Targeted resequencing identifies defective variants of decoy receptor 3 in pediatric-onset inflammatory bowel disease.

Genome-wide association studies have implicated common variation at the 20q13 locus in inflammatory bowel disease, particularly for the pediatric Crohn's form. This locus harbors tumor necrosis factor receptor superfamily (TNFRSF6B), encoding a secreted protein, decoy receptor 3 (DcR3), which binds to and neutralizes pro-inflammatory cytokines of the tumor necrosis factor superfamily. We sought to further the evidence of DcR3's role in pediatric IBD by identifying missense mutations with functional significance within TNFRSF6B. We sequenced the exons of the gene in 528 Caucasian pediatric IBD cases and 549 Caucasian healthy controls to establish the frequency of such events in each population. Sequencing revealed that our IBD cohort harbored a greater number of missense variants, yielding an odds ratio of 3.9 (P-value=0.005). Using functional assays, we established that the frequency of mutants defective in secretion from cultured cells was greater in the Crohn's category than in the controls, yielding an odds ratio of 7.1 (P-value=0.004). These results suggest that rare defective variants in TNFRSF6B have a role in the pathogenesis of some cases of IBD and that interventions targeting this group of tumor necrosis factor-family members may benefit patients with IBD.

Extended haplotype association study in Crohn's disease identifies a novel, Ashkenazi Jewish-specific missense mutation in the NF-κB pathway gene, HEATR3.

The Ashkenazi Jewish population has a several-fold higher prevalence of Crohn's disease (CD) compared with non-Jewish European ancestry populations and has a unique genetic history. Haplotype association is critical to CD etiology in this population, most notably at NOD2, in which three causal, uncommon and conditionally independent NOD2 variants reside on a shared background haplotype. We present an analysis of extended haplotypes that showed significantly greater association to CD in the Ashkenazi Jewish population compared with a non-Jewish population (145 haplotypes and no haplotypes with P-value <10(-3), respectively). Two haplotype regions, one each on chromosomes 16 and 21, conferred increased disease risk within established CD loci. We performed exome sequencing of 55 Ashkenazi Jewish individuals and follow-up genotyping focused on variants in these two regions. We observed Ashkenazi Jewish-specific nominal association at R755C in TRPM2 on chromosome 21. Within the chromosome 16 region, R642S of HEATR3 and rs9922362 of BRD7 showed genome-wide significance. Expression studies of HEATR3 demonstrated a positive role in NOD2-mediated NF-κB signaling. The BRD7 signal showed conditional dependence with only the downstream rare CD-causal variants in NOD2, but not with the background haplotype; this elaborates NOD2 as a key illustration of synthetic association.

Nitrous oxide for pain management of first-trimester instrumental termination of pregnancy under local anaesthesia and/or minimal sedation: A systematic review and meta-analysis.

BACKGROUND: Inhalation of nitrous oxide and oxygen (N2O/O2) is used to reduce pain that is spontaneous or induced by procedures. N2O/O2 could be useful in the treatment of the pain in first-trimester termination of pregnancy performed under local anaesthesia and/or minimal sedation (FTOPL). OBJECTIVE: To evaluate the usefulness of N2O/O2 to reduce pain in FTOPL. SEARCH STRATEGY: Electronic databases including PubMed, Embase, and MEDLINE were searched using keywords. STUDY SELECTION: All studies comparing the use of N2O/O2 versus a placebo in the management of pain during FTOPL during the first trimester were included. Of the 199 studies identified, four were deemed eligible for this meta-analysis. DATA COLLECTION: The extracted results were perioperative pain, immediate and delayed postoperative pain, anxiety scores, and the secondary effects (nausea, vomiting). The data were analysed using Comprehensive Meta-Analysis software version 2.2.064. MAIN RESULTS: There was a significant difference in favour of N2O/O2 for perioperative pain (p = 0.006; SMD = - 0.31; 95 % CI, -0.54 - -0.09). No difference was found, however, in postoperative pain, nor was there a difference in the secondary effects (nausea, vomiting) (p = 0.61). A significant decrease in postoperative anxiety scores was seen in the pooled placebo group (p = 0.049; SMD = 0.41; and 95 % CI, 0.001-0.83). CONCLUSIONS: N2O/O2 reduces the pain of FTOPL. N2O/O2 could be recommended in FTOPL.

