amplification cycles of 1 min. denaturation at 94°C, 1 min. primer-template annealing at 59°C and 1 min. polymerization at 72°C. A final elongation step was carried out for 5 min. at 72°C.All amplifications were carried out in a BiometraTwenty μl of the PCR product and ten μl of a 100 bp size marker  were subjected to electrophoresis in a 2 % agarose gel (25 min. at 100 V). Gels were stained with ethidium bromide (0.5 μg/ml)  and analyzed on an Imagemaster Video Detection System .et al. [Taq DNA polymerase was purchased from another distributor, i.e. Promega (UK) instead of Gibco BRL (UK).PCR on purified DNA samples was performed using primers and PCR conditions according to Ventura et al. . Only thNone declared.FC carried out the molecular work and drafted the manuscript. MR and TU participated in the molecular analysis. PM, BG and PB participated in the design and co-ordination of the study. All authors read and approved the final manuscript.Trypanosoma (T.) populations used in this studyTable 1. Data on the different Click here for file


One problem in the mobilization of patients with neurological diseases, such as spinal cord injury, is the circulatory collapse that occurs while changing from supine to vertical position because of the missing venous pump due to paralyzed leg muscles. Therefore, a tilt table with integrated stepping device (tilt stepper) was developed, which allows passive stepping movements for performing locomotion training in an early state of rehabilitation. The aim of this pilot study was to investigate if passive stepping and cycling movements of the legs during tilt table training could stabilize blood circulation and prevent neurally-mediated syncope in healthy young adults.In the first experiment, healthy subjects were tested on a traditional tilt table. Subjects who had a syncope or near-syncope in this condition underwent a second trial on the tilt stepper. In the second experiment, a group of healthy subjects was investigated on a traditional tilt table, the second group on the tilt ergometer, a device that allows cycling movements during tilt table training. We used the chi-square test to compare the occurrence of near-syncope/syncope in both groups (tilt table/tilt stepper and tilt table/tilt ergometer) and ANOVA to compare the blood pressure and heart rate between the groups at the four time intervals .Separate chi-square tests performed for each experiment showed significant differences in the occurrence of near syncope or syncope based on the device used. Comparison of the two groups (tilt stepper/ tilt table) in experiment one (ANOVA) showed that blood pressure was significantly higher at the end of head-up tilt on the tilt stepper and on the tilt table there was a greater increase in heart rate (2 minutes after head-up tilt). Comparison of the two groups (tilt ergometer/tilt table) in experiment 2 (ANOVA) showed that blood pressure was significantly higher on the tilt ergometer at the end of head-up tilt and on the tilt table the increase in heart rate was significantly larger (at 6 min and end of head-up tilt).Stabilization of blood circulation and prevention of benign syncope can be achieved by passive leg movement during a tilt table test in healthy adults. Several studies have confirmed that lack of movement leads quickly to profound negative physiological and biochemical changes in all organs and systems of the body -5. It isHead-up tilt table testing has been used for over 50 years by physiologists and physicians for many purposes. This includes the study of the human body's heart rate and blood pressure adaptations to changes in position, for modeling responses to hemorrhage, as a technique for evaluating of orthostatic hypotension, as a method to study hemodynamic and neuroendocrine responses in congestive heart failure, autonomic dysfunction and hypertension, as well as a tool for drug research ,10-14. IIn addition to the traditional tilt table, a novel apparatus with stepping device (tilt stepper) was developed in 1998 at the research department of the Paraplegia Centre of the Balgrist University Hospital in Zurich, Switzerland in collaboration with the Department Orthopaedic II of the Orthopaedic Hospital of Heidelberg to enable a mobilization with stabilized circulation and to begin with a locomotion training in an early state of rehabilitation.In the tilt stepper, the patient is strapped by a safety belt to the tilt table while the legs are moved passively in a physiological stepping pattern Figure . The incThere are only a few studies that have investigated how passive movement of the legs during a tilt table treatment affects circulation. In these studies, either functional electrical stimulation of the leg muscles -21 was uThe aim of our experiments was to investigate if passive stepping and cycling movements of the legs during a tilt table test can stabilize blood circulation and prevent neurally mediated syncope in healthy young adults.With the permission from the local Ethics Committee and the informed consent of the volunteers, the response of the blood circulation was analyzed in healthy subjects. The exclusion criteria included: recurrent syncope or near-syncope in clinical history, regular medication, abuse of nicotine or alcohol, cardiovascular or neurological diseases, acute or chronic infections, psychiatric disorder and body mass index <18 or >25. All subjects underwent a physical investigation and an ECG