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Objective: To compare overlapping repair with end-to-end repair of obstetric tears and to investigate which procedure results in a higher rate of flatal incontinence.Methods: One-hundred forty-nine primiparous women sustaining a complete third- or a fourth-degree tear of the perineum were assigned randomly to a primary sphincter repair using either an end-to-end (n=75) or an overlapping surgical technique (n=74) using 3-0 polyglyconate. Outcome measures at 6 months included rates of flatal and fecal incontinence, quality-of-life scores, integrity of the internal and external anal sphincters by anal ultrasonography, and anal sphincter function as reflected by anal manometry.Results: Women who underwent overlapping repair compared with end-to-end repair had higher rates of flatal incontinence, 61% compared with 39% (odds ratio [OR] 2.44, confidence interval [CI] 1.2-5.0). The rate of fecal incontinence was also higher, 15% compared with 8% (OR 1.97, CI 0.62-6.3) but did not attain statistical significance. Rates of internal and external anal sphincter defects did not differ significantly between groups and did not correlate with anal incontinence symptoms. Fecal incontinence was higher when there was a defect in both sphincter muscles. Anal sphincter function as assessed by manometry did not differ significantly between groups.Conclusion: End-to-end repair of third- or fourth-degree obstetric anal sphincter tears is associated with lower rates of anal incontinence when compared with overlapping repair.Clinical Trial Registration: ISRCTN Register, isrctn.org, ISRCTN04149919.Level Of Evidence: I. [ABSTRACT FROM AUTHOR]

OBJECTIVE: The objective of this study was to examine in theory the clinical utility of a prenatal algorithm that uses rapid aneuploidy detection in all cases and G-banded analysis for selected cases (RAD/G algorithm). METHODS: Over a 4-year period, amniotic fluid samples were prospectively assigned into RAD (limited analysis) or RAD/G (intensive analysis) categories based upon the likelihood of the fetus having a chromosome anomaly. The samples were cultured and analyzed by standard cytogenetic methods. The rates of clinically significant chromosomal anomalies potentially undetectable by the RAD/G algorithm were calculated. RESULTS: The karyotype was normal in 3861/4054 (95.24%) cases and abnormal in 193 (4.76%). From these data, the detection rate of the RAD/G algorithm was 87.6% if all abnormalities detected by G-banding were taken into consideration and 97.6% if abnormalities having reduced predictive value were excluded (balanced rearrangements and most mosaic cases). CONCLUSIONS: Compared to G-banding alone, the RAD/G algorithm has a reduction in sensitivity due to undetectable abnormalities and mosaicism in the RAD group. However, it provides a rapid and inexpensive alternative to traditional G-banded analysis, and might be more appropriate for patients with uncomplicated, low risk pregnancies. Copyright (c) 2008 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

OBJECTIVES: To summarise the experience and evaluate the performance of the Ontario maternal serum screening (MSS) programme. SETTING: The Ontario MSS programme between October 1993 and September 2000. METHODS: This study used information collected in the Ontario MSS database, which contains data on each screened pregnancy. In the Ontario MSS programme, women are screened between 15 and 20 weeks of gestation. The risk cut-off for Down's syndrome was >or= 1 in 385 at term and women with a serum alpha-fetoprotein >or= 2.2 multiples of the unaffected population median were defined as screen-positive for open neural tube defects. RESULTS: Between 1 October 1993 and 30 September 2000, 428410 women residing in Ontario were screened for open neural tube defects, and 423895 women were screened for Down's syndrome and trisomy 18. Approximately 48% of all pregnant women in the province had MSS. The uptake rate of amniocentesis following a positive Down's syndrome screening was 67%. Of 717 cases of Down's syndrome ascertained in the screened population, 531 were detected by MSS, giving a term detection rate (DR) of 70.6%, with a false-positive rate (FPR) of 7.2%. For neural tube defects, the DR was 72.7%, with a FPR of 2.0%. The screen also detected 50% of cases of trisomy 18 at term, with a FPR of 0.2%. Coincidentally, 113 cases of chromosome aneuploidies other than Down's syndrome and trisomy 18 were detected. DISCUSSION: In the Ontario MSS programme, MSS performed as expected in the detection of Down's syndrome, open neural tube defects and trisomy 18. MSS is an effective and practical method for large-scale second trimester screening for Down's syndrome, open neural tube defects and trisomy 18, and the MSS database is an extremely useful tool in monitoring the performance of this screen. [ABSTRACT FROM AUTHOR]

Abstract Background Jacobsen syndrome is a rare contiguous gene disorder that results from a terminal deletion of the long arm of chromosome 11. It is typically characterized by intellectual disability, a variety of physical anomalies and a distinctive facial appearance. The 11q deletion has traditionally been identified by routine chromosome analysis. Array-based comparative genomic hybridization (array-CGH) has offered new opportunities to identify and refine chromosomal abnormalities in regions known to be associated with clinical syndromes. Results Using the 1 Mb BAC array (Spectral Genomics), we screened 70 chromosomally normal children with idiopathic intellectual disability (ID) and congenital abnormalities, and identified five cases with submicroscopic abnormalities believed to contribute to their phenotypes. Here, we provide detailed molecular cytogenetic descriptions and clinical presentation of two unrelated subjects with de novo submicroscopic deletions within chromosome bands 11q24-25. In subject 1 the chromosome rearrangement consisted of a 6.18 Mb deletion (from 128.25–134.43 Mb) and an adjacent 5.04 Mb duplication (from 123.15–128.19 Mb), while in subject 2, a 4.74 Mb interstitial deletion was found (from 124.29–129.03 Mb). Higher resolution array analysis (385 K Nimblegen) was used to refine all breakpoints. Deletions of the 11q24-25 region are known to be associated with Jacobsen syndrome (JBS: OMIM 147791). However, neither of the subjects had the typical features of JBS (trigonocephaly, platelet disorder, heart abnormalities). Both subjects had ID, dysmorphic features and additional phenotypic abnormalities: subject 1 had a kidney abnormality, bilateral preauricular pits, pectus excavatum, mild to moderate conductive hearing loss and behavioral concerns; subject 2 had macrocephaly, an abnormal MRI with delayed myelination, fifth finger shortening and squaring of all fingertips, and sensorineural hearing loss. Conclusion Two individuals with ID who did not have the typical clinical features of Jacobsen syndrome were found to have deletions within the JBS region at 11q24-25. Their rearrangements facilitate the refinement of the JBS critical region and suggest that a) deletion of at least 3 of the 4 platelet function critical genes (ETS-1, FLI-1 and NFRKB and JAM3) is necessary for thrombocytopenia; b) one of the critical regions for heart abnormalities (conotruncal heart defects) may lie within 129.03 – 130.6 Mb; c) deletions of KCNJ1 and ADAMTS15 may contribute to the renal anomalies in Jacobsen Syndrome; d) the critical region for MRI abnormalities involves a region from 124.6 – 129.03 Mb. Our results reiterate the benefits of array-CGH for description of new phenotype/genotype associations and refinement of previously established ones.

