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The skin microbiome can both trigger beneficial immune stimulation and pose a potential infection threat. Previous studies have shown that colonization of mouse skin with the model human skin commensal Staphylococcus epidermidis is protective against subsequent excisional wound or pathogen challenge. However, less is known about concurrent skin damage and exposure to commensal microbes, despite growing interest in interventional probiotic therapy. In this study, we address this open question by applying commensal skin bacteria at a high dose to abraded skin. Although depletion of the skin microbiome through antibiotics delayed repair from damage, probiotic-like application of commensals-including the mouse commensal Staphylococcus xylosus, 3 distinct isolates of S. epidermidis, and all other tested human skin commensals-also significantly delayed barrier repair. Increased inflammation was observed within 4 hours of S. epidermidis exposure and persisted through day 4, at which point the skin displayed a chronic wound-like inflammatory state with increased neutrophil infiltration, increased fibroblast activity, and decreased monocyte differentiation. Transcriptomic analysis suggested that the prolonged upregulation of early canonical proliferative pathways inhibited the progression of barrier repair. These results highlight the nuanced role of members of the skin microbiome in modulating barrier integrity and indicate the need for caution in their development as probiotics., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Human genetic studies show that loss of function mutations in 17-Beta hydroxysteroid dehydrogenase (HSD17β13) are associated with protection from non-alcoholic steatohepatitis (NASH). As a result, therapies that reduce HSD17β13 are being pursued for the treatment of NASH. However, inconsistent effects on steatosis, inflammation, and fibrosis pathogenesis have been reported in murine Hsd17b13 knockdown or knockout models. To clarify whether murine Hsd17b13 loss regulates liver damage and fibrosis, we characterized Hsd17b13 knockout mice subjected to pro-NASH diets or pro-inflammatory chemical-induced liver injury. There were no effects of Hsd17b13 loss on liver injury, inflammation, fibrosis, or lipids after 28 weeks on the Gubra-Amylin NASH (GAN) diet or 12 weeks on a 45% choline-deficient high-fat diet (CDAHFD). However, AAV-mediated re-expression of murine Hsd17b13 in KO mice increased liver macrophage abundance in both sexes fed the 45% CDAHFD. In contrast, there was a modest reduction in liver fibrosis, but not lipids or inflammation within Hsd17b13 null female, but not male, mice after 12 weeks of a 60% CDAHFD compared to WT littermates. Fibrosis and the abundance of liver macrophages were increased in Hsd17b13 KO females upon adenoviral re-expression of mouse HSD17β13, but this was not reflected in inflammatory markers. Additionally, we found minimal differences in liver injury, lipids, or inflammatory and fibrotic markers 48 h after acute CCl 4 exposure. In summary, murine Hsd17b13 loss has modest diet- and sex-specific effects on liver fibrosis which contrasts with human genetic studies. This suggests a disconnect between the biological function of HSD17β13 in mice and humans., Competing Interests: Conflict of interests The authors declare the following financial interests/personal relationships which may be considered as potential competing interests. Authors are either current or former employees of Pfizer and may be Pfizer shareholders., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: With states legalizing cannabis at a rapid pace, and the increasing popularity of edibles, it is important to document marketing practices to better understand how they might be appealing and misleading to consumers to guide state policymakers., Methods: A descriptive content analysis of 1229 cannabis edible packages advertised on a publicly available website between June and November 2022 and available for sale in licensed dispensaries was performed., Results: Healthy ingredient descriptors were the most common type of descriptor with 31 % of packages including words like "vegan", "gluten free" and "natural". Quality descriptors like "handcrafted" were on 28 % of packages. Other descriptors were focused on the consumer experience including expected effects (e.g., "relax") (27 %), taste or flavor (e.g., "sour") (21 %) and pharmacokinetics (e.g., "fast-acting") (19 %). Images of non-cannabis plants and outdoor nature settings were on half of packages. Images of the cannabis plant were on 33 % of packages. Flavor imagery including images of food were common (43 %). Other marketing appeals included images of people (15 %), animals (12 %) and space (10 %)., Conclusions: Package marketing used by other commercial industries was common on cannabis edible packages. Edibles marketing is distinct from other cannabis products in its ability to focus on the food ingredients which could mislead consumers into thinking the cannabis, rather than the food, is healthy or less harmful. Research examining the impact of cannabis edibles marketing strategies on appeal and harm perceptions is critically needed to guide policymakers as they establish packaging regulations to optimize public health and safety., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Introduction: Bronchial thermoplasty is an effective intervention to improve respiratory symptoms and to reduce the rate of exacerbations in uncontrolled severe asthma. A reduction in airway smooth muscle is arguably the most widely discussed mechanisms accounting for these clinical benefits. Yet, this smooth muscle reduction should also translate into an impaired response to bronchodilator drugs. This study was designed to address this question., Methods: Eight patients with clinical indication for thermoplasty were studied. They were uncontrolled severe asthmatics despite optimal environmental control, treatment of comorbidities, and the use of high-dose inhaled corticosteroids and long-acting β 2 -agonists. Lung function measured by spirometry and respiratory mechanics measured by oscillometry were examined pre- and post-bronchodilator (salbutamol, 400 μg), both before and at least 1 year after thermoplasty., Results: Consistent with previous studies, thermoplasty yielded no benefits in terms of baseline lung function and respiratory mechanics, despite improving symptoms based on two asthma questionnaires (ACQ-5 and ACT-5). The response to salbutamol was also not affected by thermoplasty based on spirometric readouts, including forced expiratory volume in 1 s (FEV 1 ), forced vital capacity (FVC), and FEV 1 /FVC ratio. However, a significant interaction was observed between thermoplasty and salbutamol for two oscillometric readouts, namely reactance at 5 Hz (X rs5 ) and reactance area (Ax), showing an attenuated response to salbutamol after thermoplasty., Conclusions: Thermoplasty attenuates the response to a bronchodilator. We argue that this result is a physiological proof of therapeutic efficacy, consistent with the well-described effect of thermoplasty in reducing the amount of airway smooth muscle., Competing Interests: Declaration of competing interest YB's laboratory received funds from Boston Scientific Inc (25800$) to conduct this project. AC is funded partially by GlaxoSmithKline, and has received consulting fees and honoraria for lectures from AstraZeneca, Sanofi, GlaxoSmithKline, Regeneron and Valeo pharma. CH, SB, MB, KG, JC and ML declare no conflict of interest., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

