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Cecal duplication is a rare congenital malformation and majority of the cases are discovered in the first years of life. Ileocolic intussusception is also a rare situation encountered in adults. A 19-year-old female presented with acute abdominal pain and bowel occlusion in relation with an ileocecal intussusception. She underwent an emergent laparotomy and ileocecal resection. A cecal duplication cyst was found to be the cause of the intussusception. While duplications and intussusception are very rare situations encountered in the adult life, the presence of both at the same time remains frankly anecdotal. The present case demonstrates that intussusception may likely be involved with any cecal lesion, like duplication., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2022 Eric Bergeron and Normand Gervais.)

Negative selection of developing T cells plays a significant role in T-cell tolerance to self-antigen. This process relies on thymic antigen-presenting cells which express both self-antigens and cosignaling molecules. Inducible T-cell costimulator (ICOS) belongs to the CD28 family of cosignaling molecules and binds to ICOS ligand (ICOSL). The ICOS signaling pathway plays important roles in shaping the immune response to infections, but its role in central tolerance is less well understood. Here we show that ICOSL is expressed by subsets of thymic dendritic cells and medullary thymic epithelial cells as well as thymic B cells. ICOS expression is upregulated as T cells mature in the thymus and correlates with T-cell receptor signal strength during thymic selection. We also provide evidence of a role for ICOS signaling in mediating negative selection. Our findings suggest that ICOS may fine-tune T-cell receptor signals during thymic selection contributing to the generation of a tolerant T-cell population., (© 2021 The Authors. Immunology & Cell Biology published by John Wiley & Sons Australia, Ltd on behalf of Australian and New Zealand Society for Immunology, Inc.)

Background: The association between obstructive sleep apnea and cognitive functioning is not yet fully understood and could be influenced by factors such as sex, age and systemic inflammation. We determined the sex- and age-specific association between obstructive sleep apnea risk and cognitive performance, and the influence of systemic inflammation on this association., Methods: We included 25,899 participants from the Canadian Longitudinal Study of Aging comprehensive cohort, aged 45-85 years (51% women). We conducted sex- and age-specific (45-59; 60-69; ≥70) general linear models between obstructive sleep apnea risk and cognitive scores, and tested the moderating and mediating effects of high-sensitivity C-reactive protein levels. Obstructive sleep apnea risk was estimated by combining the STOP and whole-body fat percentage. Cognitive tests assessed episodic verbal memory, executive functions and psychomotor speed. Levels of high-sensitivity C-reactive protein were obtained through blood samples., Results: Higher obstructive sleep apnea risk was associated with poorer episodic memory in women aged 45-59 years, and poorer executive function (p < 0.05 on multiple tests) in women aged 45-59 and 60-69 years. No such association was found in men. High-sensitivity C-reactive protein levels mediated some associations between obstructive sleep apnea risk and executive function in women and men aged <70 years., Conclusions: Being at high-risk for obstructive sleep apnea is associated with poorer cognition in women aged <70 years. These associations were partly mediated by systemic inflammation. These results underscore the importance of obstructive sleep apnea diagnosis, treatment and appropriate follow-up, particularly in middle-aged women who might already show signs of early cognitive impairments., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Objective: To analyze the use of tranexamic acid (TXA) in postpartum patients since the World Maternal Antifibrinolytic (WOMAN) trial., Methods: A retrospective chart review was conducted from May 2017 to March 2020 at a tertiary care centre to identify all patients who received TXA for postpartum bleeding. The primary outcome was to identify the proportion of patients who received TXA as per World Health Organization guidelines created using results of the World Maternal Antifibrinolytic trial., Results: A total of 231 patients were included in our analysis. Use increased over time with 18 patients in 2017, 51 in 2018, and 134 in 2019 receiving TXA. In all, 203 patients (87.9%) received TXA within recommended guidelines, and these patients were less likely to require surgery or interventional radiology (12.3% vs. 42.9%, P < 0.001) or blood transfusion (23.6% vs. 42.9%, P = 0.030), and they had a lower likelihood of overall adverse outcomes (1.62 (1.6) vs. 2.60 (2.0), P = 0.024). TXA was commonly used as the first-line agent for postpartum bleeding (48.9% of patients), more likely administered at cesarean section (77.0%) and when estimated blood loss did not meet criteria for "true" postpartum hemorrhage (41.6% of patients). Use of TXA as the first medication was associated with fewer overall adverse outcomes than misoprostol (P = 0.035). A shorter time to administration of the first medication was associated with shorter postpartum admission time (P = 0.042)., Conclusions: The majority of patients received TXA within guidelines and experienced fewer adverse outcomes. Further study is needed to identify the best order of TXA administration with additional uterotonics and whether TXA should be used prophylactically in some groups for postpartum bleeding., (Crown Copyright © 2021. Published by Elsevier Inc. All rights reserved.)

Objective: The primary objective of this clinical practice guideline is to provide gynaecologists with an algorithm and evidence to guide the use of thromboprophylaxis in gynaecological surgery., Target Population: All patients undergoing gynaecological surgery for benign or malignant indications., Benefits, Harms, and Costs: The implementation of this guideline will benefit patients undergoing gynaecological surgery and provide physicians with a standard algorithm for the use of perioperative thromboprophylaxis., Evidence: The following search terms were entered into MEDLINE, Google Scholar, and Cochrane in 2017 and 2018: VTE, PE, DVT, thromboprophylaxis, gynaecological surgery, heparin, graduated compression stocking, intermittent pneumatic stocking, obesity, pediatrics, minimally invasive surgery, heparin induced thrombocytopenia, regional anesthesia). Articles included were randomized controlled trials, meta-analyses, systematic reviews, and observational studies. Additional publications were identified from the reference lists of these articles. There were no date limits, but search results were limited to English language articles only. Searches were updated and incorporated into the guideline up to September 2018., Validation Methods: The authors rated the quality of evidence and strength of recommendations using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. See online Appendix A (Tables A1 for definitions and A2 for interpretations of strong and weak recommendations)., Intended Users: Gynaecologists and other members of the surgical team. RECOMMENDATIONS (GRADE RATINGS IN PARENTHESES)., (Copyright © 2021. Published by Elsevier Inc.)