Abstract Background Maternal obesity and pre-pregnancy diabetes mellitus, features of the metabolic syndrome (MetSyn), are individual risk factors for neural tube defects (NTD). Whether they, in combination with additional features of MetSyn, alter this risk is not known. We evaluated the risk of NTD in association with maternal features of the MetSyn. Methods We used a population-based case-control study design in the province of Ontario, Canada. Cases and controls were derived from women who underwent antenatal maternal screening (MSS) at 15 to 20 weeks' gestation. There were 89 maternal cases with, and 434 controls without, an NTD-affected singleton pregnancy. Maternal features of MetSyn were defined by the presence of pre-pregnancy diabetes mellitus, body weight ≥ 90th centile among controls, non-white ethnicity and/or serum highly sensitive C-reactive protein (hsCRP) ≥ 75th centile of controls. Since hsCRP naturally increases in pregnancy, analyses were performed with, and without, the inclusion of hsCRP in the model. Results Mean hsCRP concentrations were exceptionally high among study cases and controls (6.1 and 6.4 mg/L, respectively). When hsCRP was excluded from the model, the adjusted odds ratios for NTD were 1.9 (95% confidence interval 1.1–3.4) in the presence 1 feature of MetSyn, and 6.1 (1.1–32.9) in the presence of 2 or more features. When hsCRP was included, the respective risk estimates were attenuated to 1.6 (0.88–2.8) and 3.1 (1.2–8.3). Conclusion We found about 2-fold and 6-fold higher risk for NTD in the presence 1, and 2 or more features, of the metabolic syndrome, respectively. It is not clear whether this risk is altered by the presence of a high serum hsCRP concentration.

Objective: To provide clinical guidelines for the evaluation of women with stress urinary incontinence prior to primary anti-incontinence surgery., Options: The modalities of evaluation range from basic pelvic examination through to the use of adjuncts including ultrasound and urodynamic testing., Outcomes: These guidelines provide a comprehensive approach to the preoperative evaluation of urinary incontinence to ensure that excessive evaluation is avoided without sacrificing diagnostic accuracy., Evidence: Published opinions of experts, supplemented by evidence from clinical trials, where appropriate., Values: The quality of the evidence is rated using the criteria described by the Canadian Task Force on the Periodic Health Examination., Benefits, Harms, and Costs: Comprehensive evaluation of women considering surgery to treat urinary incontinence is essential to rule out causes of incontinence that may not be amenable to surgical treatment. Simplifying the evaluation minimizes the discomfort and embarrassment potentially experienced by women., Recommendations: VALIDATION: These guidelines have been approved by the Urogynaecology Committee and the Executive and Council of The Society of Obstetricians and Gynaecologists of Canada., (Copyright © 2018. Published by Elsevier Inc.)

Isolated congenital diaphragmatic hernia is often a sporadic event with a low recurrence risk. However, underlying genetic etiologies, such as chromosome anomalies or single gene disorders, are identified in a small number of individuals. We describe two fetuses with a unique pattern of multiple congenital anomalies, including diaphragmatic hernia, short bowel and asplenia, born to first-cousin parents. Whole exome sequencing showed that both were homozygous for a missense variant, c.950A>C, predicting p.Asp317Ala, in the H.20-Like Homeobox 1 (HLX1) gene. HLX is a homeobox transcription factor gene which is relatively conserved across species. Hlx homozygous null mice have a short bowel and reduced muscle cells in the diaphragm, closely resembling the anomalies in the two fetuses and we therefore suggest that the HLX mutation in this family could explain the fetal findings., (© 2017 Wiley Periodicals, Inc.)

The fundamental precepts that underpin the delivery of all medical care are safety and efficacy. Although these precepts, in theory, are accepted without challenge, in many settings where clinical care is delivered, there is a lack of formal oversight necessary to ensure their implementation in practice. Even though most medical specialties have national bodies that provide guidelines for good medical practice, and hospital accreditation makes reference to dissemination of such guidelines, there is usually not a mechanism to monitor medical uptake and adherence to good practice in the day-to-day delivery of care. Most hospitals require approval by an institutional review board before research protocols can be undertaken, but regional health authorities and hospitals do not usually have formal processes in place to regulate the adoption of new technologies into clinical practice. Recognizing the lack of a formal process at the hospital level to guide and regulate the introduction of new technologies or procedures, we set out to establish an oversight process to fill this gap. A committee was established to oversee innovation in the Gynaecology Division of our hospital. We describe here the establishment of this committee, the tools the committee used, and the processes used for the committee to do its work. We conclude that formal, local oversight of medical innovation is indispensible for ensuring the high standards of medical practice necessary to optimize patient safety., (Copyright © 2016 The Society of Obstetricians and Gynaecologists of Canada/La Société des obstétriciens et gynécologues du Canada. Published by Elsevier Inc. All rights reserved.)