To test the hypothesis that ApoE4 may be involved in cognitive deficits associated with aging, we investigated the impact of APOE4 status and aging on the flexibility and memory components of spatial learning in mice. Young adult (6 months) and middle-aged (14 months) ApoE4, ApoE3 and C57BL/6 male mice were tested for flexibility in an aquatic Y-maze, and for spatio-temporal memory acquisition in the Starmaze. Our results revealed a flexibility deficit of the 6-month-old ApoE4 mice compared to controls. However, this deficit was not associated with spatio-temporal memory deficit at the same age. Importantly, the ApoE4 flexibility deficit did not increase with age, nor turn into memory deficit, or was able to predict individual variations of memory performance at 14 months. By contrast, control ApoE3 mice showed a decline of flexibility at 14 months resulting in performance similar to that of ApoE4. Overall, our results suggest that ApoE4 could be associated with an acceleration of the flexibility decrease otherwise observed in normal aging., (Copyright © 2021. Published by Elsevier Inc.)

Objective: Little is known about pregnancy outcomes among women who have acquired human immunodeficiency virus (HIV) through perinatal infection and survived into adulthood. The objectives of this study were to describe pregnancy outcomes among women with perinatal HIV infection (PHIV) in Canada and to identify potential challenges in the prevention of perinatal HIV transmission in this population., Methods: A retrospective review of all pregnancies among women with PHIV who were previously followed as children at two tertiary care centres in Montréal, Québec, was conducted. Data were extracted from pediatric and obstetrical records., Results: There were 21 pregnancies among 11 women, and 18 of these pregnancies were unintentional. Mean age at first pregnancy was 19.5 years (range 15-29 years). At the first prenatal visit, 79% had a detectable viral load, 36% were immunosuppressed (CD4 T cell count <200 mm 3 ), and only 36% were receiving antiretroviral therapy (ART). At the time of delivery, although all were prescribed ART, 50% of these women still had a detectable viral load, and 36% remained immunosuppressed. All of the women harboured mutations conferring drug resistance to zidovudine and lamivudine, and the majority (73%) were also resistant to nevirapine. None of the infants were HIV infected, although all received prophylaxis with agents to which their mother's virus was resistant., Conclusion: Unplanned pregnancies, difficulties with adherence to ART, and drug resistance were identified challenges in the management of pregnancies among women with PHIV. This study highlights a gap in the reproductive counselling of adolescents with PHIV and the need for close follow-up and adherence support during pregnancy in this population., (Copyright © 2019 The Society of Obstetricians and Gynaecologists of Canada/La Société des obstétriciens et gynécologues du Canada. Published by Elsevier Inc. All rights reserved.)

Objective: The purpose of this report is to develop a consensus for Canadian national guidelines specific to a tele-medicine approach to screening for diabetic retinopathy (DR) using evidence-based and clinical data., Methods: Canadian Tele-Screening Grading Scales for DR and diabetic macular edema (DME) were created primarily based on severity grading scales outlined by the International Clinical Diabetic Retinopathy Disease Severity Scale (ICDR) and the Scottish DR Grading Scheme 2007. Other grading scales used in international screening programs and the clinical expertise of the Canadian Retina Research Network members and retina specialists nationwide were also used in the creation of the guidelines., Results: National Tele-Screening Guidelines for DR and DME with and without optical coherence tomography (OCT) images are proposed. These outline a diagnosis and management algorithm for patients presenting with different stages of DR and/or DME. General guidelines detailing the requirements for imaged retina fields, image quality, quality control, and follow-up care and the role of visual acuity, pupil dilation, OCT, ultra-wide-field imaging, and artificial intelligence are discussed., Conclusions: Tele-retina screening can help to address the need for timely and effective screening for DR, whose prevalence continues to rise. A standardized and evidence-based national approach to DR tele-screening has been proposed, based on DR/DME grading using two 45° image fields or a single widefield or ultra-wide-field image, preferable use of OCT imaging, and a focus on local quality control measures., (Copyright © 2020 Canadian Ophthalmological Society. Published by Elsevier Inc. All rights reserved.)