was completed one week before the experiment.In the first experiment, we examined 12 healthy young adults (age 24 ± 5 years) on a traditional tilt table. The subjects, who had syncope or near-syncope were treated on the tilt stepper after a waiting period of 4 weeks. Syncope was defined as a transient loss of consciousness associated with a loss of postural tone. Near-syncope was defined as the appearance of pallor, nausea, light-headedness, diaphoresis or blurred vision. Both conditions were associated with the following hemodynamic changes: a decrease in systolic blood pressure > 60% from baseline values or an absolute value < 80 mmHg (vasodepressor response) and/or a decrease in heart rate > 30 % form the baseline value or an absolute value < 40 beats/min (cardio-inhibitory response) .In the second experiment, we enrolled 42 healthy subjects (age 27 ± 4 years). They were randomized into two groups: group I (23 subjects) was put on a traditional tilt table, while the Group II (19 subjects) on a tilt ergometer. The age of the subjects was restricted to below 35 years, because the cardiovascular response is strongly dependent on age .The aim of the first experiment was to investigate if the blood circulation could be stabilized in people who have a disposition for an "early" appearance of a neurally-mediated syncope on a traditional tilt table. The appearance of a neurally-mediated syncope is physiological and it may occur in all subjects. The interpersonal difference lies in the duration that the subject can be in standing posture until syncope or near-syncope occurs. A decrease of the systolic blood pressure up to maximal 15 mmHg and/or an increase in heart rate up to 20 bpm during the first 6 minutes are considered as a normal reaction to compensate the change in the position of the body .The blood pressure was non-invasively measured with a tonometric blood pressure device. Subjects who suffered a syncope or near-syncope during the first session on the traditional tilt table were in the second session treated on the tilt stepper. In the second experiment, we investigated the effect of passively induced movements on circulation by a cycle ergometer on a tilt table. We enrolled 42 subjects: 23 on a traditional tilt table and 19 on the tilt ergometer.In both experiments, after 15 minutes of rest the subjects were tilted head-upright at a 75° angle and were returned to the supine position if a syncope or near-syncope occurred or after completion at 30 minutes. Heart rate and blood pressure were measured continuously and non-invasively. Head-up tilt tests were performed in the morning in a dim room. All subjects were instructed to fast overnight and relax the muscles of their lower limbs during the trials. This was monitored with an EMG-measurement on legs , randomly tested in the first experiment and regularly tested during the second experiment. The EMG signals were amplified and transferred to a personal computer. They were recorded by a data acquisition tool .The tilt stepper is a traditional tilt table  combined with an integrated leg drive that allows a passive movement of the lower extremities Figures  and 2The leg drive that is connected to the thigh by a cuff induces a hip flexion or extension movement. As the feet of the patient are fixed to footplates, the knee is also flexed or extended, respectively. In those phases where the hip and knee joints are extended, the leg pushes down a spring-dampened footplate, which is then again pushed against a foot spring that is mounted within these plates. This footplate generates a loading force on the foot sole of the patient during extension. Applying this cycle of flexion and extension in an alternating way leads to physiological kinetics of the generated motion. A special mechanism is mounted under the hip joint and allows for adjustment of hip extension up to 20°.Depending on the blood circulation condition of the patient, the device can be tilted to different angles up to a vertical position. This makes it possible for the patient to become accustomed, step-by-step, to the upright position in combination with passive leg movements. The speed of the alternating stepping movements and the range of motion of hip/knee joints can be adjusted by a control panel. The basic construction consists of a linear drive , with a precision ball screw that is driven by a synchronous motor via toothed belt . The movement frequencies range from 0.2 to 0.5 Hz (i.e. one cycle of flexion and extension takes between 2 and 5 sec).To secure subjects on the tilt table during experiments, fixation with a special harness was used during all experiments Figure .The tilt ergometer consists of a traditional tilt table with an additional ergometer device (Tera Joy Germany) that allows a passive cycling movement of the lower extremities. From a technical point of view, the tilt ergometer construction is simpler than the tilt stepper, but it generates a non-physiological motion concerning gait phase related forces on the foot sole. The cycle frequency was between 0.2–0.5 Hz.Blood pressure was measured continuously and non-invasively by a Colin CBM-7000 . The Colin CBM – 7000 is a tonometric blood pressure device that allows measuring beat-to-beat blood pressure , continuous arterial blood pressure waveform, beat-to-beat and continuous electrocardiography.In both experiments we used the chi-square test to compare the occurrence of near-syncope/syncope