Background: Gynaecologists who are asked to assess patients with pain in the genital area are not generally trained to consider neurogenic causes for the pain, nor are they generally familiar with the surgical procedures that can eliminate this pain., Case: A 54-year-old woman who had undergone multiple laparotomies for Caesarean section, abdominal hysterectomy, treatment of ovarian cysts, and lysis of adhesions through a transverse abdominal approach presented with a seven- to eight-month history of severe neuropathic left-sided groin, labial, and perineal pain. Neurectomy involving the iliohypogastric, ilioinguinal, and genitofemoral nerves was performed. Postoperatively the patient experienced complete resolution of the pain., Conclusion: Neuropathic pain should be considered in the differential diagnosis of women with an extensive history of lower abdominal surgery. Neurectomy is an effective treatment for this.

Background: We report a consanguineous couple that has experienced three consecutive pregnancy losses following the foetal ultrasound finding of short limbs. Post-termination examination revealed no skeletal dysplasia, but some subtle proximal limb shortening in two foetuses, and a spectrum of mildly dysmorphic features. Karyotype was normal in all three foetuses (46, XX) and comparative genomic hybridization microarray analysis detected no pathogenic copy number variants., Results: Whole-exome sequencing and genome-wide homozygosity mapping revealed a previously reported frameshift mutation in the OBSL1 gene (c.1273insA p.T425nfsX40), consistent with a diagnosis of 3-M Syndrome 2 (OMIM #612921), which had not been anticipated from the clinical findings., Conclusions: Our study provides novel insight into the early clinical manifestations of this form of 3-M syndrome, and demonstrates the utility of whole exome sequencing as a tool for prenatal diagnosis in particular when there is a family history suggestive of a recurrent set of clinical symptoms.

Charcot-Marie-Tooth (CMT) disease is a group of hereditary disorders affecting the motor and sensory nerves of the peripheral nervous system. CMT patterns of inheritance include dominant, recessive, and X-linked disorders. Charcot-Marie-Tooth disease, type 1B (CMT1B, OMIM 118200) is an autosomal dominant neuropathy caused by mutations in myelin protein zero (MPZ, OMIM 159440), a structural protein of peripheral myelin. Most causative MPZ mutations are missense sequence variants; however, recent clinical reports have described cases of CMT1B caused by increased dosage of the MPZ gene, with over-expression of the MPZ protein suspected to be causative of the disorder. We report an unusual case of early onset de novo CMT1B, caused by amplification of a familial, apparently benign, MPZ duplication., (Copyright © 2013. Published by Elsevier Masson SAS.)

Background: Rare, recurrent genomic imbalances facilitate the association of genotype with abnormalities at the "whole body" level. However, at the cellular level, the functional consequences of recurrent genomic abnormalities and how they can be linked to the phenotype are much less investigated., Method and Results: We report an example of a functional analysis of two genes from a new, overlapping microdeletion of 2p13.2 region (from 72,140,702-72,924,626). The subjects shared intellectual disability (ID), language delay, hyperactivity, facial asymmetry, ear malformations, and vertebral and/or craniofacial abnormalities. The overlapping region included two genes, EXOC6B and CYP26B1, which are involved in exocytosis/Notch signaling and retinoic acid (RA) metabolism, respectively, and are of critical importance for early morphogenesis, symmetry as well as craniofacial, skeleton and brain development. The abnormal function of EXOC6B was documented in patient lymphoblasts by its reduced expression and with perturbed expression of Notch signaling pathway genes HES1 and RBPJ, previously noted to be the consequence of EXOC6B dysfunction in animal and cell line models. Similarly, the function of CYP26B1 was affected by the deletion since the retinoic acid induced expression of this gene in patient lymphoblasts was significantly lower compared to controls (8% of controls)., Conclusion: Haploinsufficiency of CYP26B1 and EXOC6B genes involved in retinoic acid and exocyst/Notch signaling pathways, respectively, has not been reported previously in humans. The developmental anomalies and phenotypic features of our subjects are in keeping with the dysfunction of these genes, considering their known role. Documenting their dysfunction at the cellular level in patient cells enhanced our understanding of biological processes which contribute to the clinical phenotype.

Objective: This study aimed to assess the quantitative impact of maternal weight discrepancy on the screen result for Down syndrome when using Integrated Prenatal Screening and First Trimester Combined Screening., Methods: The study population consisted of 78,165 women undergoing prenatal screening in Ontario, Canada, and 158 pregnancies affected with Down syndrome at one Ontario center. The study assessed quantitative alterations of the multiple of the median values of first and second-trimester serum markers and the risks of Down syndrome at a set of theoretical weight discrepancies., Results: Weight discrepancies have the greatest impact on screening results when the initial risk is close to the risk cut-off. When the weight discrepancy is 5 lb or greater and the denominator of the initial risk is within 50 of the risk cut-off, the chance that a screen result will change from positive to negative or from negative to positive is 47-55% for women undertaking Integrated Prenatal Screening. This chance is 33-43% for women undertaking First Trimester Combined Screening., Conclusion: A weight discrepancy of five or more pounds has a significant impact on the risk of Down syndrome; correction of maternal weight would improve the accuracy of the screening test., (© 2013 John Wiley & Sons, Ltd.)