Purpose: Although relatively unknown within the field of rehabilitation, qualitative longitudinal research is ideal for rehabilitation and disability research that aims to understand health-related challenges over time. We describe the strengths and challenges of longitudinal qualitative research using two concrete examples. Materials and methods: Qualitative longitudinal research often involves in-depth interviews of participants on multiple occasions over time. Analytic approaches are complex, summarizing data both cross-sectionally and longitudinally. We present two detailed analytic approaches used in research with people living with HIV in Zambia and Canada. Results: Our experiences provide three recommendations. First, development of the initial analytic coding framework should include both inductive and deductive approaches. Second, given the large quantity of data generated through longitudinal qualitative research, it is important to proactively develop strategies for data analysis and management. Third, as retention of participants is challenging over time, we recommend the use of a consistent interviewer over the duration of the study to promote a trusting relationship. Conclusions: Longitudinal qualitative research has much to offer researchers and can provide clinicians with insights on the challenges of living with chronic and episodic disability. The flexibility in analytic approaches allows for diverse strategies to best address the rehabilitation and disability research questions and allow for insights into living with disability over time.

Objective: Rates of cannabis use during pregnancy and while breastfeeding are increasing in Canada. Some observational studies have found associations between cannabis use in pregnancy and low birthweight, preterm labour, and admission to the intensive care unit. This study aimed to evaluate women's perceptions about transmission of cannabis to the fetus, and whether receiving information from a health care provider influenced their decision to stop using cannabis during pregnancy., Methods: Pregnant women presenting to obstetrical, midwifery, and family practice clinics in the greater Hamilton, Ontario area were asked to complete an anonymous survey. Chi-square tests were used to investigate whether patient knowledge was influenced by health care providers or by self-directed learning and if this information influenced their decision to discontinue cannabis use., Results: Of the 478 women surveyed, the vast majority perceived that cannabis is transmitted to the fetus during pregnancy and to the infant while breastfeeding (94.3% and 91.2%, respectively). The majority of women (99%) indicated that the advent of cannabis legalization did not influence their choice to use cannabis in pregnancy. Women who continued to use cannabis during pregnancy were more likely to report receiving information on cannabis from a health care provider (52%) than those who chose to discontinue use in pregnancy (35%) (P = 0.035)., Conclusions: In our study, the proportion of pregnant women who understood that cannabis could be transmitted to the fetus in utero and to the infant via breastmilk was high. Despite this, 4.2% of women reported that they continued to use cannabis in pregnancy. More work is needed to understand why some women continue to use cannabis in pregnancy despite being informed of its risks., (Copyright © 2020 The Society of Obstetricians and Gynaecologists of Canada/La Société des obstétriciens et gynécologues du Canada. Published by Elsevier Inc. All rights reserved.)

Objective: To determine the reproductive outcomes resulting from transfer of lower-grade blastocysts to support the practice of cryopreserving and transferring lower-grade embryos., Design: Retrospective chart review., Setting: Single infertility center., Patients: Women who have undergone a fresh (n = 570) or frozen (n = 885) transfer of a single blastocyst embryo between December 2013 and December 2018., Interventions: None., Main Outcome Measures: The primary outcome was live birth rate. The secondary outcomes included implantation rate, ongoing pregnancy rate, associations with inner cell mass (ICM) and trophectoderm epithelium (TE) grades determined by morphological assessment, and antenatal/perinatal complications., Results: Reproductive outcomes directly correlated with embryo quality. Transfers of AA embryos resulted in a 41.4% live birth rate compared to 31.1% for BB embryos and 13.3% for CC embryos. The TE grade was significantly associated with the live birth rate. Embryos with a TE grade of "B" had an odds ratio of 0.677 and embryos with a TE grade of "C" had an odds ratio of 0.394 compared to embryos with a TE grade of "A" for live birth., Conclusion: Embryos with a TE "C" grade should be considered for transfer and cryopreservation, as they are shown to result in appreciable live birth rates. Such treatment should involve a thorough discussion with patients, however, as these live birth rates are significantly lower than those associated with higher-grade embryos., (Crown Copyright © 2020 Published by Elsevier Inc. on behalf of American Society for Reproductive Medicine.)

Rationale, Aims, and Objectives: A comprehensive electronic guide (e-module) describing an interprofessional, evidence-informed approach to HIV rehabilitation was developed as an education resource for rehabilitation professionals. We developed a guideline implementation tool, consisting of a 10-week, case-based education intervention delivered by email, that was perceived to increase rehabilitation professionals' (occupational therapists (OTs), physical therapists (PTs), and speech language pathologists (SLPs)) knowledge and confidence to apply best practices in HIV rehabilitation. This study aimed to increase understanding of how the design of the guideline implementation tool facilitated increased awareness of and access to the e-module among rehabilitation professionals., Methods: We conducted a single group intervention study with rehabilitation professionals in Canada and the United Kingdom. Six case studies targeting HIV pathophysiology and associated conditions, an interprofessional approach to rehabilitation assessment and treatment, and psychosocial issues experienced by people living with HIV, were emailed to participants at 2-week intervals. Individual semi-structured interviews were conducted post-intervention. Interview transcripts were analysed using a descriptive qualitative approach., Results: Twenty-six individuals (17 from Canada, and 9 from the UK; 16 PTs, 7 OTs, 3 SLPs) were interviewed. One main theme related to design features of the intervention that facilitated learning and access to the e-module emerged. Subthemes highlighted features of the case-based intervention, including technical feasibility, terminology, formatting and layout, hyperlinks, number and frequency of case studies, and diverse and realistic case scenarios relevant to the learner's practice, that participants described as facilitating access to information and learning., Conclusion: Electronically administered case studies were perceived as complementary knowledge tools that increased access to an evidence-informed guide to HIV rehabilitation. Findings provide guidance on using case studies as a guideline implementation tool to facilitate access to information and related resources to optimize learning., (© 2018 John Wiley & Sons, Ltd.)