Background: The optimal duration of dual antiplatelet therapy (DAPT) after percutaneous coronary intervention with stenting requires consideration of patient characteristics, and decision makers require a comprehensive overview of the evidence., Methods: We performed an umbrella review of systematic reviews (SRs) of randomized controlled trials of extended DAPT (> 12 months) compared with DAPT for 6 to 12 months after percutaneous coronary intervention with stenting. Outcomes of interest were death, myocardial infarction (MI), stroke, stent thrombosis, major adverse cardiac and cerebrovascular events, bleeding, and urgent revascularization. We aimed to assess the evidence of benefits and harms among clinically important subgroups (eg, elderly patients, those with diabetes, prior MI, acute coronary syndrome). We assessed the quality of the included reviews by use of A Measurement Tool to Assess Systematic Reviews (AMSTAR)., Results: Sixteen SRs involving 8 randomized controlled trials were included. Most scored 7 or more points on the AMSTAR checklist. There was no significant difference in outcomes with extended DAPT compared with 6 months of DAPT in most SRs, with the exception of an increased risk of major bleeding. Compared with 12 months, extended DAPT may reduce the risk of MI and stent thrombosis; however, the findings were not consistent across all reviews. There have been conflicting reports of an increased risk of death with extended DAPT. Few SRs assessed outcomes among patient subgroups., Conclusions: Extended DAPT may reduce the risk of MI and stent thrombosis but increase the risk of major bleeding and death. Whether the effects of extended DAPT are consistent across patient subgroups is unclear, and future SRs should address this knowledge gap., (Copyright © 2019 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Objective: There is no consensus on the use of cytomegalovirus (CMV)-specific hyperimmunoglobulins (CSHIGs) for suspected congenital CMV infections during pregnancy, but this therapy is currently used in some countries. The objectives of this study were to describe tolerability and pregnancy outcome following treatment with monthly intravenous CSHIG and compare rates of positive PCR and postnatal symptoms according to whether CSHIGs were given or not., Methods: This retrospective cohort study included all pregnant women who were diagnosed with primary CMV infection or congenital CMV infection at the Centre Hospitalier Universitaire Sainte-Justine (Montreal, QC) between 2005 and 2016. CSHIG was discussed with pregnant women who received positive CMV PCR results from amniotic fluid or if ultrasound anomalies suggested congenital infection and there was serologic evidence of maternal primary infection (therapeutic group). CSHIG was also offered as prophylaxis in pregnant women without fetal ultrasound anomalies but with evidence of maternal primary infection, when amniocentesis either had negative results or was not performed (prophylactic group). A matched analysis was performed to control for timing of maternal infection, amniocentesis, and type and timing of ultrasound anomaly., Results: Sixteen women received CSHIG, and 55 had no CMV-specific treatment. CSHIG treatment was well-tolerated. In bivariate analyses, the risk of congenital CMV infection and postnatal symptoms did not significantly decrease with CSHIG treatment, in both the therapeutic and the prophylactic groups. After matching, there was still no difference in outcomes between CSHIG-treated and untreated women., Conclusion: The effectiveness of CSHIG in preventing congenital CMV infection and its clinical manifestations could not be demonstrated., (Copyright © 2018 Society of Obstetricians and Gynaecologists of Canada. Published by Elsevier Inc. All rights reserved.)

The purpose of this study was to evaluate functional measures of diminished sympathetic activity after postganglionic neuronal loss in the conscious rat. To produce variable degrees of sympathetic postganglionic neuronal loss, adult rats were treated daily with toxic doses of guanethidine (100mg/kg) for either 5days or 11days, followed by a recovery period of at least 18days. Heart rate, blood pressure, cardiac baroreflex responsiveness, urinalysis (for catecholamine metabolite, 3-methoxy-4-hydroxyphenylethylenglycol; MHPG), and pupillometry were performed during the recovery period. At the end of the recovery period stereology of superior cervical ganglia (SCG) was performed to determine the degree of neuronal loss. Total number of SCG neurons was correlated to physiological outcomes using regression analysis. Whereas guanethidine treatment for 11days caused significant reduction in the number of neurons (15,646±1460 vs. 31,958±1588), guanethidine treatment for 5days caused variable levels of neuronal depletion (26,009±3518). Regression analysis showed that only changes in urinary MHPG levels and systolic blood pressure significantly correlated with reduction of SCG neurons (r 2 =0.45 and 0.19, both p<0.05). Although cardiac baroreflex-induced reflex tachycardia (345.7±19.6 vs. 449.7±20.3) and pupil/iris ratio (0.50±0.03% vs. 0.61±0.02%) were significantly attenuated in the 11-day guanethidine treated rats there was no significant relationship between these measurements and the number of remaining SCG neurons after treatment (p>0.05). These data suggest that basal systolic blood pressure and urinary MHPG levels predict drug-induced depletion of sympathetic activity in vivo., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective: hepatitis C virus (HCV) is an increasingly important public health problem worldwide. Health care workers providing care to women of childbearing age are uniquely placed in their practices to identify a significant proportion of at-risk patients and to provide appropriate screening and counselling. The primary objective of this guideline is to provide accurate, current information to those offering reproductive care to women living with HCV. This document is also intended to raise awareness of HCV in both the medical and general populations., Options: the areas of clinical practice considered in formulating this guideline are disease prevention, targeted screening of individuals at risk of contracting HCV, management of identified patients in the context of reproductive care, and the appropriate referral of patients to those with particular expertise., Outcomes: implementation of these guidelines should facilitate identification of infected individuals. It should also result in improved physical and mental well-being for patients and their families and reduction in transmission rates., Evidence: the literature between 1966 and 2000, including non- English language publications, was extensively searched utilizing Medline. A multidisciplinary group consisting of experts within the fields of obstetrics and gynaecology, infectious diseases, hepatology, and public health convened in Montreal in February 2000. The working group also included a patient and a representative from the Hepatitis C Society of Canada. The level of evidence for the recommendations has been determined using the criteria described by the Canadian Task Force on Periodic Health Examination., Benefits, Harms and Costs: the public health benefits of increased identification of at-risk individuals, diagnosis, treatment, implementation of risk reduction behaviours, and reduced transmission rates, both on an individual and at the community level, are significant. However, it must be remembered that the diagnosis of a chronic disease may have far reaching effects for the individual patient and her family., Recommendations: VALIDATION: references were collected through Medline searches and comparison made to existing current guidelines for assessment of consistency. External reviewers expert in their field were also consulted., (Copyright © 2017. Published by Elsevier Inc.)

In this article, a specific targeting Magnetic Resonance Imaging (MRI) nanoplatform, composed by iron oxide nanoparticle (NP) with cRGD peptides as targeting agent onto NP surface, is explored for the diagnosis of brain tumors by MRI using intracranial U87MG mice xenograft tumor. This article is part of a Special Issue entitled "Recent Advances in Bionanomaterials" Guest Editor: Dr. Marie-Louise Saboungi and Dr. Samuel D. Bader., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background: Despite the efficacy of raltegravir in reducing viral load in HIV-infected patients, evidence for its safety in late pregnancy is lacking. A high rate of placental transfer was recently demonstrated., Case: A treatment-naïve 34-year-old HIV-1-positive woman of African origin began treatment with zidovudine/lamivudine, lopinavir/ritonavir, and raltegravir at 35 weeks of pregnancy. After 11 days of treatment with raltegravir, a substantial reduction in viral load was achieved. Concurrently, she had a 23-fold increase in serum alanine aminotransferase and a 10-fold increase in serum aspartate aminotransferase, both of which returned to normal when raltegravir treatment was discontinued. A healthy boy was delivered at term. The infant's tests for HIV were negative at five months, and he had no health problems at eight months., Conclusion: This is the first case report, to our knowledge, of increased maternal serum transaminase levels following the use of raltegravir in a woman at a late stage of pregnancy.