Introduction and Hypothesis: Little evidence is available concerning the ability of women with urinary incontinence (UI) to properly assess their problem. This study compared women's assessments of their UI type with physicians' diagnoses., Methods: Women referred to a urogynecology clinic for UI were asked to anonymously answer a short validated Questionnaire for Urinary Incontinence Diagnosis (QUID) before their physician visit. Women completed the QUID and read a brief explanation of its interpretation, after which they were asked to choose their UI type: stress, urge, or mixed. Physicians, blinded to patients' answers, conducted routine examinations and indicated their diagnoses of incontinence types. Sample size was representative of typical clinic volumes. Levels of agreement among physician diagnoses, QUID scores, and patient self-assessments of UI type were calculated with kappa (κ) statistics. Physician diagnosis was the gold standard., Results: We had 497 patients return the questionnaire; 338 met inclusion criteria. Mean age was 53 (± 13) years. Levels of agreement among physician diagnoses and patients' assessments of UI type (κ=0.411, p<0.01) and QUID scores (κ=0.378, p<0.01) were significant. Significant level of agreement was found among QUID scores and patients' assessments of UI type (κ=0.497, p<0.001)., Conclusions: With aid of a brief standardized questionnaire, women can accurately assess their UI type. This suggests women could be educated about UI via good-quality Internet health sites and choose appropriate conservative management options.

Deletions at 2p16.3 involving exons of NRXN1 are associated with susceptibility for autism and schizophrenia, and similar deletions have been identified in individuals with developmental delay and dysmorphic features. We have identified 34 probands with exonic NRXN1 deletions following referral for clinical microarray-based comparative genomic hybridization. To more firmly establish the full phenotypic spectrum associated with exonic NRXN1 deletions, we report the clinical features of 27 individuals with NRXN1 deletions, who represent 23 of these 34 families. The frequency of exonic NRXN1 deletions among our postnatally diagnosed patients (0.11%) is significantly higher than the frequency among reported controls (0.02%; P = 6.08 × 10(-7) ), supporting a role for these deletions in the development of abnormal phenotypes. Generally, most individuals with NRXN1 exonic deletions have developmental delay (particularly speech), abnormal behaviors, and mild dysmorphic features. In our cohort, autism spectrum disorders were diagnosed in 43% (10/23), and 16% (4/25) had epilepsy. The presence of NRXN1 deletions in normal parents and siblings suggests reduced penetrance and/or variable expressivity, which may be influenced by genetic, environmental, and/or stochastic factors. The pathogenicity of these deletions may also be affected by the location of the deletion within the gene. Counseling should appropriately represent this spectrum of possibilities when discussing recurrence risks or expectations for a child found to have a deletion in NRXN1., (Copyright © 2013 Wiley Periodicals, Inc.)

Background/objectives: The Ontario Prenatal Screening Program (OPSP) follows internationally recognized standardized procedures for laboratories and genetics clinics. However, it has been found that some procedures are subject to interpretation, so the current procedures are designed to facilitate a unified approach in the interpretation of literature recommendations. In Ontario, the OPSP offers multiple screening modalities with integrated prenatal screening (including both first and second trimester markers) being the most commonly chosen option. Other screening modalities include first trimester screening, second trimester quad screening, serum integrated screening, and NT-Quad., Methods: The standardization was based on a literature review and on current practices in Ontario., Results/discussion: The main finding of the review was a paucity of published data relating to the procedures and the decision-making processes involved in prenatal screening. The purpose of this publication is to provide the most up-to-date and pertinent information for clinical laboratory professionals involved with prenatal screening for Down syndrome, trisomy 18 and open neural tube defects., (Copyright © 2012 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

Microdeletions of 1q43q44 result in a recognizable clinical disorder characterized by moderate to severe intellectual disability (ID) with limited or no expressive speech, characteristic facial features, hand and foot anomalies, microcephaly (MIC), abnormalities (agenesis/hypogenesis) of the corpus callosum (ACC), and seizures (SZR). Critical regions have been proposed for some of the more prominent features of this disorder such as MIC and ACC, yet conflicting data have prevented precise determination of the causative genes. In this study, the largest of pure interstitial and terminal deletions of 1q43q44 to date, we characterized 22 individuals by high-resolution oligonucleotide microarray-based comparative genomic hybridization. We propose critical regions and candidate genes for the MIC, ACC, and SZR phenotypes associated with this microdeletion syndrome. Three cases with MIC had small overlapping or intragenic deletions of AKT3, an isoform of the protein kinase B family. The deletion of only AKT3 in two cases implicates haploinsufficiency of this gene in the MIC phenotype. Likewise, based on the smallest region of overlap among the affected individuals, we suggest a critical region for ACC that contains ZNF238, a transcriptional and chromatin regulator highly expressed in the developing and adult brain. Finally, we describe a critical region for the SZR phenotype which contains three genes (FAM36A, C1ORF199, and HNRNPU). Although ~90% of cases in this study and in the literature fit these proposed models, the existence of phenotypic variability suggests other mechanisms such as variable expressivity, incomplete penetrance, position effects, or multigenic factors could account for additional complexity in some cases.

Purpose of Review: There is a significant risk of anal incontinence in women who sustain a third or fourth degree tear of the external anal sphincter (EAS) at the time of delivery. Optimizing the surgical correction of these injuries should result in the best functional outcome for women. The purpose of this review is to examine recent evidence., Recent Findings: The results of randomized trials are conflicting. Four trials have found no difference between the overlapping and end-to-end repairs. One trial found the overlapping procedure superior and one found the end-to-end procedure to be superior. Repair of the internal anal sphincter is an important part of the surgical repair. Surgeon experience with specific surgical procedures does not significantly affect outcomes. Methodological limitations have compromised the conclusions of the majority of the studies and longer-term follow-up is still needed., Summary: At present, the bulk of the evidence (follow-up to 12 months) finds that there is no difference in symptomatic outcomes between the end-to-end or the overlapping repair of EAS defects. A surgeon should use the technique with which they are most familiar. Obstetricians should familiarize themselves with the most up-to-date evidence concerning the anatomy of the EAS and take care to identify and repair both the internal anal sphincter and EAS at the time of an obstetrical injury. Surgeon experience with specific repair procedures does not affect outcomes of EAS defect repair., ((C) 2011 Lippincott Williams & Wilkins, Inc.)