We qualitatively evaluated a novel educational program to help people living with HIV understand the role of rehabilitation, facilitate access to rehabilitation, and promote self-management of chronic disease in Canada. The program incorporated components of self-efficacy, client-centered care, peer education, and problem-based learning. Delivery of the community-engaged program was viewed as feasible and acceptable; however, a flexible delivery model was deemed important. Perceived learning was related to rehabilitation, advocacy, and taking responsibility for one's health. A co-leader model and access to online resources were strengths. Future work should assess the ability to apply advocacy knowledge and skills to access rehabilitation services.

Objective: The objective of this study is to describe the collaborative development of a rehabilitation guide for people living with human immunodeficiency virus (HIV) which was adapted from an online resource for clinicians., Methods: We adapted a comprehensive evidence-informed online clinical resource for people living with HIV using a three-phase participatory process. In Phase 1, we interviewed 26 clinicians and 16 people living with HIV to gather recommendations on how to adapt and format the content to benefit people living with HIV. In Phase 2, we adapted the patient education resource using the recommendations that emerged from Phase 1. Phase 3 consisted of comprehensive stakeholder review of the revised resource on the adaptability, usability, communicability, and relevance of the information. Stakeholders participated in an interview to obtain in-depth information on their perspectives. Transcribed interviews underwent qualitative content analysis., Results: Stakeholders indicated that the e-guide had utility for people living with HIV, community HIV service organizations, and care providers., Conclusion: Engaging people living with HIV resulted in a more relevant and meaningful resource that incorporated patients' values, needs, and preferences., Implications: Involving multiple stakeholders and user groups in the adaptation and evaluation of online patient education resources can assist in meeting patients' needs through increasing the relevance, organization and presentation of the content, and incorporating patients' values and needs. Implications for Rehabilitation Online patient education resources should be adapted in order to maximize relevance and meaningfulness to patients. Involving multiple stakeholders in the adaptation and evaluation of online patient education resources can assist in meeting patients' needs. Involving multiple stakeholders increases the relevance, organization and presentation of the content and allows the incorporation of patient values and needs. This collaborative approach with an emphasis on meaningful participation of patients and community may be of interest to others interested in promoting knowledge translation.

Objectives: To examine the episodic disability experiences of older women living with HIV over time., Design: Qualitative longitudinal study, conducting semistructured in-depth interviews on four occasions over a 20-month time frame. Inductive thematic analyses were conducted cross-sectionally and longitudinally., Setting: Participants were recruited from HIV community organisations in Canada., Participants: 10 women aged 50 years or older living with HIV for more than 6 years., Results: Two major themes related to the episodic nature of the women's disability. Women were living with multiple and complex sources of uncertainty over time including: unpredictable health challenges, worrying about cognition, unreliable weather, fearing stigma and the effects of disclosure, maintaining housing and adequate finances, and fulfilling gendered and family roles. Women describe strategies to deal with uncertainty over time including withdrawing and limiting activities and participation and engaging in meaningful activities., Conclusions: This longitudinal study highlighted the disabling effects of HIV over time in which unpredictable fluctuations in illness and health resulted in uncertainty and worrying about the future. Environmental factors, such as stigma and weather, may put older women living with HIV at a greater risk for social isolation. Strategies to promote dealing with uncertainty and building resilience are warranted., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

As people living with HIV (PLWH) live longer, increased understanding of individuals' values and perceptions of successful aging can assist health providers in working with PLWH to set meaningful goals as they age. The purpose of this qualitative study was to understand how PLWH define successful aging and their perceptions of contributors to successful aging. Fourteen men and ten women over the age of 50 years (mean age 57 years; mean time since diagnosis 18 years) participated in individual interviews. Interviews were analyzed using directed content analysis. Six themes emerged: accepting limitations, staying positive, maintaining social supports, taking responsibility, living a healthy lifestyle, and engaging in meaningful activities. The participants emphasized individual control. This highlights the importance of working with PLWH to understand their values and aspirations, and create patient-centered goals. From a research perspective this reinforces calls to include the subjective experiences of older adults in developing successful aging criteria.

People living with HIV may experience disability which is episodic in nature, characterized by periods of wellness and illness. The purpose of this longitudinal qualitative study was to understand how the episodic nature of HIV and the associated uncertainty shape the disability experience of older adults living with HIV over time. Fourteen men and 10 women who were HIV positive and over 50 years (mean age: 57 years; range: 50-73) participated in 4 interviews over 20 months. Longitudinal analyses of the transcribed interviews identified 4 phenotypes of episodic disability over time: decreasing, increasing, stable, or significant fluctuations. Although all participants experienced uncertainty, acceptance and optimism were hallmarks of those whose phenotypes were stable or improved over time. Understanding a person's episodic trajectory may help to tailor interventions to promote stability, mitigate an upward trajectory of increasing disability, and increase the time between episodes of illness.

Improvement on spatial tasks is observed during a late, postnatal developmental period (PND18 - PND24).  The purpose of the current work was 1) to determine whether the emergence of spatial-behavioral function was based on the ability to generate appropriate behavioral output; 2) to assess whether mossy fiber connectivity patterns preceded the emergence of spatial-behavioral function; 3) to explore functional changes in the hippocampus to determine whether activity in hippocampal networks occurred in a training-dependent or developmentally-dependent fashion.  To these ends, male, Long Evans rats were trained on a spatial water or dry maze task for one day (PND16, PND18 or PND20) then euthanized.  Training on these 2 tasks with opposing behavioral demands (swimming versus exploration) was hypothesized to control for behavioral topology.  Only at PND20 was there evidence of spatial-behavioral function for both tasks.  Examination of synaptophysin staining in the CA3 region (i.e., mossy fiber projections) revealed enhanced connectivity patterns that preceded the emergence of spatial behavior.  Analysis of c-Fos labeling (functional changes) revealed developmentally-dependent increases in c-Fos positive cells in the dentate gyrus, CA3 and CA1 regions whereas training-dependent increases were noted in the CA3 and CA1 regions for the water-maze trained groups.  Results suggest that changes in mossy fiber connectivity in association with enhanced hippocampal functioning precede the emergence of spatial behavior observed at PND20.  The combination of neuroanatomical and behavioural results confirms the hypothesis that this time represents a sensitive period for hippocampal development and modification and the emergence of spatial/ cognitive function.