Background: Listeriosis is one of the most severe foodborne illnesses worldwide. Most infections with Listeria are sporadic, but outbreaks do occur. Pregnant women exposed to this organism are at increased risk of chorioamnionitis, preterm labour, prematurity and intrauterine fetal demise. Severe neonatal infection can also occur., Cases: Two recent outbreaks in Canada prompted a reassessment of the prevalence and the perinatal impact of this disease. We describe here three cases of perinatal listeriosis. The aim of our report is to demonstrate the variable clinical presentations and to emphasize the difficulty in diagnosing perinatal listeriosis., Conclusion: Perinatal listeriosis is a severe disease with many possible clinical presentations. Clinical diagnosis may be difficult, so clinicians must maintain a high index of suspicion.

Some surfaces present folding patterns formed by juxtapositions of ridges and valleys as, for example, the cortical surface of the human brain. The fundamental problem with ridges is to find a correspondence among and analyze the variability among them. Many techniques to achieve these goals exist but use scalar functions. Depth maps are used to efficiently project the geometry of folds into a scalar function in the case where a natural projection plane exists. However, in most cases of curved surfaces, there is no natural projection plane to represent folding patterns. This paper studies the problem of shape matching and analysis of folding patterns by extending the notion of depth maps when no natural projection plane exists. The novel depth measure is called a depth potential function. The depth potential function integrates the information known from the curvature of the surface into a point-of-view invariant representation. The main advantage of the depth potential function is that it is computed by solving a time independent Poisson equation. The Poisson equation endows our surface representation with a significant computational advantage that makes it orders of magnitude faster to compute compared with other available surface representations. The method described in this paper was validated using both synthetic surfaces and cortical surfaces of human brain acquired by magnetic resonance imaging. On average, the improvement in shape matching when using the depth potential was of 11%, which is considerable.

Pancreatic cancer is one of the most aggressive and devastating human malignancies. Despite new knowledge in the molecular profile of pancreatic cancer and its precursor lesions, survival rates have changed very little over the last 40 years. Therefore, a better understanding of the detailed mechanisms underlying the pathogenesis of this disease is critical if we expect to develop new and effective strategies for prevention, early diagnosis and treatment of pancreatic cancer. The review herein focuses on a distinctive signaling pathway, the Notch pathway, which has recently been associated with carcinogenesis, including pancreatic cancer. It is aimed at summarizing key results which support a role for this pathway in the initiation, progression and maintenance of pancreatic cancer as a rationale for targeting and inhibiting this pathway in pancreatic cancer patients.

Objective: To review the evidence and provide recommendations on immunization in pregnancy., Outcomes: Outcomes evaluated include effectiveness of immunization, and risks and benefits for mother and fetus., Evidence: The Medline and Cochrane databases were searched for articles published up to June 2007 on the topic of immunization in pregnancy., Values: The evidence obtained was reviewed and evaluated by the Infectious Diseases Committee of the Society of Obstetricians and Gynaecologists of Canada (SOGC) under the leadership of the principal authors, and recommendations were made according to guidelines developed by the Canadian Task Force on Preventive Health Care., Benefits, Harms, and Costs: Implementation of the recommendations in this guideline should result in more appropriate immunization of pregnant and breastfeeding women, decreased risk of contraindicated immunization, and better disease prevention. Recommendations 1. All women of childbearing age should be evaluated for the possibility of pregnancy before immunization. (III-A) 2. Health care providers should obtain an immunization history from all women accessing prenatal care. (III-A) 3. In general, live and/or live-attenuated virus vaccines are contraindicated during pregnancy, as there is a, largely theoretical, risk to the fetus. (II-3) 4. Women who have inadvertently received immunization with live or live-attenuated vaccines during pregnancy should not be counselled to terminate the pregnancy because of a teratogenic risk. (II-2) 5. Non-pregnant women immunized with a live or live-attenuated vaccine should be counselled to delay pregnancy for at least four weeks. (III) 6. Inactivated viral vaccines, bacterial vaccines, and toxoids are considered safe in pregnancy. (II-1) 7. Women who are breastfeeding can still be immunized (passive-active immunization, live or killed vaccines). (II-1) 8. Pregnant women should be offered the influenza vaccine when pregnant during the influenza season. (II-1).

Background: Myocardial infarction (MI) contains a risk factor for developing episodes of Major Depressive Disorder (MDD). Apoptosis is commonly observed in the reperfused myocardial infarcted heart, and recent findings suggest the existence of apoptosis in MDD. Cytokines, which are released by ischemic myocardium and which may induce apoptosis, have been proposed as a possible cause for MDD., Methods: Myocardial infarction was produced in anesthetized rats by a 40-minute occlusion of the left anterior descending coronary artery followed by 72 hours of reperfusion. Determination of apoptosis was done in the amygdala, hippocampus and vermis of MI and Sham rats treated or not with pentoxyfilline (PTX), a cytokine synthesis inhibitor (10 mg/kg/day intraperitoneal)., Results: Compared to Sham rats, the amygdala of MI rats showed significantly reduced P13K activity, increased Bax/Bcl-2 ratio, caspase-3 activity, and TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling)-positive cells. The effect of MI on apoptosis was completely reversed in presence of PTX. No statistical difference was observed in the hippocampus and the vermis in the different groups for any of the biochemical measurements., Conclusions: These results indicated that MI induce apoptosis in amygdala by a cytokine-sensitive mechanism and may explain the MDD observed following myocardial infarction.