Protocadherin11 is located on both the X and Y chromosomes in Homo sapiens but only on the X chromosome in other hominid species. The pairing of PCDH11Y with PCDH11X arose following a duplicative 3.5 Mb translocation from the ancestral X chromosome to the Y chromosome several million years ago. The genes are highly expressed in fetal brain and spinal cord. The evolutionary consequence of this duplication has been proposed to include the sexual dimorphism of cerebral asymmetry and the hominid specific transition to the capacity for language. We report a case of a male child referred for genetic investigation of severe language delay. Microarray analysis indicated the presence of a 220 Kb intragenic deletion at Xq21.31 involving the PCDH11X gene. Fluorescence in situ hybridization using a BAC probe mapping to intron 2 of the Protocadherin11X/Y gene pair confirmed loss of the locus on both the X and Y chromosomes. The X chromosome deletion was maternally inherited, but the Y chromosome deletion was found to be a de novo occurrence in this child. This finding lends support to the hypothesis that the Protocadherin11X/Y gene plays a role in language development in humans and that rare copy number variation is a possible mechanism for communication disorders., (Copyright © 2011 Wiley-Liss, Inc.)

Nablus mask-like facial syndrome (NMLFS) has been reported in six patients with a recognizable facial appearance, along with other clinical features. Microdeletions of 8q21.3-8q22.1 were identified in all six cases, with the deleted region in common being 8q22.1 (2.78 Mb in length). In this report, we describe a child with speech delay and features of an autistic spectrum disorder and with a 1.6 Mb deletion of 8q22.1. The deletion has significant chromosomal overlap with previously reported examples of NMLFS, but our patient lacks the clinical features noted in the published cases., (Copyright 2010 Elsevier Masson SAS. All rights reserved.)

Objective: To increase primary care providers' awareness and use of genetic services; increase their knowledge of genetic issues; increase their confidence in core genetic competencies; change their attitudes toward genetic testing for hereditary diseases; and increase their confidence as primary care genetic resources., Design: Participants completed a workshop and 3 questionnaires: a baseline questionnaire, a survey that provided immediate feedback on the workshop itself, and a follow-up questionnaire 6 months later., Setting: Ontario., Participants: Primary care providers suggested by deans of nursing, midwifery, family medicine, and obstetric programs, as well as coordinators of nurse practitioner programs, in Ontario and by the Ontario College of Family Physicians., Intervention: A complex educational intervention was developed, including an interactive workshop and PowerPoint educational modules on genetic topics for participants' use (available at www.mtsinai.on.ca/FamMedGen/)., Main Outcome Measures: Awareness and use of genetic services, knowledge of genetics, confidence in core clinical genetic skills, attitudes toward genetic testing, and teaching activities related to genetics., Results: The workshop was attended by 29 participants; of those, 21 completed the baseline questionnaire and the 6-month follow-up questionnaire. There was no significant change found in awareness or reported use of genetic services. There was significant improvement in self-assessed knowledge of (P = .001) and confidence in (P = .005) skills related to adult-onset genetic disorders. There were significant increases in confidence in many core genetic competencies, including assessing risk of hereditary disorders (P = .033), deciding who should be offered referral for genetic counseling (P = .003), discussing prenatal testing options (P = .034), discussing benefits, risks, and limitations of genetic testing (P = .033), and describing what to expect at a genetic counseling session (P = .022). There was a significant increase in the number of primary care providers agreeing that genetic testing was beneficial in the management of adult-onset diseases (P = .031) and in their confidence in being primary care genetic resources for adult-onset genetic disorders (P = .006)., Conclusion: Educational interventions that include interactive peer resource workshops and educational modules can increase knowledge of and confidence in the core competencies needed for the delivery of genetic services in primary care.

Hereditary sensory and autonomic neuropathy type II (HSAN II) leads to severe mutilations because of impaired nociception and autonomic dysfunction. Here we show that loss-of-function mutations in FAM134B, encoding a newly identified cis-Golgi protein, cause HSAN II. Fam134b knockdown results in structural alterations of the cis-Golgi compartment and induces apoptosis in some primary dorsal root ganglion neurons. This implicates FAM134B as critical in long-term survival of nociceptive and autonomic ganglion neurons.

Ultraluminous X-ray sources are extragalactic objects located outside the nucleus of the host galaxy with bolometric luminosities exceeding 10(39) erg s(-1). These extreme luminosities-if the emission is isotropic and below the theoretical (Eddington) limit, where the radiation pressure is balanced by the gravitational pressure-imply the presence of an accreting black hole with a mass of approximately 10(2)-10(5) solar masses (M[symbol: see text]). The existence of such intermediate-mass black holes is in dispute, and though many candidates have been proposed, none are widely accepted as definitive. Here we report the detection of a variable X-ray source with a maximum 0.2-10 keV luminosity of up to 1.1 x 10(42) erg s(-1) in the edge-on spiral galaxy ESO 243-49, with an implied conservative lower limit for the mass of the black hole of approximately 500M[symbol: see text].