Background: Hepatocellular carcinoma (HCC) is one of the most deadly cancers in the world and its incidence rate has consistently increased over the past 15 years in Canada. Although transarterial embolization therapies are palliative options commonly used for the treatment of HCC, their efficacy is still controversial. The objective of this guideline is to review the efficacy and safety of transarterial embolization therapies for the treatment of HCC and to develop evidence-based recommendations., Method: A review of the scientific literature published up to October 2013 was performed. A total of 38 studies were included., Recommendations: Considering the evidence available to date, the CEPO recommends the following: (i) transarterial chemoembolization therapy (TACE) be considered a standard of practice for the palliative treatment of HCC in eligible patients; (ii) drug-eluting beads (DEB)-TACE be considered an alternative and equivalent treatment to conventional TACE in terms of oncological efficacy (overall survival) and incidence of severe toxicities; (iii) the decision to treat with TACE or DEB-TACE be discussed in tumour boards; (iv) bland embolization (TAE) not be considered for the treatment of HCC; (v) radioembolization (TARE) not be considered outside of a clinical trial setting; and (vi) sorafenib combined with TACE not be considered outside of a clinical trial setting., (© 2014 International Hepato-Pancreato-Biliary Association.)

The purpose of this qualitative study was to develop a theoretical model describing the disability experienced by older adults living with HIV. Forty nine HIV positive men and women over the age of 50 years participated in in-depth qualitative interviews. Transcribed interviews were analyzed using grounded theory techniques. Uncertainty or worrying about the future was at the core of the model. Components of disability including symptoms and impairments, difficulties with day to day activities and challenges to social participation were experienced in the context of extrinsic or environmental factors (social support, stigma) and intrinsic contextual factors (positive living strategies, age). Time was an overarching component of the model. The model suggests areas for interventions to prevent or reduce disability related to the consequences of aging with HIV and improve overall quality of life., (© The Author(s) 2014.)

Due to advances in treatment, people with HIV are living longer and developing disabilities related to the virus, adverse side effects of medications, and aging. Illness-related uncertainty has been shown to contribute to disablement; however, there is little understanding of the uncertainties related to aging with HIV. The purpose of this research was to describe the contribution of uncertainty to the disability experienced by older adults living with HIV. Forty-nine men and women living with HIV and 50 years or older participated in in-depth qualitative interviews exploring various aspects of social participation and disability. Transcriptions of the interviews were analyzed using a grounded theory approach. Age-related uncertainties were described in the following themes: source of health challenge; health providers' age-related knowledge and skills; financial uncertainty; transition to retirement; appropriate long-term housing, and uncertainty over who would care for them. While not directly attributable to aging, the episodic nature of HIV left many with uncertainties related to when their next episode of illness would occur and often resulted in an inability to plan in advance. Results highlight the need to focus on the notion of successful and positive aging with the view to identifying effective interventions that reduce disability and enhance the overall health of older adults with HIV. This work builds on previous studies highlighting the role of uncertainty in the disability experience by identifying age-related components specific to older adults aging with HIV.

Objective: Despite the very good prognosis of endometrial cancer, a number of patients with localized disease relapse following surgery. Therefore, various adjuvant therapeutic approaches have been studied. The objective of this review is to evaluate the efficacy and safety of neoadjuvant and adjuvant therapies in patients with resectable endometrial cancer and to develop evidence-based recommendations., Methods: A review of the scientific literature published between January 1990 and June 2012 was performed. The search was limited to published phase III clinical trials and meta-analyses evaluating the efficacy of neoadjuvant or adjuvant therapies in patients with endometrial carcinoma or carcinosarcoma. A total of 23 studies and five meta-analyses were identified., Results: The selected literature showed that in patients with a low risk of recurrence, post-surgical observation is safe and recommended in most cases. There are several therapeutic modalities available for treatment of endometrial cancers with higher risk of recurrence, including vaginal brachytherapy, external beam radiotherapy, chemotherapy, or a combination of these., Conclusions: Considering the evidence available to date, the CEPO recommends the following: (1)post-surgical observation for most patients with a low recurrence risk; (2)adjuvant vaginal brachytherapy for patients with an intermediate recurrence risk; (3)adjuvant pelvic radiotherapy with or without vaginal brachytherapy for patients with a high recurrence risk; addition of adjuvant chemotherapy may be considered as an option for selected patients (excellent functional status, no significant co-morbidities, poor prognostic factors); (4)adjuvant chemotherapy and pelvic radiotherapy with or without brachytherapy and para-aortic irradiation for patients with advanced disease;, (© 2013.)

Background: Adoption of the laparoscopic approach for colorectal cancer treatment has been slow owing to initial case study results suggesting high recurrence rates at port sites. The use of laparoscopic surgery for colorectal cancer still raises a number of concerns, particularly with the technique's complexity, learning curve and longer duration. After exploring the scientific literature comparing open and laparoscopic surgery for the treatment of colorectal cancer with respect to oncologic efficacy and shortterm outcomes, the Comité de l'évolution des pratiques en oncologie (CEPO) made recommendations for surgical practice in Quebec., Methods: Scientific literature published from January 1995 to April 2012 was reviewed. Phase III clinical trials and meta-analyses were included., Results: Sixteen randomized trials and 10 meta-analyses were retrieved. Analysis of the literature confirmed that for curative treatment of colorectal cancer, laparoscopy is not inferior to open surgery with respect to survival and recurrence rates. Moreover, laparoscopic surgery provides short-term advantages, including a shorter hospital stay, reduced analgesic use and faster recovery of intestinal function. However, this approach does require a longer operative time., Conclusion: Considering the evidence, the CEPO recommends that laparoscopic resection be considered an option for the curative treatment of colon and rectal cancer; that decisions regarding surgical approach take into consideration surgeon experience, tumour stage, potential contraindications and patient expectations; and that laparoscopic resection for rectal cancer be performed only by appropriately trained surgeons who perform a sufficient volume annually to maintain competence.