in both groups (tilt table/tilt stepper and tilt table/tilt ergometer). We performed 2 by 4 repeated measures ANOVAs with 2 between factors (device group – namely tilt table vs. tilt stepper or tilt table vs. tilt ergometer), 4 within factors  and in their interaction (groups × time) for blood pressure and heart rate. Pairwise comparisons were made with the t-test with additional Bonferroni's correction.2 (1.1) = 6.465, p = 0.011). Table In the first experiment, 7 of 12 subjects (58%) had a syncope or near-syncope on the traditional tilt table. There was an obvious increase in heart rate in the first 6 minutes after changing the position from supine to upright. None of these 7 subjects had a syncope or near-syncope during the treatment session on the tilt stepper 4 weeks later. Comparing the occurrence of near syncope/syncope in both sessions with the chi-square test, there was a significant difference  = 4.66, p < 0.0743), but there were significant differences between groups  = 6.33, p < 0.0016)) and in the interactions  = 7.24, p < 0.0022). The blood pressure differs between the two treatments at the end of head – up tilt (p < 0.0029), but not at 2 minutes (p < 1.000) and at 6 minutes (p < 1.000) . However, there could be shown a trend for a higher blood pressure at 2 minutes and at 6 minutes after head-up tilt in the group treated in the tilt stepper.There were significant differences for heart rate within each group  = 12.17, p < 0.0130) between groups  = 21.16, p < 0.0001) and in the interactions  = 8.68, p < 0.0009). For the group treated on the traditional tilt table, pairwise comparisons with the t-test with additional Bonferroni's correction showed a significantly higher heart rate at 2 minutes (p < 0.0.0060), but no significant differences at 6 minutes (p < 0.2051) and at the end of head-up tilt (p < 1.000).2 (1.1) = 5.443) there was a significant difference (p = 0.021)  who were on the traditional tilt table had syncope (3) or near-syncope (10). None of the 19 subjects who were on the tilt ergometer had syncope but 4 subjects had near-syncope (21%). Comparing the occurrence of near syncope/syncope in both sessions with the chi-square test  = 34.43, p < 0.0001) between groups  = 13.42, p < 0.0001)) and in the interactions  = 10.95, p < 0.0001). Pairwise comparisons with the t-test  showed no significant differences at 2 minutes (p < 0.5221) and at 6 minutes (p < 0.4429) but a significant difference at the end of head – up tilt (p < 0.0001). However, there could be shown a trend for a higher blood pressure at 2 minutes and at 6 minutes after head-up tilt in the group treated on the tilt ergometer. There were significant differences for heart rate within each group  = 12.17, p < 0.0130), between groups  = 21.16, p < 0.0001), and in the interactions  = 8.68, p < 0.0009). Pairwise comparisons with the t-test  showed no significant differences at 2 minutes (p < 0.3317), but a significantly higher heart rate in the group treated on the tilt table at 6 minutes (p < 0.0007) and at the end of head – up tilt (p < 0.0002).All subjects on the tilt stepper and tilt ergometer completed 30 minutes of head-up tilt. The duration of the head-up tilt was different in the group on the traditional tilt table, as an abrupt decrease of blood pressure or symptoms of near-syncope occurred.In the head-up tilt position the subject stands on the footplates on the tilt stepper, whereas in the tilt ergometer the harness holds the whole body weight. The subjects who were investigated on the tilt stepper felt comfortable during the whole experiment, whereas the subjects examined on the tilt ergometer in experiment two complained of discomfort. The subjects on the tilt ergometer experienced more discomfort because of the perception of no lower limb support. These statements were subjective; no standardized assessment instrument was used to measure the comfort.Tables In Figures Figure Figure The tilt table is an apparatus that has become an important part in the evaluation of patients with unexplained syncope or loss of consciousness ,24,33. IAlthough the tilt table has become an accepted diagnostic tool, there are no comparable studies with the tilt table in which the effect of passive leg motion on circulation have been investigated.The aim of these two experiments was to investigate if passive leg movements during head-up tilt can prevent syncope. The data in the present study show a stabilizing effect on the blood circulation and this study suggests that there is an effect on preventing neurally-mediated syncope by both devices. In the first experiment, none of the subjects who had syncope/near-syncope on the traditional tilt table had syncope/near-syncope four weeks later on the tilt stepper. In the second experiment, only 4 subjects who were treated on the tilt ergometer had near-syncope. In both experiments the increase of heart rate was larger in the group tested on the traditional tilt table. A correlation between heart rate and appearance of syncope was described ,36. An iIn the first experiment we treated the same subject twice on a tilt table. It cannot be excluded that an adaptation to the orthostatic change occurred in these subjects. However, there was an interval of four weeks between the first treatment on the traditional tilt table and the second treatment on the tilt stepper. Therefore, a training effect or an effect of habituation, such as described in another study in which