Pallister-Killian syndrome (PKS) is a genetic disorder characterized by mental retardation, seizures, streaks of hypo- or hyperpigmentation and dysmorphic features. PKS is associated with tissue-limited mosaic partial tetrasomy of 12p, usually caused by an isochromosome 12p. The mosaicism is usually detected in cultured skin fibroblasts or amniotic cells and rarely in phytohemagluttinin-stimulated lymphocytes, which suggests stimulation of T-lymphocytes may distort the percentage of abnormal cells. We recently reported on the identification by microarray-based comparative genomic hybridization (aCGH) of a previously unsuspected case of partial tetrasomy of 12p caused by an isochromosome 12p. Here we report on seven additional individuals with partial tetrasomy of 12p characterized by our laboratory. All individuals were referred for mental retardation/developmental delay and/or dysmorphic features. In each case, aCGH using genomic DNA extracted from whole peripheral blood detected copy-number gain for all clones for the short arm of chromosome 12. In all but one case, FISH on metaphases from cultured lymphocytes did not detect the copy-number gain; in the remaining case, metaphase FISH on cultured lymphocytes showed an isochromosome in 10% of cells. However, interphase FISH using probes to 12p on peripheral blood smears showed additional hybridization signals in 18-70% of cells. Microarray and FISH analysis on cultured skin biopsies from four individuals confirmed the presence of an isochromosome 12p. Our results demonstrate the usefulness of aCGH with genomic DNA from whole peripheral blood to detect chromosome abnormalities that are not present in stimulated blood cultures and would otherwise require invasive skin biopsies for identification.

Background: The current pyramidal system of health care delivery, in which subspecialized physicians with the most complete knowledge and expertise are difficult to access, is inefficient and ineffective at delivering the best care to the majority of patients. Urinary incontinence care exemplifies this problem. Patients can wait up to one year to see a urogynaecologist, regardless of the complexity of their problem. Many women who do not require subspecialized care could have their incontinence managed in a more timely fashion if they had access to education and conservative interventions via a new, more accessible model of care., Methods: We studied a modification of urinary incontinence care that departed from the traditional methods of care delivery in two distinct ways. First, patients were permitted to refer themselves directly to the specialty care team. Second, standardized questionnaires and evaluation tools facilitated assessment and management of the patients by a continence educator and nurses, without direct contact between patient and physician. This step-wise model of care was compared with the traditional method of care delivery (medical model), in which the management of all patients was provided by a physician., Results: Two hundred thirty-two women participated in this study: 154 in the step-wise arm and 78 in the medical model arm. Neither the demographics nor the pre-treatment incontinence severity of the two groups differed significantly. Patients in both groups showed significant improvement in all measures of urinary incontinence after treatment. Patients in the self-referral model experienced significantly better resolution of stress incontinence and irritated bladder symptoms. Their quality of life was also significantly better and their treatment satisfaction higher., Conclusion: The step-wise model of care delivery involving a continence advisor and nurses was as effective in the management of urinary incontinence as the traditional medical model.

Background: The primary purpose of this study was to determine the intraoperative cystocopy practices of Canadian gynaecologists. The secondary aim was to identify barriers for the use of cystoscopy in this same population., Methods: An 18-item questionnaire was sent to all active members of the Society of Obstetricians and Gynaecologists of Canada. The questionnaire included questions about basic demographic data and specific questions regarding cystoscopy use and barriers to use., Results: The response rate was 23% (236/1006). Two hundred thirty-one respondents practised gynaecology, and, of these, 48% (111/230) used intraoperative cystoscopy routinely (16/111, 14%), selectively (84/111, 75%), or for other reasons (12/111, 11%), primarily during tension-free vaginal tape procedures. The respondents used cystoscopy with the following procedures: colposuspension (61%), vaginal hysterectomy (23%), vaginal vault suspension (21%), and culdoplasty (20%). Cystoscopy was most commonly performed transurethrally (73%) with a 30 degree cystoscope. Lack of training was the most common reason cystoscopy was not used (70/118, 59%). Increased physician age (RR 0.47; CI 0.38-0.59, P<0.01) and duration in practice of more than 10 years (RR 0.62; CI 0.46-0.83, P<0.01) was associated with significantly decreased cystoscopy use., Conclusion: Intraoperative cystoscopy is used by a significant number of Canadian gynaecologists for the detection of lower urinary tract injuries during gynaecologic surgery. Lack of training is the primary barrier to use of cystoscopy, and increasing physician age and duration of practice>10 years are associated with decreased use of cystoscopy.

Background: Prior to the availability of modern laparoscopic surgical techniques and equipment, ectopic pregnancy was managed predominately by laparotomy. An alternative surgical approach, by posterior colpotomy, was advocated as a diagnostic and a therapeutic approach that often avoided laparotomy., Cases: We report two recent cases in which ectopic pregnancies were managed by posterior colpotomy to avoid any scars on the abdomen. One case involved a salpingectomy and the other a salpingostomy., Conclusion: Posterior colpotomy is a safe, cost-effective, and time efficient method of managing ectopic pregnancy.