Objectives: To establish how aware Belgian emergency physicians are of common treatment costs and radiation doses., Materials and Methods: Using a questionnaire survey on a voluntary basis, 60 emergency physicians from four universities and four district hospitals were asked to estimate treatment costs and radiation doses involved in the management of a patient with pulmonary embolism. The responses of permanent and resident physicians were then compared with actual data defined by the Belgian legislation. Physicians' error was calculated as a percentage of the real value using the formula [(real-estimated)/real]×100., Results: Fifty questionnaires were fully completed and analysed. Estimated costs of diagnostic procedures (chest radiograph, ECG, pulmonary-computed tomography, Doppler legs, cardiac ultrasound, ventilation/perfusion scintigraphy), laboratory tests (standard, D-dimers, arterial blood gases), drugs (alteplase, enoxiparine, acenocoumarol) and hospitalization (emergency department, intensive care and pneumology units) were within 25% of real costs for 38, 14, 18 and 30%, respectively, of permanent physicians and 31, 12, 8 and 27% of resident physicians. Drug prices were generally largely overestimated.Mean error of the physicians' estimates of the radiation dose of imaging modalities (chest radiograph, computed tomography and scintigraphy) was 1805% for permanent physicians versus 4997% for resident physicians. There was no significant difference between the two groups for the different items studied., Conclusion: Emergency doctors, whether permanent physicians or resident physicians, have a limited knowledge of both costs and radiation doses of investigations and treatments they prescribe every day.

During sleep, warm-blooded animals exhibit cyclic alternations between rapid-eye-movement (REM) and nonrapid-eye-movement (non-REM) states, characterized by distinct patterns of brain activity apparent in electroencephalographic (EEG) recordings coupled with corresponding changes in physiological measures, including body temperature. Recently we have shown that urethane-anesthetized rats display cyclic alternations between an activated state and a deactivated state that are highly similar in both EEG and physiological characteristics to REM and non-REM sleep states, respectively. Here, using intracranial local field potential recordings from urethane-anesthetized rats, we show that brain-state alternations were correlated to core temperature fluctuations induced using a feedback-controlled heating system. Activated (REM-like) states predominated during the rising phase of the temperature cycle, whereas deactivated (non-REM-like) states predominated during the falling phase. Brain-state alternations persisted following the elimination of core temperature fluctuations by the use of a constant heating protocol, but the timing and rhythmicity of state alternations were altered. In contrast, thermal fluctuations applied to the ventral surface (and especially the scrotum) of rats in the absence or independently of core temperature fluctuations appeared to induce brain-state alternations. Heating brought about activated patterns, whereas cooling produced deactivated patterns. This shows that although alternations of sleeplike brain states under urethane anesthesia can be independent of imposed temperature variations, they can also be entrained through the activation of peripheral thermoreceptors. Overall, these results imply that brain state and bodily metabolism are highly related during unconsciousness and that the brain mechanisms underlying sleep cycling and thermoregulation likely represent independent, yet coupled oscillators.

Polycythemia vera (PV) is an acquired myeloproliferative disorder with primary expansion of the red cell mass leading to an increased risk of thrombosis and less frequently to myelofibrosis and secondary acute leukemia. Standard therapies include cytoreduction with either phlebotomy or chemotherapeutic agents and antithrombotic drugs. Because long-term exposure to cytotoxic chemotherapy may increase the risk of acute transformation, new therapeutic options are needed. Tipifarnib is a nonpeptidomimetic inhibitor of farnesyl transferase that was developed as a potential inhibitor of RAS signaling. In the present study we report that tipifarnib used at pharmacologically achievable concentrations strongly inhibits the erythroid burst-forming unit (BFU-E) autonomous growth that characterizes patients with PV. Moreover, at low tipifarnib concentrations (0.15 muM), the inhibitory effect was preferentially observed in PV BFU-E progenitors and not in normal BFU-E progenitors and was not rescued by erythropoietin (EPO). Thus tipifarnib may specifically target PV stem cells and may be of clinical interest in the treatment of patients with PV.

Angioedema (AE) is a rare but potentially life-threatening side effect of therapy with inhibitors of angiotensin-converting enzyme (ACE), the main bradykinin (BK)- inactivating metallopeptidase in humans. The pathogenesis of ACE inhibitor (ACEi)- associated AE (AE+) is presently unknown, although there is increasing evidence of a kinin role. We analyzed the metabolism of endogenous BK (B(2) receptor agonist) and its active metabolite, des-Arg(9)-BK (B(1) receptor agonist), in the presence of an ACEi during in vitro contact activation of plasma from hypertensive patients (n = 39) who presented AE+. Kinetic parameters were compared with those measured in a control group (AE-) of hypertensive patients (n = 39) who never manifested any acute or chronic side effects while treated with an ACEi. The different kinetic parameters were analyzed using a mathematical model (y = k t(alpha) e(-beta t)) previously applied to a normal, healthy population. The slope of BK degradation, but not its formation from high-molecular-weight kininogen, was lower in AE+ patients when compared with the AE- controls. des-Arg(9)-BK accumulation during the kinetic measurements was significantly higher in AE+ plasma. This accumulation of the B(1) agonist in AE+ patients paralleled its half-life of degradation. In conclusion, our results show, for the first time, that an abnormality of endogenous des-Arg(9)-BK degradation exists in the plasma of patients with ACEi-associated AE, suggesting that its pathogenetic mechanism lies in the catabolic site of kinin metabolism.