Hair follicle formation and cycling involve extensive and continuous interactions between epithelial and mesenchymal components. A system for rapidly and reproducibly generating hair follicles from dissociated epithelial and mesenchymal cells is described here. The system serves both as a tool for measuring the trichogenic property of cells and as a tool for studying the mechanisms that dissociated cells use to assemble an organ. In this system, hair follicles develop when dissociated cells, isolated from newborn mouse skin, are injected into adult mouse truncal skin. This morphogenetic process involves the aggregation of epithelial cells to form clusters that are sculpted by apoptosis to generate "infundibular cysts". From the "infundibular cysts", hair germs form centrifugally followed by follicular buds and then pegs that grow asymmetrically to differentiate into cycling mature pilosebaceous structures. Marker studies correlate the molecular differentiation of these follicles with in situ systems. This study suggests that the earliest phase of a developing epithelial-mesenchymal system--even from dissociated cell preparations--requires an epithelial platform.

Objectives: To compare the efficacy of a single 100 micro g intramuscular (IM) carbetocin injection, a long-acting oxytocin agonist, to a 2-hour 10 IU oxytocin intravenous (IV) infusion, in reducing the incidence and severity of postpartum hemorrhage (PPH) in women at risk for this condition., Methods: A randomized, double-blind, placebo-controlled study was conducted at 2 hospital centres, including 160 women with at least 1 risk factor for PPH. Eighty-three women received 100 microg carbetocin IM and an IV placebo immediately after placental delivery, while 77 women received placebo IM and oxytocin IV infusion. Complete blood count was collected at entry and 24 hours postpartum. All outcome measures, including the need for additional uterotonic agents or uterine massage, blood loss, and drop in hemoglobin and hematocrit, were analyzed using chi-square, Fisher exact, and Student t tests., Results: Population profile and risk factors for PPH were similar for each group. No significant difference was observed in the number of women requiring additional uterotonic medication (12 in each group). However, in the carbetocin group, 36 of the 83 women (43.4%) required at least 1 uterine massage compared to 48 of the 77 women (62.3%) in the oxytocin group (P <.02). Overall, uterotonic intervention was clinically indicated in 37 of the women (44.6%) receiving carbetocin compared to 49 of the women (63.6%) given an IV oxytocin infusion (P <.02). There were no differences in laboratory PPH indicators between the 2 groups.

Objective: The purpose of this study was to evaluate the rate and indications of cesarean delivery after a successful external cephalic version., Study Design: A case-control study was performed from patients who were delivered in a tertiary care center between 1987 and 2000. Each patient who underwent a successful external cephalic version (study group) was compared with the next woman with the same parity, who was delivered at term (control group). Nulliparous and multiparous women were analyzed separately. Chi-squared, Mann-Whitney, and Student t tests were used for statistical analysis. Multivariate logistic regression analysis was performed where appropriate., Results: A total of 602 patients were included in this study. The rates of cesarean delivery in nulliparous women (29.8% vs 15.9%; P<.001) and in multiparous women (15.9% vs 4.7%; P<.001) were significantly higher when compared with the control group. Patients with successful external cephalic version were more likely to have a cesarean delivery for dystocia (nulliparous, 22.5% vs 11.9%; P=.01; multiparous, 10.9% vs 1.3%; P<.01). After an adjustment for confounding variables, a successful external cephalic version was associated with an increased rate of cesarean delivery at term (nulliparous: odds ratio, 2.04; 95% CI, 1.13-3.68; multiparous: odds ratio, 4.30; 95% CI, 1.76-10.54)., Conclusion: The rate of cesarean delivery for dystocia is increased after a successful trial of external cephalic version in both nulliparous and multiparous women.

Objective: The purpose of this study was to evaluate the efficacy of sublingual nitroglycerin as a tocolytic agent for external cephalic version in parous women., Study Design: A double-blinded randomized controlled trial was performed. Patients with parity of >or=1 at 36 to 40 weeks of gestation who were eligible for external cephalic version were included. Patients were randomized to receive either two sublingual sprays of 400 mug of nitroglycerin or two sprays of placebo 3 minutes before the trial of external cephalic version. Rates of successful external cephalic version and side effects were compared between groups., Results: Of 99 patients in the study, 50 patients received sublingual nitroglycerin, and 49 patients received placebo. There were no differences in maternal age, gestational age, estimated fetal weight, amniotic fluid index, and placental location between the two groups. The success rate of external cephalic version was 48% in the nitroglycerin group compared with 63% in the placebo group (P=.13). There was a higher incidence of headaches in the nitroglycerin group (42% vs 4%, P<.001)., Conclusion: Sublingual nitroglycerin was associated with a higher rate of headache and did not improve the rate of successful external cephalic version.

Objective: This study was undertaken to assess the association between amniotic fluid index (AFI), success of external cephalic version (ECV), and obstetric outcome in patients undergoing ECV., Study Design: A prospective observational study was performed that included all patients who had a trial of ECV from 1987 to 2000 in our center. Rates of success, fetal heart decelerations during trial at ECV, and cesarean deliveries were calculated. Groups were divided by an AFI performed immediately before ECV: AFI less than 10 cm, 10 to 15 cm, and more than 15 cm., Results: In our group of 1361 patients undergoing ECV, the rate of success was related to the AFI in both parous women (49.1%, 63.5% and 72.1% [P<.001] for each AFI group, respectively) and nulliparous women (36.5%, 43.6%, and 57.3% [P<.001]). The rate of cesarean section delivery was related to AFI in nulliparous but not multiparous patients (P<.001). The rate of prolonged fetal heart rate decelerations was not significantly related to the AFI., Conclusion: The rate of successful ECV and cesarean section deliveries is related to the amniotic fluid volume. This information may be used to consent patient before a trial of ECV.