patients suffering from syncope were treated each day over 6 weeks, seems to be unrealistic .The results in both experiments indicate that blood circulation can be stabilized by passive leg movements. However, the movements of the two devices used in these experiments are very different: on the tilt stepper there are stepping like movements and the legs can be loaded during extension and unloaded in flexion. In the tilt ergometer, the movements are the other way round. There might be more afferent input from the load receptors in the tilt stepper compared to the tilt ergometer. For example it could be shown that the load moments acting about the bilateral hip, knee and ankle joint axes during cycling are found to be generally lower than those induced during normal level walking  and concIn conclusion, we could show that both passive cycle and stepping movements of the legs during head-up tilt testing can stabilize blood circulation and prevent syncope in young healthy people. In further studies, we aim to investigate if the tilt stepper could become a helpful device for patients suffering from neurological diseases.


There is evidence that groups of people with schizophrenia have deficits in Theory of Mind (ToM) capabilities. Previous studies have found these to be linked to psychotic symptoms (or psychotic symptom severity) particularly the presence of delusions and hallucinations.A visual joke ToM paradigm was employed where subjects were asked to describe two types of cartoon images, those of a purely Physical nature and those requiring inferences of mental states for interpretation, and to grade them for humour and difficulty. Twenty individuals with a DSM-lV diagnosis of schizophrenia and 20 healthy matched controls were studied. Severity of current psychopathology was measured using the Krawiecka standardized scale of psychotic symptoms. IQ was estimated using the Ammons and Ammons quick test.Individuals with schizophrenia performed significantly worse than controls in both conditions, this difference being most marked in the ToM condition. No relationship was found for poor ToM performance and psychotic positive symptomatology, specifically delusions and hallucinations.There was evidence for a compromised ToM capability in the schizophrenia group on this visual joke task. In this instance this could not be linked to particular symptomatology. Theory of Mind (ToM) describes the ability to recognise that other people have minds containing beliefs and intentions and to be able to interpret these correctly. The term, first coined by Premack and Woodruff , is alsoToM ability has been conceived as a capacity to represent epistemic mental states comprising an agent and an attitude to the truth of a proposition e.g. "Peter believes that it is raining" ,5. The tIt is widely reported that there are observed ToM deficits in schizophrenia from the numerous behavioural and neuroimaging studies that have been conducted investigating this phenomenon [e.g. ]. It is Sarfati et al used a strictly pictorial task in which 3 picture cartoon sequences were shown depicting a character producing an action and the participants had to choose the fourth and final picture from a choice of three images . SuccessSarfati et al then enlarged this experimental protocol by introducing a verbal dimension to the task . There wLangdon et al, used a task comprised of 4 card black and white cartoon picture sequences of four varieties: social script stories testing logical reasoning about people without needing to infer mental states, mechanical stories testing Physical cause and effect reasoning, false belief stories testing general mind reading abilities and capture stories testing inhibitory control. Cards were place face down in a square layout and participants had to turn the cards over and place them in the correct order to show a logical sequence of events. In order to control for possible contributory effects of executive dysfunction, inhibitory control was tested using capture picture-sequences and executive planning was tested using the Tower of London task.In both studies, it was found that individuals with schizophrenia showed a selective ToM impairment which could not be completely explained by reasoning, planning deficits or poor inhibitory control ,19.Brüne showed individuals a muddled cartoon 4 picture sequence depicting a ToM scenario between characters . The parCorcoran et al used visual jokes to look at potential ToM deficits in schizophrenia . Two setThe primary interest of the current study was to examine the associations between specific schizophrenic symptoms and ToM capabilities using the cartoon method devised by Corcoran , but witForty participants aged from 19–65 years were recruited for this study. Twenty of these had a diagnosis of DSM IV schizophrenia . These wTo assess their present symptomatology, the schizophrenia patients were assessed on the Krawiecka Standardized Scale for Rating Chronic Psychotic Patients . SymptomAll participants in this study gave written, informed consent.Sixty-three single-image cartoon jokes, printed on A4 cards were generously provided by the authors of previous studies . Thirty-It was explained to the subjects that they would be shown cartoons intended to be funny. The two complete sets of cartoons were then shown to each subject in turn. The order in which they were presented was alternated so that half the participants viewed the ToM cartoons