Object: Selective posterior rhizotomy (SPR) may result in considerable benefit for children with spastic cerebral palsy. To date, however, there have been few studies in which validated functional outcome measures have been used to report surgical results beyond 3 years. The authors analyzed data obtained from the McGill Rhizotomy Database to determine long-term functional performance outcomes in patients who underwent lumbosacral dorsal rhizotomy performed using intraoperative electrophysiological monitoring., Methods: The study population was composed of children with debilitating spasticity who underwent SPR and were evaluated by a multidisciplinary team preoperatively and at 6 months and 1 year postoperatively. Quantitative standardized assessments of activities of daily living (ADL) were obtained using the Pediatric Evaluation of Disability Inventory (PEDI). Of 57 patients who met the entry criteria for the study, 41 completed the 3-year assessments and 30 completed the 5-year assessments. Statistical analysis demonstrated significant improvement in the mobility and self-care domains of the functional skills dimension at 1 year after SPR. The preoperative and 1-, 3-, and 5-year postoperative scaled scores for the mobility domain were 56, 64, 77.2, and 77.8, respectively. The scaled score for the self-care domain increased from 59 presurgery to 67.9, 81.6, and 82.4 at the 1-, 3-, and 5-year postoperative assessments, respectively., Conclusions: The results of this study support the presence of significant improvements in functional performance, based on PEDI scores obtained 1 year after SPR. The improvements persisted at the 3- and 5-year follow-up examinations. The authors conclude that SPR performed using intraoperative stimulation is valuable in the augmentation of motor function and self-care skills essential to the performance of ADL.

Background: Angioedema has been reported during recombinant tissue plasminogen activator (rtPA) treatment of acute ischemic stroke, often with concomitant use of angiotensin I-converting enzyme inhibitor treatment. Angioedema has been partly attributed to the nonapeptide bradykinin (BK), although its precise role has been poorly documented until now. The purposes of this report are 2-fold. First, we sought to define and characterize the in vitro kinin-forming capacity of rtPA when incubated with human plasma at a concentration within the therapeutic concentration range of rtPA attained in blood in vivo during fibrinolysis. Second, we sought to define the mechanism by which rtPA liberates BK from purified human single-chain high-molecular-weight kininogen, a key constituent of the contact system of plasma and the precursor of BK., Summary of Report: When incubated with human plasma, in the presence of an angiotensin I-converting enzyme inhibitor, rtPA generates BK, which is further metabolized to des-Arg9-BK. The quantity of kinins generated by rtPA is similar to that observed during the activation of the contact system of plasma with a negatively charged surface, suggesting that it is physiologically relevant. The total amount of des-Arg9-BK liberated during the incubation period depends on the aminopeptidase P activity, its main degrading peptidase. Additionally, incubations using purified proteins of the fibrinolytic and the contact system pathways show that the rtPA kinin-forming capacity is mediated by plasmin., Conclusions: We conclude that rtPA used in vitro at a therapeutic concentration has the capacity to generate significant quantities of kinins from human plasma. This kinin-forming activity depends on the activation of the fibrinolytic pathway. These data suggest that angioedema associated with rtPA treatment of ischemic stroke results directly from plasmin-mediated release of BK.

Suprasegmental effects following selective posterior rhizotomy have been frequently reported. However, few studies have used validated functional outcome measures to report the surgical results beyond 3 years. The authors analyzed data obtained from the McGill Rhizotomy Database to determine the long-term impact of lumbosacral dorsal rhizotomy on fine motor skills. The study population comprised children with debilitating spasticity who underwent SPR and were evaluated by a multidisciplinary team preoperatively, at 6 months and 1 year postoperatively. Quantitative standardized assessments of upper extremity function were obtained using the fine motor skills section of the Peabody Developmental Motor Scales (PDMS) test. Of 70 patients who met the entry criteria for the study, 45 and 25 completed the 3- and 5-year assessments, respectively. Statistical analysis demonstrated significant improvements in grasping, hand use, eye-hand coordination, and manual dexterity at 1 year after SPR. More importantly, all improvements were maintained at 3 and 5 years following SPR. This study supports that significant improvements in upper extremity fine motor function using the PDMS evaluative measure are present after SPR and that these suprasegmental benefits are durable., (Copyright 2002 S. Karger AG, Basel)

In the serum of 116 healthy individuals, exogenous bradykinin (BK) half-life (27 +/- 10 s) was lower than that of des-Arg(9)-BK (643 +/- 436 s) and was statistically different in men compared with women. The potentiating effect of an angiotensin-converting enzyme (ACE) inhibitor was, however, more extensive for BK (9.0-fold) than for des-Arg(9)-BK (2.2- fold). The activities of ACE, aminopeptidase P (APP), and kininase I were respectively 44 +/- 12, 22 +/- 9, and 62 +/- 10 nmol x min(-1) x ml(-1). A mathematical model (y = kt(alpha)e(-beta t), t > 0), applied to the BK kinetically released from endogenous high-molecular-weight kininogen (HK) during plasma activation in the presence of an ACE inhibitor, revealed a significant difference in the rate of formation of BK between men and women. For des-Arg(9)-BK, the active metabolite of BK, the rate of degradation was higher in women compared with men, correlating significantly with serum APP activity (r(2) = 0.6485, P < 0.001). In conclusion, these results constitute a basis for future pathophysiological studies of inflammatory processes where activation of the contact system of plasma and the kinins is involved.

The purposes of this study were to evaluate and to compare the effects of simultaneous angiotensin-converting enzyme (ACE) and neutral endopeptidase 24.11 (NEP) inhibition by the vasopeptidase inhibitor omapatrilat (1 mg. kg(-1). day(-1)) with those of the selective ACE inhibitor enalapril (1 mg. kg(-1). day(-1)) on survival, cardiac hemodynamics, and bradykinin (BK) and des-Arg(9)-BK levels in cardiac tissues 24 h after myocardial infarction (MI) in rats. The effect of the co-administration of both B(1) and B(2) kinin receptor antagonists (2.5 mg. kg(-1). day(-1) each) with metallopeptidase inhibitors was also evaluated. The pharmacological treatments were infused subcutaneously using micro-osmotic pumps for 5 days starting 4 days before the ligation of the left coronary artery. Immunoreactive kinins were quantified by highly sensitive and specific competitive enzyme immunoassays. The post-MI mortality of untreated rats with a large MI was high; 74% of rats dying prior to the hemodynamic study. Mortality in the other MI groups was not significantly different from that of the untreated MI rats. Cardiac BK levels were not significantly different in the MI vehicle-treated group compared with the sham-operated rats. Both omapatrilat and enalapril treatments of MI rats significantly increased cardiac BK concentrations compared with the sham-operated group (P < 0.05). However, cardiac BK levels were significantly increased only in the MI omapatrilat-treated rats compared with the MI vehicle-treated group (P < 0.01). Cardiac des-Arg(9)-BK concentrations were not significantly modified by MI, and MI with omapatrilat or enalapril treatment compared with the sham-operated group. The co-administration of both kinin receptor antagonists with MI omapatrilat- and enalapril-treated rats had no significant effect on cardiac BK and des-Arg(9)-BK levels. Thus, the significant increase of cardiac BK concentrations by omapatrilat could be related to a biochemical or a cardiac hemodynamic parameter on early (24 h) post-MI state.