[Emergency contraception: CNGOF Contraception Guidelines]. / La contraception d'urgence. RPC Contraception CNGOF.

OBJECTIVES: Edit, by the French National College of Gynecologists and Obstetricians (CNGOF), recommendations based on the evidence available in the literature for the use in terms of effectiveness, safety and side effects of emergency contraception (EC). METHODS: A review of the literature was conducted by consulting Medline, Cochrane Library and international recommendations in French and English from January 1, 1979 to May 1, 2018. RESULTS: It is recommended to inform patients that EC is not 100% effective. A pregnancy test is recommended if there is a delay after taking an EC. It is recommended to use EC as soon as possible after the unprotected intercourse. In the absence of long-term contraception, in the first 72hours after unprotected intercourse, ulipristal acetate (UPA) and levonorgestrel (LNG) may be offered with a superiority of UPA from 0 to 72h. Beyond 72hours, the data suggest a better efficiency of the UPA. However, taking into account practical elements (access to EC, cost, impact on the taking of hormonal contraception after UPA), it is difficult to recommend the UPA as a priority between 0 and 72h. Menstruation is more likely to happen early with LNG. The copper IUD is an effective method that can be used in EC until 120hours after unprotected intercourse or when there is a risk of contraceptive failure. CONCLUSIONS: EC is not 100% effective. The closer the intake of EC with the unprotected intercourse, the more effective is the EC in terms of pregnancy rate.

[Contraception: CNGOF Guidelines for Clinical Practice (Short Version)]. / Contraception : Recommandations pour la Pratique Clinique du CNGOF (texte court).

The French College of Obstetrics and Gynecology (CNGOF) releases its first global recommendations for clinical practice in contraception, to provide physicians with an updated synthesis of available data as a basis for their practice. The French Health Authority (HAS) methodology was used. Twelve practical issues were selected by the organizing committee and the task force members. The available literature was screened until December 2017, and allowed the release of evidence-based, graded recommendations. This synthesis is issued from 12 developed texts, previously reviewed by experts and physicians from public and private practices, with an experience in the contraceptive field. Male and female sterilization, as well as the use of hormonal treatments without contraceptive label were excluded from the field of this analysis. Specific practical recommendations on the management of contraception prescription, patient information including efficacy, risks, and benefits of the different contraception methods, follow up, intrauterine contraception, emergency contraception, local and natural methods, contraception in teenagers and after 40, contraception in vascular high-risk situations, and in case of cancer risk are provided. The short/mid-term future of contraception mostly relies on improving the use of currently available methods. This includes reinforced information for users and increased access to contraception for women, whatever the social and clinical context. That is the goal of these recommendations.

Two miscarriages, consecutive or non-consecutive, does it change something?

OBJECTIVES: To assess the rate of anomalies in the etiological evaluation of patients presenting recurrent early miscarriages (RM) according to miscarriage chronology (number of miscarriages, history of live birth and succession of RM). METHODS: Retrospective single centre study including RM, defined as at least 2 miscarriages at less than 14 weeks of gestation (WG) between the 1st January 2012 and the 31st December 2015. Clinical data and etiological evaluation include blood glucose levels, screening for antiphospholipid syndrome (APS), endocrine assessment, vitamin levels, pelvic imaging, karyotyping of both partners, chronic endometritis and thrombophilia screening. RESULTS: Two hundred and eighty-eight patients were included over this period, 118 (41%) patients had no history of live birth. Two hundred and twenty-three (77%) patients had consecutive RM and 65 (22%) patients had non-consecutive RM. For consecutive RM, 62,8% had thrombophilic disorders versus 69,8% for non-consecutive RM (P>0,05); 44,7% had endocrine disorders or vitamin deficiencies versus 39,7%; 34,6% of patients with consecutive RM had uterine anomalies versus 45,5% respectively. No difference was found depending on the recurrence of RM or the history of live birth (P>0.05) apart from the age of the patient. Fifty-nine (17.4%) patients had uterine anomalies. There are 24 chronic endometritis on 31 biospsies performed. Seventy-eight (27%) patients were offered treatment. Ninety-four (90%) patients showed good therapy compliance. Eighty-one (78%) patients became pregnant. CONCLUSION: An etiological evaluation provides, for over half of the cases, an etiology or the identification of risk factors responsible for RM, as well as in some cases offering an adapted, efficient, therapeutic approach. This evaluation should be offered regardless of the obstetric history of the patient.