Objective: The purpose of this study was to compare the efficacy of sublingual nitroglycerin with that of intravenous ritodrine as a tocolytic agent for external cephalic version in nulliparous women., Study Design: We performed a double-blinded, randomized trial. Nulliparous patients, between 36 and 40 weeks of gestation, were assigned randomly to receive either (1) an intravenous infusion of ritodrine (111 microg/min) for 20 minutes, followed by two puffs of sublingual placebo or (2) an intravenous infusion of sodium chloride 0.9% (placebo) for 20 minutes, followed by two puffs of sublingual 0.4 mg of nitroglycerin. Three minutes after the administration of the sublingual spray, an external cephalic version was attempted. The rate of successful external cephalic version and side effects was compared between groups., Results: Of 74 randomly assigned patients, 38 patients received intravenous ritodrine, and 36 patients received sublingual nitroglycerin. Although not statistically significant, the rate of the successful external cephalic version was higher in the ritodrine group compared with the nitroglycerin group (45% vs 25%, P =.075). The rate of headaches was higher in patients who received nitroglycerin (28% vs 8%, P =.02). Mean blood pressure and maternal heart rate were lower in the nitroglycerin group 10 minutes after the administration of the medication. However, there was no significant difference in the rate of palpitations, hypotension, or fetal bradycardia between the two groups., Conclusion: When compared with intravenous ritodrine, sublingual nitroglycerin was associated with a higher rate of headache, lower blood pressure, and a trend toward a lower rate of successful external cephalic version.

Large increases in cAMP concentration inside the cell are generally growth inhibitory for most cell lines of mesenchymal and epithelial origin. Moreover, recent data suggest a role of cAMP in survival of different cell types. Herein, the ability of forskolin (an adenylyl cyclase activator) and IBMX (3-isobutyl-1-methylxanthine) (a phosphodiesterase inhibitor) to modulate cell cycle progression and survival of human pancreatic cancer cells was evaluated. We showed that forskolin + IBMX inhibited serum-induced ERK activities, Rb hyperphosphorylation, Cdk2 activity, and p27(Kip1) downregulation and caused G1 arrest in MIA PaCa-2 cells. Furthermore, forskolin + IBMX protected pancreatic cells against apoptosis induced by prolonged inhibition of ERK activities by preventing Bcl-X(L) downregulation, activation of caspases 3, 6, 8, and 9, and PARP cleavage and by inducing Bad phosphorylation (ser112). Taken together, our data demonstrate for the first time that cAMP is an inhibitor of cell cycle progression and apoptosis in human pancreatic cancer cells., (Copyright 2001 Academic Press.)

Objective: This study was undertaken to compare the efficacy and safety of intravenous administration of atosiban versus ritodrine for the treatment of preterm labor., Study Design: Women with preterm labor and intact membranes diagnosed at 23 to 33 gestational weeks (n = 247) were randomly assigned to treatment arms and received atosiban (6.75 mg intravenous bolus, 300 microg/min for 3 hours, then 100 microg/min intravenously) or ritodrine (0.10-0.35 mg/min intravenously) for as long as 18 hours. Tocolytic effectiveness was assessed in terms of the numbers of women who had not been delivered after 48 hours and after 7 days. Safety was assessed in terms of maternal side effects and neonatal morbidity. Secondary outcomes included mean gestational age at delivery and mean birth weight. An intent-to-treat analysis was performed with the Cochran-Mantel-Haenszel test., Results: The proportion of women who had not been delivered at 48 hours was 84.9% (n = 107) in the atosiban group and 86.8% (n = 105) in the ritodrine group. At 7 days 92 women had still not been delivered in both the atosiban (73.0%) and ritodrine (76.0%) groups. Neither of these differences was statistically significant. The incidence of maternal cardiovascular side effects was substantially lower in the atosiban group (4.0% vs 84.3%, P <.001). In addition, intravenous therapy was terminated more frequently as a result of maternal adverse events in the ritodrine group (29.8%) than in the atosiban group (0.8%). The overall occurrences of fetal adverse events in the two treatment groups were comparable. Neonatal morbidity was similar between the treatment groups after adjustment for unbalanced enrollment of women with multiple pregnancies and for gestational ages within treatment groups., Conclusion: Atosiban was comparable in clinical effectiveness to conventional ritodrine therapy but was better tolerated than ritodrine, with no evidence of significant maternal or fetal adverse events. Neonatal morbidity, which was similar between the two treatment arms, was apparently related to the gestational age of the infant rather than to the exposure to either tocolytic agent.

Caveolae are plasma membrane microdomains that have been implicated in organizing and concentrating certain signaling molecules. Caveolins, constitute the main structural proteins of caveolae. Caveolae are abundant in terminally differentiated cell types. However, caveolin-1 is down-regulated in transformed cells and may have a potential tumor suppressor activity. In the lung, caveolae are present in the endothelium, smooth muscle cells, fibroblasts as well as in type I pneumocytes. The presence of caveolae and caveolin expression in the bronchial epithelium, although probable, has not been investigated in human. We were interested to see if the bronchial epithelia express caveolins and if this expression was modified in cancer cells. We thus tested for caveolin-1 and -2 expression several bronchial epithelial primary cell lines as well as eight lung cancer cell lines and one larynx tumor cell line. Both caveolin-1 and -2 are expressed in all normal bronchial cell lines. With the exception of Calu-1 cell line, all cancer cell lines showed very low or no expression of caveolin-1 while caveolin-2 expression was similar to the one observed in normal bronchial epithelial cells., (Copyright 1999 Academic Press.)

Objective: To assess the relationship of personality and clinical characteristics with survival in patients with advanced chronic obstructive pulmonary disease (COPD)., Design: Prospective double-blind study., Setting: Outpatient clinic of a teaching Veterans Affairs Hospital in central New York. PATIENT PARTICIPATION: Sixteen male patients (mean age, 62.2 +/- 2.5 years) with severe COPD INTERVENTIONS: Patients were administered Minnesota Multiphasic Personality Inventory (MMPI) test; their clinical features were recorded from hospital records at the time of admission into the study. All were followed up for 4 years after the initial assessment or until their death., Measurements and Main Results: The nine survivors and seven nonsurvivors were similar in age, pulmonary function test (PFT) results, oxygenation, number of medications, or concomitant illnesses. However, the nonsurvivors had higher MMPI and clinical illness scores compared with the survivors (p < 0.01 and < 0.05, respectively)., Conclusions: The 4-year mortality in male veterans with severe COPD is influenced by overall psychological distress and difficulty in coping with their disease, which seem to be important prognostic indicators irrespective of PFT results or oxygenation.