Background: Severe hypotensive reactions have been described after the transfusion of platelets or red cells through negatively-charged bedside white cell-reduction filters. The possibility of a role for bradykinin (BK) in the genesis of these reactions has been raised., Study Design and Methods: To understand if an anomaly of BK metabolism is associated with these reactions, the metabolism of BK and des-Arg9-BK was studied in the sera of four patients who presented with a severe hypotensive transfusion reaction. Tests were performed in the absence and the presence of complete in vitro inhibition of angiotensin-converting enzyme (ACE) activity by enalaprilat., Results: In the presence of ACE inhibition (enalaprilat), the half-life (t1/2) of BK measured in the sera of patients who presented with a severe hypotensive transfusion reaction (361 +/- 90 sec) was not significantly different from that measured in the sera of normal controls (249 +/- 16 sec). In the presence of ACE inhibition (enalaprilat), the t1/2 of des-Arg9-BK was significantly greater in patients who presented with a severe hypotensive transfusion reaction (1549 +/- 319 sec) than in normal controls (661 +/- 38 sec) (p < 0.001)., Conclusion: A metabolic anomaly mainly affecting the degradation of des-Arg9-BK could be responsible for its accumulation in vivo. Des-Arg9-BK could be responsible, at least in part, for severe hypotensive transfusion reactions.

Angioedema (AE) associated with angiotensin-converting enzyme inhibitors (ACEi) is a rare, but potentially life-threatening adverse reaction. Several studies have suggested that bradykinin (BK) is responsible for ACEi-induced AE, but the mechanism remains unclear. We investigated the metabolism of BK and des-Arg9-BK in the serum of 20 patients with a history of ACEi-associated AE and 21 control (C) subjects. Synthetic BK was incubated with the sera for various periods of time and residual BK and generated des-Arg9-BK were quantified by specific and sensitive enzyme immunoassays. No significant difference of half-life (t1/2) of both BK and des-Arg9-BK could be measured between C subjects and patients with AE (AE) in absence of ACEi. However, an analysis according to the prolonged (+) or not (-) t1/2 of des-Arg9-BK allowed a new stratification of C subjects and AE patients in four subgroups. The preincubation of sera with enalaprilat at a concentration inhibiting ACE significantly prevented the rapid degradation of BK and des-Arg9-BK in these four subgroups. In presence of ACEi, a subgroup (50%) of AE patients (AE + ) had a particularly significant rise of the t1/2 of des-Arg9-BK. Once ACE was inhibited, the concentration or the nature of the ACEi had no significant effect on the t1/2 of des-Arg9-BK. However, a test dilution of AE + sera with a control (C) serum showed that an enzyme defect rather than a circulating inhibitor could be responsible for the abnormal metabolism of des-Arg9-BK when ACE is inhibited. In conclusion, half of the patients with ACEi-associated AE present in serum had an enzyme defect involved in the des-Arg9-BK metabolism leading to its accumulation. The B1 agonist could be responsible, at least in part, for the local inflammatory reaction associated with the AE.

The role of angiotensin-converting enzyme (ACE) in the metabolism of bradykinin (BK) has been studied in several tissues. However, and contrary to angiotensin I, the metabolism of BK at the cardiac level has not been investigated. In this study, we define the participation of ACE in the carboxy-terminal degradation of BK in heart membranes of the dog, human, rabbit, and rat. The calculation of the kinetic parameters characterizing the metabolism of BK and the generated des-Arg9-BK can be summarized as follows: the half-life (t1/2) of BK [dog (218 +/- 32 s) > human (143 +/- 9 s) = rat (150 +/- 4 s) > rabbit (22 +/- 2 s)] and of des-Arg9-BK [dog (1,042 +/- 40 s) > human (891 +/- 87 s) > rat (621 +/- 65 s) > rabbit (89 +/- 8 s)] both showed significant differences according to species. Enalaprilat, an ACE inhibitor, significantly prevented the rapid degradation of BK and des-Arg9-BK in all species studied, whereas retrothiorphan, a neutral endopeptidase inhibitor, and losartan, an angiotensin II type I receptor antagonist, did not affect this metabolism. The relative importance of ACE in the cardiac metabolism of BK was species related: dog (68.4 +/- 3.2%) = human (72.2 +/- 2.0%) > rabbit (47.7 +/- 5.0%) = rat (45.3 +/- 3.9%). ACE participation in the metabolism of des-Arg9-BK was as follows: rabbit (57.0 +/- 4.0%) > dog (39.9 +/- 8.8%) = human (25.4 +/- 5.5%) = rat (36.0 +/- 7.0%). The participation of cardiac kininase I (carboxypeptidase M) in the transformation of BK into des-Arg9-BK was minor: human (2.6 +/- 0.1%) > dog (0.9 +/- 0.1%) = rabbit (1.0 +/- 0.1%) = rat (1.0 +/- 0.1%). These results demonstrate that ACE is the major BK-degrading enzyme in cardiac membranes. However, the metabolism of exogenous BK by heart membranes is species dependent. Our observations could explain some discrepancies regarding the contribution of kinins in the cardioprotective effects of ACE inhibitors.

Among the different enzymes responsible for the metabolism of bradykinin (BK), three peptidases look relevant in vivo: kininase I (KI), which transforms BK into its active metabolite, [des-Arg9]BK; kininase II (KII); and neutral endopeptidase, which inactivate BK and [des-Arg9]BK. The in vitro incubation of BK and [des-Arg9]BK in the serum of four species with or without enalaprilat and the quantification of the immunoreactivity of both peptides at different time intervals allowed the measurement of the kinetic parameters characterizing their metabolic pathways. Highly sensitive chemiluminescent enzyme immunoassays were used to measure the residual concentrations of BK and [des-Arg9]BK. Half-life (t1/2) of BK showed significant difference among species: rats (10 +/- 1 s) = dogs (13 +/- 1 s) < rabbits (31 +/- 1 s) < humans (49 +/- 2 s). t1/2 values of [des-Arg9]BK were also species dependent: rats (96 +/- 6 s) < < rabbits (314 +/- 6 s) = dogs (323 +/- 11 s) = humans (325 +/- 12 s). Enalaprilat significantly prevented the rapid BK and [des-Arg9]BK degradation in all species except that of [des-Arg9]BK in rat serum. Relative amount of BK hydrolyzed by serum KII was given as follows: rabbits (93.7 +/- 14.8%) = rats (83.6 +/- 6.7%) = humans (76.0 +/- 7.5%) > dogs (50.0 +/- 3.9%). Its importance in the hydrolysis of [des-Arg9]BK was 5.2 +/- 0.5% in rats < < 33.9 +/- 1.5% in humans < 52.0 +/- 1.1% in rabbits < 65.1 +/- 3.4% in dogs. The participation of serum KI in the transformation of BK into [des-Arg9]BK was dogs (67.2 +/- 5.3%) > > humans (3.4 +/- 1.2%) = rabbits (1.8 +/- 0.2%) = rats (1.4 +/- 0.3%). Finally, no significant difference on t1/2 values for BK and [des-Arg9]BK could be demonstrated between serum and plasma treated with either sodium citrate or a thrombin inhibitor. These results revealed striking species differences in the serum metabolism of kinins that could address at least partially some of the controversial data related to the cardioprotective role of kinins.

Sixty rats were grown in the presence of 10 (n = 30) and 100 (n = 30) micrograms kg-1 body mass of clenbuterol for a period of 10 d. An immunoextraction step coupled with a competitive enzyme immunoassay allowed the quantification of clenbuterol in hair upon 20 (10 micrograms kg-1) and 30 d (10 micrograms kg-1) after the last dose. This accumulation in hair contrasts with the rapid clearance in tissues. The nature of the immunoreactive material was confirmed by mass spectrometry.

Objective: To evaluate the efficacy of a limited dietary intervention delivered by dietitians in a single counseling session on plasma lipid levels in free-living subjects with hyperlipidemia., Design: A 2-month, nonrandomized comparative study of dietary counseling efficacy in subjects with hyperlipidemia. Dietary instruction was conducted in a lipid clinic by dietitians. Subjects were instructed to follow a diet low in saturated fat and cholesterol (National Education Cholesterol Program step 1 or 2 diets) for 2 months with concomitant energy restriction for weight reduction when necessary. Another group of patients who did not receive dietary counseling during the same period served as a control., Subjects: Ambulatory patients were recruited from the Lipid Clinic of the Montreal Clinical Research Institute., Intervention: Dietary counseling was provided to 104 subjects with hypercholesterolemia and 113 subjects with hypertriglyceridemia. They were compared with 72 subjects with hypercholesterolemia and 80 subjects with hypertriglyceridemia who did not receive dietary counseling., Results: In the hypercholesterolemic group, significant reductions in plasma cholesterol (mean +/- standard deviation = -5.7 +/- 11.7%) and low-density lipoprotein cholesterol (LDL-C) (-7.3 +/- 14.2%) and no changes in plasma very-low-density lipoprotein cholesterol (VLDL-C) or high-density lipoprotein cholesterol (HDL-C) were observed after dietary counseling. The LDL-C response to diet was normally distributed, and 20% of the individuals with hypercholesterolemia reached LDL-C levels below 4.1 mmol/L. In patients with hypercholesterolemia and no clinical evidence of familial hypercholesterolemia, (n = 76) the reductions in plasma cholesterol (-6.6 +/- 10.8%) and LDL-C (-8.2 +/- 14%) were more pronounced. Among the latter patients, 27.6% reached LDL-C levels below 4.1 mmol/L. In subjects with hypertriglyceridemia, the reductions in plasma cholesterol (-4.8 +/- 12.8%), triglycerides (-20.7 +/- 33%), and VLDL-C (-19.5 +/- 29%) were associated with an increase in LDL-C (+8.5 +/- 25.7%) and HDL-C (+5.5 +/- 18%). Of the subjects with hypertriglyceridemia, 20% had triglyceride levels below 2.3 mmol/L after treatment. No significant changes were observed in the control groups during the same period., Conclusions: Dietary counseling of subjects with hypercholesterolemia or hypertriglyceridemia was associated with beneficial changes in plasma lipid levels after 2 months of dietary intervention. However, longer and more controlled dietary interventions are necessary for most patients to achieve lipid goals.

The postpericardiotomy syndrome occurs in 10% to 40% of patients who undergo open-heart surgery. Its frequency is reportedly decreased when pericardial drainage is used. To challenge this, 50 consecutive patients (1 was disqualified) were randomly assigned to two groups: one in which only the anterior mediastinum was drained (group 1) and the other in which the anterior mediastinum and posterior pericardium were drained (group 2). The surgical procedures performed were: coronary artery bypass grafting in 14 patients, valve surgery in 23 and repair of congenital defects in 12. The two groups were similar with respect to age and the volume of blood drained. Significant differences were found only for the duration of bypass and volume of blood given. At 7 to 10 days there were no differences in the frequency of fever, thoracic pain or presence of arthralgia. Findings were similar in both groups for leukocyte count, sedimentation rate, serum lactic dehydrogenase value and for the frequency of positive blood, urine and sputum cultures. Six patients (three in each group) had a postpericardiotomy syndrome that required steroid treatment and prolonged hospitalization for 10 more days. However, none had postpericardiotomy syndrome complicating coronary artery bypass surgery. None of the patients had cardiac tamponade. This study demonstrates that pericardial drainage has no effect on the frequency of postpericardiotomy syndrome and appears to be unnecessary after open-heart surgery.