Background: Jacobsen syndrome is a rare contiguous gene disorder that results from a terminal deletion of the long arm of chromosome 11. It is typically characterized by intellectual disability, a variety of physical anomalies and a distinctive facial appearance. The 11q deletion has traditionally been identified by routine chromosome analysis. Array-based comparative genomic hybridization (array-CGH) has offered new opportunities to identify and refine chromosomal abnormalities in regions known to be associated with clinical syndromes., Results: Using the 1 Mb BAC array (Spectral Genomics), we screened 70 chromosomally normal children with idiopathic intellectual disability (ID) and congenital abnormalities, and identified five cases with submicroscopic abnormalities believed to contribute to their phenotypes. Here, we provide detailed molecular cytogenetic descriptions and clinical presentation of two unrelated subjects with de novo submicroscopic deletions within chromosome bands 11q24-25. In subject 1 the chromosome rearrangement consisted of a 6.18 Mb deletion (from 128.25-134.43 Mb) and an adjacent 5.04 Mb duplication (from 123.15-128.19 Mb), while in subject 2, a 4.74 Mb interstitial deletion was found (from 124.29-129.03 Mb). Higher resolution array analysis (385 K Nimblegen) was used to refine all breakpoints. Deletions of the 11q24-25 region are known to be associated with Jacobsen syndrome (JBS: OMIM 147791). However, neither of the subjects had the typical features of JBS (trigonocephaly, platelet disorder, heart abnormalities). Both subjects had ID, dysmorphic features and additional phenotypic abnormalities: subject 1 had a kidney abnormality, bilateral preauricular pits, pectus excavatum, mild to moderate conductive hearing loss and behavioral concerns; subject 2 had macrocephaly, an abnormal MRI with delayed myelination, fifth finger shortening and squaring of all fingertips, and sensorineural hearing loss., Conclusion: Two individuals with ID who did not have the typical clinical features of Jacobsen syndrome were found to have deletions within the JBS region at 11q24-25. Their rearrangements facilitate the refinement of the JBS critical region and suggest that a) deletion of at least 3 of the 4 platelet function critical genes (ETS-1, FLI-1 and NFRKB and JAM3) is necessary for thrombocytopenia; b) one of the critical regions for heart abnormalities (conotruncal heart defects) may lie within 129.03 - 130.6 Mb; c) deletions of KCNJ1 and ADAMTS15 may contribute to the renal anomalies in Jacobsen Syndrome; d) the critical region for MRI abnormalities involves a region from 124.6 - 129.03 Mb. Our results reiterate the benefits of array-CGH for description of new phenotype/genotype associations and refinement of previously established ones.

This document has been archived because it contains outdated information. It should not be consulted for clinical use, but for historical research only. Please visit the journal website for the most recent guidelines.

This document has been archived because it contains outdated information. It should not be consulted for clinical use, but for historical research only. Please visit the journal website for the most recent guidelines.

The heterogeneity of autism spectrum disorders (ASDs) confounds attempts to identify causes and pathogenesis. Identifiable endophenotypes and reliable biomarkers within ASDs would help to focus molecular research and uncover genetic causes and developmental mechanisms. We used dense surface-modelling techniques to compare the facial morphology of 72 boys with ASD and 128 first-degree relatives to that of 254 unrelated controls. Pattern-matching algorithms were able to discriminate between the faces of ASD boys and those of matched controls (AUC=0.82) and also discriminate between the faces of unaffected mothers of ASD children and matched female controls (AUC=0.76). We detected significant facial asymmetry in boys with ASD (P<0.01), notably depth-wise in the supra- and periorbital regions anterior to the frontal pole of the right hemisphere of the brain. Unaffected mothers of children with ASD display similar significant facial asymmetry, more exaggerated than that in matched controls (P<0.03) and, in particular, show vertical asymmetry of the periorbital region. Unaffected fathers of children with ASD did not show facial asymmetry to a significant degree compared to controls. Two thirds of unaffected male siblings tested were classified unseen as more facially similar to unrelated boys with ASD than to unrelated controls. These unaffected male siblings and two small groups of girls with ASD and female siblings, all show overall directional asymmetry, but without achieving statistical significance in two-tailed t-tests of individual asymmetry of ASD family and matched control groups. We conclude that previously identified right dominant asymmetry of the frontal poles of boys with ASD could explain their facial asymmetry through the direct effect of brain growth. The atypical facial asymmetry of unaffected mothers of children with ASD requires further brain studies before the same explanation can be proposed. An alternative explanation, not mutually exclusive, is a simultaneous and parallel action on face and brain growth by genetic factors. Both possibilities suggest the need for coordinated face and brain studies on ASD probands and their first-degree relatives, especially on unaffected mothers, given that their unusual facial asymmetry suggests an ASD susceptibility arising from maternal genes.

Background: Maternal obesity and pre-pregnancy diabetes mellitus, features of the metabolic syndrome (MetSyn), are individual risk factors for neural tube defects (NTD). Whether they, in combination with additional features of MetSyn, alter this risk is not known. We evaluated the risk of NTD in association with maternal features of the MetSyn., Methods: We used a population-based case-control study design in the province of Ontario, Canada. Cases and controls were derived from women who underwent antenatal maternal screening (MSS) at 15 to 20 weeks' gestation. There were 89 maternal cases with, and 434 controls without, an NTD-affected singleton pregnancy. Maternal features of MetSyn were defined by the presence of pre-pregnancy diabetes mellitus, body weight > or = 90th centile among controls, non-white ethnicity and/or serum highly sensitive C-reactive protein (hsCRP) > or = 75th centile of controls. Since hsCRP naturally increases in pregnancy, analyses were performed with, and without, the inclusion of hsCRP in the model., Results: Mean hsCRP concentrations were exceptionally high among study cases and controls (6.1 and 6.4 mg/L, respectively). When hsCRP was excluded from the model, the adjusted odds ratios for NTD were 1.9 (95% confidence interval 1.1-3.4) in the presence 1 feature of MetSyn, and 6.1 (1.1-32.9) in the presence of 2 or more features. When hsCRP was included, the respective risk estimates were attenuated to 1.6 (0.88-2.8) and 3.1 (1.2-8.3)., Conclusion: We found about 2-fold and 6-fold higher risk for NTD in the presence 1, and 2 or more features, of the metabolic syndrome, respectively. It is not clear whether this risk is altered by the presence of a high serum hsCRP concentration.