Objective: Our purpose was to study the effect of ritodrine tocolysis on the success rate of external cephalic version at > or = 36 weeks' gestation., Study Design: This was a prospective, double-blinded, randomized study. All patients were > or = 36 weeks' gestation, confirmed by early ultrasonography. External cephalic version assessment included nonstress testing before and after external cephalic version and ultrasonographic evaluation of type of breech, estimated fetal weight, position of placenta and fetal spine, and amniotic fluid index. Patients were excluded if the breech was not mobile or if they had any contraindications to tocolysis or external cephalic version. After randomization 283 patients received either ritodrine (111 micrograms/min) or identical placebo by intravenous infusion for > or = 20 minutes. Up to three attempts at external cephalic version under ultrasonographic surveillance were performed. With an alpha error of 0.05 and a beta of 0.2, 264 patients were required to complete this study., Results: There were no differences between study groups in maternal age, body mass index, gestational age, amniotic fluid index, position of fetal spine, and placental location. Statistical analysis controlled for parity because parity had a major influence on success rates. There was a higher success rate in the group receiving ritodrine tocolysis (52% vs 42%, p = 0.028). Ritodrine improved success rates in nulliparous patients (43% vs 25%, p = 0.026) but not in parous subjects (66% vs 58%, p = 0.385)., Conclusion: Ritodrine tocolysis improves the success rate of external cephalic version performed at > or = 36 weeks in nulliparous patients.

Erythromycin, the standard treatment for chlamydial infection in pregnant women, commonly causes side-effects, which limits its efficacy. In a randomised, double-blind study, we compared amoxycillin with erythromycin in this setting. 210 pregnant women with Chlamydia trachomatis infection were randomly assigned 7 days' treatment with amoxycillin (500 mg three times daily) or erythromycin (500 mg four times daily). Control cultures were obtained 21 days after treatment, during late pregnancy, and from the infant within a week of birth. Treatment was judged a failure if any post-treatment culture was positive or if the patient had to stop therapy because of severe side-effects. 11 women (5.2%) were lost to follow-up. 1 (of 100) amoxycillin-treated women had to stop treatment because of severe side-effects compared with 12 (of 99) erythromycin-treated women (p = 0.002). 1 woman in the amoxycillin group had a positive culture at the third-trimester examination. No positive post-treatment culture was found in the erythromycin group. Severe gastrointestinal side-effects were more common in women who received erythromycin (31 vs 6%, p < 0.001). The overall failure rate was therefore 2% in the amoxycillin group and 12% in the erythromycin group (p = 0.005). These results suggest that amoxycillin is an acceptable alternative to erythromycin for C trachomatis infection in pregnant women.

The cardiac electrophysiological effects of rilmenidine, a novel antihypertensive agent, and clonidine were studied in the conscious dog. Sinus rate, corrected sinus recovery time (CSRT) and Wenckebach point (WP) were measured in seven intact dogs. Atrial rate and atrial effective refractory period (AERP) were measured in six atrioventricular (AV)-blocked dogs with ventricular pacing. In both groups, blood pressure was also monitored. Each dog received with at least a three-day interval rilmenidine as dihydrogen phosphate and clonidine as hydrochloride in four successive intravenous injections, 30 min apart. In intact dogs, rilmenidine was administered at 50, 50, 100 and 200 micrograms/kg and clonidine at 2.5, 2.5, 5 and 10 micrograms/kg. In AV-blocked dogs, doses of rilmenidine were 25, 25, 50 and 100 micrograms/kg, those of clonidine 5, 5, 10 and 20 micrograms/kg. Rilmenidine and clonidine decreased sinus rate and atrial rate from the first dose. In this regard, rilmenidine was respectively 24 and 23 times less potent than clonidine. A lengthening of CSRT was observed at all doses with rilmenidine and at the last three doses with clonidine (ratio: 17) and a lowering of WP at all doses with rilmenidine and clonidine (ratio: 22). A shortening of AERP was also seen with rilmenidine and clonidine from the second dose (ratio: 6). All these effects may at least partly be explained by a cholinergic activation mechanism. In intact dogs both drugs produced a lowering of mean blood pressure (ratio: 17), whereas in AV-blocked dogs, in which ventricular rate was kept constant by pacing, pressure effects were more complex, being the resultant of hypotensive and hypertensive effects, the latter due to alpha vascular stimulation. Taken together, these results indicate that in the conscious dog, rilmenidine and clonidine exert qualitatively identical electrophysiological effects, but with different potency ratios.

The authors report two cases of primary popliteal venous aneurysm. This condition is rare. The lesion may be clinically asymptomatic and may remain unrecognised since it is discovered most often during the investigation of thrombo-embolic complications. The diagnosis is based upon ultrasonography and phlebography. Asymptomatic forms should merely be monitored. Apart from anticoagulants, the treatment of symptomatic forms is surgical. Methods remain controversial.

The cardiac vagolytic effects of disopyramide and its mono-N-dealkylated metabolite (MND), and their interactions with the cardiac cholinergic system, were assessed using in vivo and in vitro experiments. In chloralose anesthetized dogs, disopyramide phosphate (0.25 mg/kg/min) and MND at equimolar dose (0.173 mg/kg/min) reduced vagal bradycardia. As indicated by the ED80, MND exhibits a vagolytic activity 1.5-2 times less potent than disopyramide. Concomitantly, increases in heart rate and mean blood pressure were observed with disopyramide, whereas with MND only a rise in mean blood pressure occurred. In conscious dogs, where vagal tone is fully expressed, disopyramide and MND increased heart rate and, interestingly, prevented any atropine-induced additional tachycardia, though heart rate was relatively low. Binding studies on rat heart membranes yielded Ki values 2-2.5 times higher for MND than for disopyramide, and demonstrated that neither disopyramide nor MND binding modified the cardiac muscarinic receptor sites. Taken together, these results show that disopyramide exhibits a more potent cardiac vagolytic action than MND, very likely linked to a greater ability to bind to cardiac muscarinic receptors. They also show that disopyramide and MND are very potent in preventing atropine-induced "excess tachycardia", very likely by inhibiting the ionic pacemaker current(s) involved in its genesis.

The feasibility and reliability of measuring sleep-related breathing disorders with a portable monitor (PM) were assessed in a heterogeneous population, consisting of 31 patients recruited from a sleep laboratory and pulmonary disease clinic, 16 participants in a genetic-epidemiologic study of sleep apnea, and four volunteers with no specific sleep complaints. The validity of measurements made by the PM was assessed with comparisons of respiratory parameters made with the PM to those determined with in-hospital polysomnography (PSG) (25 studies). Reproducibility was assessed in 29 subjects who underwent in-home monitoring on two occasions. There was a high level of agreement between the number of respiratory events (apneas or hypopneas) per hour of estimated sleep (respiratory disturbance index, RDI) recorded with the PM and PSG and log-transformed (r = 0.96). Using a RDI of greater than or equal to 10 to define "abnormality," 20 of the 21 subjects who would have been classified as abnormal with PSG were classified similarly with use of the PM. A similar high level of agreement was demonstrated for the log-transformed RDI determined with replicate in-home studies (r = 0.94). No evidence of a "first-night effect" for the RDI was suggested in studies performed with the PM; ie, RDI was 18.4 +/- 27.7 and 17.4 +/- 25.7 (mean +/- SD) for first and second night studies, respectively (p = 0.21). A second compared with an initial study with the PM would have resulted in reclassification of abnormality based on an RDI of greater than or equal to 10 in one subject. These findings suggest that measurement of the RDI with in-home monitoring provides a valid and highly reproducible index for assessment of sleep-related respiratory disturbances for use in epidemiologic studies of general populations.

Ultrasonographic determination of biparietal diameter/femur length ratios performed at 16 or 17 weeks' gestation in fetuses with trisomy 21 were not statistically different from those of 155 normal fetuses. It appears that this test could not be used for screening for trisomy 21.

The distribution of symptoms, physiologic responses, and upper airway structure in members of one family with three generations of subjects with sleep apnea (SA) is reported. Questionnaire data were obtained from ten family members (ages 7 to 66 years), overnight sleep studies were performed in nine subjects, and ventilatory responses to hyperoxic hypercapnia and to eucapnic hypoxia and cephalometry were obtained in five subjects. All ten family members reported habitual snoring or nighttime snorting/gasping; five of ten family members also reported excessive daytime sleepiness. All studied subjects except for a pregnant woman had greater than ten apneas/hypopneas per hour. Ventilatory responses to hypoxia were markedly reduced in all five subjects studied (less than or equal to 0.51 L/min/SaO2); hypercapnic responses were reduced in three of five subjects (less than or equal to 0.61 L/min/mm Hg CO2). No subject was morbidly obese (body mass index less than 29 kg/m2) or demonstrated retrognathia. The posterior airway space was reduced in three subjects, and the mandibular to hyoid distance was increased in four subjects. The two subjects with the longest soft palates and the most inferiorly displaced hyoids had the most severe sleep disorder. Sleep apnea was present, albeit less profound, in the one subject with normal anatomy who had an abnormal hypoxic ventilatory response. The distribution of these physiologic and anatomic measurements in this family provides further support for a genetic basis for SA, and suggests that the disorder may occur as a result of interactions between ventilatory control abnormalities and anatomic risk factors.

Fifty-six patients with presumed ocular histoplasmosis syndrome who exhibited a disciform macular detachment or macular scar in one fundus and one or more inactive atrophic lesions within the high-risk area of the second eye were seen at the Retina Service of Maisonneuve-Rosemont Hospital, Montreal, between 1972 and 1984. All 56 were followed for at least 10 months. Of the 56, 28 had received prophylactic argon laser photocoagulation of the inactive chorioretinal lesions. The rate of activation of the lesions was similar in the treated and untreated groups (10/28 over a mean follow-up period of 44.2 months and 11/28 over a mean period of 43.2 months respectively). In the untreated group there was an increased risk of activation with a higher number of lesions (t = 2.386). In both groups the risk of activation increased with the proximity of the lesions to the centre of the fovea (chi 2 = 29.97). Of the 10 treated eyes that showed activation, 4 did so within 1 month, which suggests that prophylactic photocoagulation may not be without risk of complications.

The nonstress test remains the most widely used method of antepartum fetal health assessment in multiple gestations. However, few data are available on factors influencing its results in those cases. Our observation on 530 such tests has shown results similar to those in singleton gestations. Prematurity was associated with a higher rate of nonreactive tests; however, order and mode of presentation had no impact.

Reversal of normal cerebral asymmetry has been reported to be more frequent in children with higher cortical dysfunction and in schizophrenics, in whom it has clinical significance as well. As there are few studies of bipolar patients, we attempted to determine if significant reversal would be found in a clearly diagnosed sample of bipolar patients. As technical differences may account for varying results, we used two previously reported methods and a modified technique. Correlations of computed tomography (CT) findings with neuropsychological variables (Halstead Reitan Battery and WAIS subtests) were also studied. Bipolars and controls did not differ on any CT measure, nor were there meaningful correlations between asymmetry and neuropsychological variables. If if is confirmed that schizophrenics have increased reversed cerebral asymmetry but bipolars do not, it may point to an important difference, as all other CT abnormalities initially described in schizophrenics are now also noted in bipolar patients.

A comprehensive quantitative computed tomography (CT) study of the diencephalic region of 23 chronic schizophrenic patients and 23 normal controls was done. The third ventricle width, the Sylvian fissure widths, and the densities of the head of the caudate nucleus, thalamic nucleus, and medial temporal lobe were measured. In the schizophrenic patients, there was a significant increase in third ventricle and Sylvian fissure widths and a significantly greater density of both periventricular nuclei. The several explanations for this atypical association of atrophy with greater density are discussed.