TPA and cycloheximide modulate the activation of NF-kappa B and the induction and stability of nitric oxide synthase transcript in primary neonatal rat hepatocytes.

12-O-Tetradecanoylphorbol 13-acetate (TPA) elicited a transient increase in the transcription of the inducible nitric oxide synthase (iNOS) gene coupled with a shortening of the half-life of its mRNA in primary neonatal rat hepatocytes. These effects of TPA were preceded by a surge in nuclear translocation of the transcription factor NF-kappa B, and followed by a mounting accumulation of NO-2 in the growth medium. Even cycloheximide (CHX) added by itself elicited an early, sustained activation of NF-kappa B followed by an intense induction of iNOS gene expression, irrespective of what degree of protein synthesis inhibition was brought about by the several concentrations tested. When given together, TPA and CHX exerted additive effects on hepatocellular iNOS mRNA levels. These results suggest the likelihood of an ordered sequence of events by which an activated NF-kappa B mediates the induction of iNOS gene expression in TPA- and/or CHX-treated primary hepatocytes.

Expression of plasminogen activator inhibitor-1 in human adipose tissue: a role for TNF-alpha?

Elevated plasminogen activator inhibitor-1 (PAI-1) plasma levels, responsible for reduced fibrinolysis, are associated with animal and human obesity and with increased cardiovascular disease. The expression of PAI-1 has been found recently in animal and human adipose tissue. Factors and mechanisms regulating such an expression remain to be elucidated. In omental and/or subcutaneous biopsies from obese non-diabetic patients, incubated in Medium 199, we have confirmed that human adipose tissue expresses PAI-1 protein and mRNA; furthermore we have demonstrated that such an expression is clearly evident also in collagenase isolated human adipocytes and that it is stimulated by incubation itself and enhanced by exogenous human tumor necrosis factor-alpha (h-TNF-alpha). Since human adipose tissue produces TNF-alpha, to further characterize the relationship of PAI-1 to TNF-alpha, human fat biopsies were also incubated with Pentoxifylline (PTX) or Genistein, both known to inhibit endogenous TNF-alpha through different mechanisms. PTX caused a dose-dependent decrease of basal PAI-1 protein release, reaching 80% maximal inhibitory effect at 10(-3)M, the same inhibitory effect caused by Genistein at 100 microg/ml. This was associated to a marked inhibition of PAI-1 mRNA and of endogenous TNF-alpha production. Furthermore, when human fat biopsies were incubated in the presence of polyclonal rabbit neutralizing anti-human TNF-alpha antibody (at a concentration able to inhibit 100 UI/ml human TNF-alpha activity), a modest but significant decrease of the incubation induced expression of PAI-1 mRNA was observed (19.8+/-19.0% decrease, P = 0.04, n = 7). In conclusion, the results of this study demonstrate that PAI-I expression is present in human isolated adipocytes and that it is enhanced in human adipose tissue in vitro by exogenous TNF-alpha. Furthermore our data support the possibility of a main role of endogenous TNF-alpha on human adipose tissue PAI-1 expression. This cytokine, produced by human adipose tissue and causing insulin resistance, may be a link in the clinical relationship between insulin-resistance syndrome and increased PAI-1 plasma levels.