first, and half viewed the ToM cartoons second.The subjects were shown each joke one by one and instructed to indicate to the observer when they believed they had understood its meaning. This response time was then recorded to the nearest second using a stopwatch. The participants then gave a short explanation of their interpretation of the joke's meaning. Responses were scored 1 for a correct answer and 0 for an incorrect answer. For a theory of mind answer to be correct, appropriate mental state language had to be used. Furthermore, participants were asked to subjectively grade each cartoon image for humour and difficulty on a scale of 1–5, where 1 was not funny or very easy and 5 very funny or very difficult respectively.Simple Physical descriptions of the scenario were required for the Physical joke responses to be scored correct. An example of acceptable responses can be viewed in Table Tests were all performed in quiet, distraction-free rooms.Data analysis was performed using SPSS for Windows Version 11.0.General linear model repeated measures ANOVA was used to determine the significance of any difference in the Physical versus ToM scores seen between the groups. General linear model ANCOVA controlling for Physical joke score was used to investigate the selectivity of any group difference in ToM capabilities. Linear regression analysis was used to relate Physical and ToM scores to Krawiecka sub-totals for positive, negative and non specific symptoms, individual Krawiecka symptoms, medication dose and joke block presentation order. Independent two-tailed t-tests were used to compare the group score differences in the two conditions , the average subjective ratings for humour and difficulty assigned to the stimuli by the participants, and the average response times to get the jokes.Using general linear model, repeated measures ANOVA, highly significant main effects were found for repeated measure  and group  as well as a significant interaction of group by joke . Table Follow-up t-tests comparing individuals with schizophrenia to controls were highly significant for both the ToM condition (p < 0.0001) and the Physical condition (p < 0.001).Additionally, within both the patient and control groups, scores were significantly worse for ToM jokes than Physical jokes (p < 0.0001 for both groups). However, the significant interaction showed that the difference of 10.6 for the patient group was greater than that for the controls (5.6). Using the general linear model, ANCOVA, controlling for Physical joke score, a significant group difference on ToM joke scores was still evident, F = 19.5, p < 0.05.The two groups were well matched for age, IQ and sex, and any difference between them was shown to be insignificant by independent 2-tailed t-test (p > 0.1). It was unnecessary, therefore, to perform regression analyses to co-vary for these factors.It was found via independent T-test analysis that there was no significant difference between the schizophrenia patients and control participants' subjective ratings for humour and difficulty or between the average response times of correct responses p > 0.05). Results are summarized in Table . ResultsFurthermore, linear regression indicated that the order of presentation of the joke sets had no significant effect on ToM or Physical joke scores.Correlations were run to investigate the relationships between performances on ToM and Physical jokes and different symptom scores . These data are displayed in Table As stated, performance was not significantly reduced in association with increasing severity of positive or negative symptoms as a whole or delusions and hallucinations specifically.The features of depression, incoherence and poverty of speech were also analysed to see if they could be having an effect on the patients ToM and Physical joke performance but there were no significant findings.The converted equivalent daily chlorpromazine patient medication doses were correlated to performance and also found to be non significant for both cartoon conditions.This study showed that individuals with schizophrenia and normal IQ had a poorer understanding of both types of jokes (and at least a reduced ability to relay their humorous intent) than matched healthy controls. This is to be expected, as schizophrenia patients have previously been reported to show poor appreciation of humour . It seemHowever, the difference between the Physical and ToM joke scores was significantly greater for schizophrenia patients, than controls. This implies that it is some aspect of the schizophrenia disease process that is associated with ToM impairment in the patient group, rather than a general difficulty with appreciation of humour.If the schizophrenia group had a poorer understanding of the jokes then we would expect this to be reflected in the subjective gradings for humour and difficulty. As shown in table It was found that both groups found the ToM jokes significantly more difficult than the Physical ones. The former were certainly more detailed and by their very nature were comprised of characters in ToM scenarios. It could be that these jokes were more difficult to understand, but there was no significant difference between the response times of the two joke types for either group. Poor verbal report of mentalistic terms may be an intrinsic feature of schizophrenia and this could have resulted in this schizophrenia group's poor performance on this