Objective: The objective of the study was to evaluate the effectiveness of a new self-positioning women's incontinence pessary., Study Design: Thirty-two women were enrolled and followed up for 12 months. Evaluation included baseline questionnaires, physical examination including pelvic organ prolapse quantification (POP-Q) scores, cotton swab testing, and assessment of Kegel strength. A pad test and 7 day urolog were also performed before and after pessary fitting., Results: Incontinence questionnaire scores were all significantly reduced as percent of baseline: stress incontinence, 7 of 15 (47%) (P = .000); urge incontinence, 5 of 14 (36%) (P = .002); the urogenital distress inventory (short form); 2 of 6 (33%) (P = .002); and incontinence impact questionnaire (short form), 4 of 8 (50%) (P = .002). Leaking episodes decreased by 4 (7 day urolog) (P = .028) and pad weights by 11 g (P = .006). Among women successfully fitted at 2 weeks, 16 of 21 or 76% continued using their pessary at 1 year. There were no complications with pessary use., Conclusion: The Uresta incontinence pessary significantly reduces urinary incontinence and is easy for women to use.

Background: Low maternal vitamin B(12) status may be a risk factor for neural tube defects (NTDs). Prior studies used relatively insensitive measures of B(12), did not adjust for folate levels, and were conducted in countries without folic acid food fortification. In Canada, flour has been fortified with folic acid since mid-1997., Methods: We completed a population-based case-control study in Ontario. We measured serum holotranscobalamin (holoTC), a sensitive indicator of B(12) status, at 15 to 20 weeks' gestation. There were 89 women with an NTD and 422 unaffected pregnant controls. A low serum holoTC was defined as less than 55.3 pmol/L, the bottom quartile value in the controls., Results: The geometric mean serum holoTC levels were 67.8 pmol/L in cases and 81.2 pmol/L in controls. There was a trend of increasing risk with lower levels of holoTC, reaching an adjusted odds ratio of 2.9 (95% confidence interval = 1.2-6.9) when comparing the lowest versus highest quartile., Conclusions: There was almost a tripling in the risk for NTD in the presence of low maternal B(12) status, measured by holoTC. The benefits of adding synthetic B(12) to current recommendations for periconceptional folic acid tablet supplements or folic-acid-fortified foods need to be considered. It remains to be determined what fraction of NTD cases in a universally folate-fortified environment might be prevented by higher periconceptional intake of B(12).

Objective: To outline the evidence for the efficacy of surgical procedures used for the primary treatment of urinary incontinence., Options: The range of surgical options available for the primary treatment of urinary incontinence in women., Outcomes: The best possible outcomes for women undergoing primary surgery for urinary incontinence. To provide a current understanding of the evidence available as the basis of an informed discussion of the anticipated outcome of surgery., Evidence: A systematic review of clinical trials of the outcomes of primary surgical treatment of urinary incontinence., Values: The quality of the evidence is rated using the criteria described by the Canadian Task Force on periodic health examination (Table)., Benefits, Harms, and Costs: Careful consideration of the surgical options available will result in informed choice, which is essential to the process of determining the most appropriate surgery for a woman. Use of a range of surgeries that have the highest proven efficacy is most likely to result in long-term patient satisfaction.

Objective: Urinary incontinence (UI) is a prevalent health issue that has significant detrimental effects on quality of life. The Internet offers a unique vehicle for incontinent women to access information that could facilitate conservative self-help therapy. An evaluation of Canadian websites offering female UI information was conducted to determine their quality and readability., Methods: We evaluated websites using published general quality criteria for health sites and a quality assessment tool compiled by the authors for specific UI information derived from published, peer-reviewed clinical practice guidelines. Three health care professionals reviewed sites for quality, Canadian content, and interactivity. The readability of health information was also evaluated., Results: Fifty-six Canadian sites (18 professional, 22 organizational, 16 commercial) were evaluated. Significant agreement was found among the raters' evaluations on all measures. For all sites, the mean scores were general quality, 9/14; specific UI quality, 30/122; reading ease, 37/100; grade level, 10.9. The median score for Canadian content was high, but for interactivity it was low. The only significant difference between site types was for general quality (F [2,165]=3.38, P=0.036). Post hoc Tukey's tests showed a significant difference between organizational and commercial sites, with organizational sites having higher general quality., Conclusion: Canadian websites providing female UI information have moderately high general quality, low specific UI information quality, minimal interactivity, and more than minimal Canadian content. The reading level of most sites is too high for average consumers. A webliography of the best sites has been developed to guide patients.

Objectives: 1. To present the prenatal cytogenetic findings and postnatal outcome of 12 cases with an isodicentric chromosome composed of the short arm of the Y chromosome.2. To review the literature and provide recommendations for cytogenetic analysis and counseling., Methods: Prenatal and postnatal cytogenetic data and clinical findings of isodicentric Yp ascertained in six institutions were gathered and reviewed., Results: Nine of the twelve cases were referred for advanced maternal age (AMA), one of which was a twin pregnancy with one twin having an increased nuchal translucency measurement. The remaining cases were referred owing to a family history of hemophilia and an abnormal maternal serum screen, respectively. Nine of these pregnancies resulted in the birth of a normal-appearing male infant with subsequent normal growth and psychomotor development. Follow-up ranged from birth to 7 years. In two cases, the pregnancy was terminated and the fetuses showed male external genitalia. In the case ascertained because of an increased nuchal translucency measurement, the prenatal diagnosis of 45,X was made. At birth, there were ambiguous genitalia, and postnatal cytogenetic studies found an isodicentric Yp. In 11 of the 12 cases, mosaicism was present., Conclusion: Our cases show that the prenatal finding of an isodicentric Yp, with or without 45,X mosaicism, is compatible with normal male phenotype in most cases, particularly in the absence of other anomalies. To ensure accuracy in cytogenetic reporting and prenatal counseling, the identification of a structurally abnormal or small Y chromosome, either alone or in the presence of 45,X colonies, should be followed immediately by confirmatory molecular cytogenetic investigations as well as by ultrasound determination of the phenotypic sex of the fetus., (Copyright 2006 John Wiley & Sons, Ltd.)

This document has been archived because it contains outdated information. It should not be consulted for clinical use, but for historical research only. Please visit the journal website for the most recent guidelines.