Learning a partial-weight-bearing skill: effectiveness of two forms of feedback.

BACKGROUND AND PURPOSE: Partial weight bearing (PWB) is a skill commonly taught by physical therapists. This study compared the effects of practice with either augmented feedback provided during the task (concurrent feedback) or augmented feedback provided after the task (postresponse feedback) for the learning of PWB with crutches. SUBJECTS: Sixty young adults without known impairment of the neuromusculoskeletal system volunteered for the study. METHODS: Subjects practiced supporting 30% of body weight while stepping onto a floor scale. Augmented feedback was provided during each trial for the concurrent feedback group and either following each trial or after every five trials for the postresponse feedback groups. Subjects returned 2 days later for a no-feedback retention test. RESULTS: During practice, the concurrent feedback group was more accurate and consistent than either of the postresponse feedback groups. During retention, however, the postresponse feedback groups were the most accurate; all groups were equally consistent during retention. CONCLUSION AND DISCUSSION: These results suggest that practice with concurrent feedback is beneficial for the immediate performance but not for the learning of this sensorimotor skill.

Real-time three-dimensional stress echocardiography: a Review of current applications.

Cardiovascular stress testing plays a crucial role in the initial detection of coronary artery disease. In exercise stress echocardiography, the rapid acquisition of echocardiographic images is critical for accuracy. Real-time three-dimensional echocardiography permits the rapid acquisition of a volumetric data set that includes the entire left ventricle and allows the review of multiple, standard two-dimensional images from a single volumetric data set. Volumetric data can be obtained using both apical and parasternal windows. Often, satisfactory images are obtained in the majority of both prestress and poststress imaging using only an apical volume set. The following is a review of the current applications of real-time three-dimensional echocardiography in stress testing.

Management of high-risk gestational trophoblastic disease--the Memorial Hospital experience.

Thirty-two patients with high-risk gestational trophoblastic disease (GTD), defined as metastases to the brain or liver (regardless of hCG level or duration of disease) or prior unsuccessful chemotherapy are reviewed. In this classification, an antecedent term pregnancy is not considered to be an independent high-risk factor. Initial chemotherapy in 15 (46.8%) patients consisted of methotrexate, actinomycin D, and chlorambucil (MAC), actinomycin D alone in seven (21.8%), etoposide, methotrexate, actinomycin D, cytoxan on covin (EMACO) EMACO in three (9.4%), ITMA (hydroxyurea, vincristine, methotrexate, folinic acid, cyclophosphamide, actinomycin D, adriamycin, and melphalan) in three (9.4%). The remaining patients were treated with actinomycin D and 6-mercaptopurine (1), CHAMOCA (1), carboplatin and Taxol (1), and methotrexate (1). All patients with brain metastases were treated with cranial radiotherapy. Overall complete remission was achieved in 14 of 32 (43.7%) patients. Five of 9 (55.5%) patients whose disease followed a term pregnancy survived compared to nine of 23 (39.1%) patients whose disease followed other types of pregnancies. The data analyzed according to the clinical classification of 'high-risk' indicates that an overall survival rate of 70% was achieved. The Memorial Hospital classification therefore identifies patients who need primary chemotherapy more aggressive than MAC and similar to the WHO scoring system is a better predictor of survival than the clinical classification.

Assessment of left ventricular systolic function using contrast two-dimensional echocardiography with a high-frequency transducer in the awake murine model of myocardial infarction.

The estimation of global left ventricular function using M-mode echocardiography has technical limitations in the murine model of myocardial infarction (MI), but the recent improvements in 2-dimensional (2-D) echocardiography using a high-frequency transducer provide more accessible images. Furthermore, intravenous injection of contrast agent has the additional benefit of enhancing the endocardial border in the murine heart. The present study was designed to evaluate the value of 2-D echocardiography with intravenous injection of contrast agent in the assessment of global systolic function of the murine heart with MI. Two-dimensional and M-mode echocardiography without and with intravenous injection of contrast agent (Optison, 0.1-0.15 ml) were performed in 76 awake mice 2 days before and 2 days after left coronary artery ligation. Fractional shortening (FS) was calculated from the end-diastolic and end-systolic diameters on M-mode echocardiography, and fractional area change (FAC) from the end-diastolic and end-systolic areas on 2-D echocardiography. Both FS and FAC were compared with the areas of hypoperfusion observed in the pathological samples. The use of contrast agent improved the number of hearts that could be evaluated by both the M-mode and 2-D method (M-mode: non-contrast 87% vs contrast 99%, p<0.01; 2-D: non-contrast 26% vs contrast 89%, p<0.001). FAC from the 2-D method correlated better with the region of hypoperfusion in the pathological samples than did FS from the M-mode method (FAC: r=0.84 vs FS: r=0.51). In conclusion, FAC obtained from 2-D contrast echocardiography is useful for noninvasive assessment of global systolic function in infarcted murine hearts and can be used to serially assess systolic function in various models of the murine heart.

Assessment of segmental wall motion abnormalities using contrast two-dimensional echocardiography in awake mice.

Murine models of cardiac disease are becoming an important tool for studying pathophysiological processes. Development of methods to accurately assess ventricular function are therefore important. The purpose of this study was to evaluate the feasibility of echocardiographic assessment of segmental wall motion abnormalities in a murine model of myocardial infarction. Two-dimensional contrast (C+) and noncontrast (C-) echocardiography were performed in 76 awake mice 2 days before and 2 days after left coronary ligation. The short-axis images obtained with two-dimensional echocardiography and corresponding postmortem cross-sectional histological samples stained with Evans blue dye were each divided into 16 segments, and all matched segments were examined for correlation between wall motion abnormalities and myocardial hypoperfusion. With the use of contrast enhancement, the number of visualized segments was significantly increased (base: C- 86%, C+ 98%; midpapillary: C- 57%, C+ 89%; apex: C- 30%, C+ 74%). Agreement between echocardiographically assessed regional wall motion abnormalities and pathologically determined hypoperfusion in basal, midpapillary, and apical levels were 90%, 93%, and 93%, respectively. Agreement between echocardiographically normal wall motion and pathologically normal findings in basal, midpapillary, and apical levels were 99%, 88%, and 71%, respectively. Thus echocardiographic assessment of segmental wall motion in awake mice was feasible and the accuracy was improved with the use of a contrast agent.

Anesthetic inhibition in ischemic and nonischemic murine heart: comparison with conscious echocardiographic approach.

It is well known that the level of anesthesia obtained by intraperitoneal injection is variable and may alter cardiac function. In this study, we compared the effects of different anesthetics on cardiac function with the conscious state using high-resolution two-dimensional echocardiography in nonischemic and ischemic mice. Eighty-four mice were tested before and after surgery with ligation of the coronary artery. All 84 mice were studied in the conscious state and under high-dose intraperitoneal anesthesia. Twenty-two of 84 mice were studied under low-dose intraperitoneal anesthesia. Another 22 mice were also studied under gas anesthesia and spontaneous breathing. Experiments in the conscious state were performed by two investigators before the administration of anesthesia: one investigator held the animal and the transducer and the other operated the ultrasound equipment. Left ventricular systolic function was measured, and measurements obtained after surgery were compared with infarcted areas assessed by histological staining. Results showed that both high- and low-dose intraperitoneal anesthesia significantly reduced heart rates and left ventricular contractility in both pre- and postsurgical mice as opposed to conscious mice (P < 0.01). There were significantly higher correlation coefficients between mean fractional area change (FAC) and infarcted area in conscious state compared with high-dose intraperitoneal anesthesia (P < 0.05). The correlation coefficient between FAC and infarcted area during gas anesthesia was also significantly higher compared with high-dose intraperitoneal anesthesia (P < 0.05). In conclusion, conscious experiments or the use of gas anesthesia is preferred for echocardiographic assessment of cardiac function in mice because intraperitoneal injection significantly induces a significant reduction in heart rate and left ventricular systolic function.