set of jokes.Language and thought are intrinsically linked and the question arises as to whether disordered verbalisation in schizophrenia is a speech disturbance only or part of a disorder in thinking . LikewisThis data suggests that, as predicted, schizophrenia patients have problems in interpreting the thoughts of others, supporting the findings of previous work . The cloThere is however an alternative interpretation to these results. The individuals with schizophrenia may not be showing a domain -specific difficulty with ToM function but rather may be performing differentially more poorly than the control group on the more difficult ToM condition, such that the observed deficit could reflect a differential sensitivity to increased task difficulty.When the obtained totals for positive Krawiecka symptoms were analysed it was found that there was not a significant relationship between higher positive symptomatology and poor ToM performance, contrary to what had been predicted. Closer scrutiny of individual positive symptoms also revealed that neither delusions, hallucinations nor speech incoherence were significantly linked to an impaired ToM performance. Previous studies have shown paranoid delusions to be significantly related to poor ToM performance, in both first and second order ToM tasks and in both verbal and pictorial paradigms ,28 32].  32. 28] These findings might be attributed to several individuals who despite scoring the maximum Krawiecka score (4) for delusions, hallucinations or both, performed similarly to controls in the ToM condition.Alternatively, perhaps the nature of our patients' delusions and hallucinations may not be those specifically implicated in ToM impairment. Unfortunately, our sample size was too small to allow further investigation of patients with different types of delusion. Unlike the findings of previous research, negative features of schizophrenia were not associated with ToM capabilities. However, the mean Krawiecka scores for these features were low within the subject group, and our number of subjects was relatively small.This study was limited especially for symptom sub-groups analyses, by its relatively small sample size, although we did find disease effects. With a large sample, further symptom-specific sub-groups could be made . Furthermore, another control group of non-schizophrenia, psychiatric patients may have been useful to explore more closely the role of diagnosis as opposed to symptoms. One of our previous studies used a psychiatric control group of patients with a psychotic affective disorder and found that positive psychotic symptomatology was linked to poor ToM performance and was not diagnosis specific . This imWe believe that the Physical cartoons themselves acted as an adequate internal control. If the schizophrenia group had performed as poorly on the Physical cartoons as they did on the ToM cartoons, this could imply either a general verbalization deficit or a general cognitive impairment. Since this was not the pattern found, our results count against a domain-general interpretation of this type. Furthermore, as mentioned previously, regression analysis showed no significant effect of language impairment, as assessed using the Krawiecka symptoms of poverty of speech and incoherence of speech, on ToM joke performance. ANCOVA also showed that the group differences on the ToM jokes could not be accounted for by the group differences on the Physical jokes. This was taken as evidence for an observable and selective compromise of ToM capacity within the schizophrenia group.However, an unrelated cognitive neuropsychological task could have been implemented testing another cognitive domain  and this could have been used to further elaborate whether the observed compromised ToM function was a specific deficit or secondary to general cognitive impairment .Further research is then required in ToM and schizophrenia to see whether the presence of schizophrenia itself is enough to impair ToM capabilities or whether ToM impairment is due, instead, to presence of particular symptoms or presence of some general neuropsychological deficit. A further question that we did not address at all in the present study was whether the ToM deficits observed in schizophrenia could be state (related to fluctuating symptom severity) or trait in nature.The schizophrenia group performed significantly worse in both the Physical and ToM conditions on this visual joke task than the matched control group. The performance on the ToM condition was significantly worse and is taken as evidence for a compromised ToM capability in the schizophrenia group which is in keeping with previous research. In this instance poor ToM performance could not be significantly linked to any particular symptomatology as had been hypothesised.The author(s) declare that they have no competing interests.DM conceived and designed the study, collected neuropsychological test data and drafted the manuscript. HT helped implement the study and collect neuropsychological test data and co wrote first draft. DMac and DCO were involved in the psychiatric ratings of the patients and revisions of later drafts. PM advised on statistical analysis and helped to write the corresponding sections. SL supervised clinical aspects of study and revised later drafts and ECJ revised final draft and approved this version to be published.The pre-publication history for this paper can be accessed here: