Guideline No. 441: Antenatal Fetal Health Surveillance.

OBJECTIVE: To summarize the current evidence and to make recommendations for antenatal fetal health surveillance (FHS) to detect perinatal risk factors and potential fetal decompensation in the antenatal period and to allow for timely intervention to prevent perinatal morbidity and/or mortality. TARGET POPULATION: Pregnant individuals with or without maternal, fetal, or pregnancy-associated perinatal risk factors for antenatal fetal decompensation. OPTIONS: To use basic and/or advanced antenatal testing modalities, based on risk factors for potential fetal decompensation. OUTCOMES: Early identification of potential fetal decompensation allows for interventions that may support fetal adaptation to maintain well-being or expedite delivery. BENEFITS, HARMS, AND COSTS: Antenatal FHS in pregnant individuals with identified perinatal risk factors may reduce the chance of adverse outcomes. Given the high false-positive rate, FHS may increase unnecessary interventions, which may result in harm, including parental anxiety, premature or operative birth, and increased use of health care resources. Optimization of surveillance protocols based on evidence-informed practice may improve perinatal outcomes and reduce harm. EVIDENCE: Medline, PubMed, Embase, and the Cochrane Library were searched from inception to January 2022, using medical subject headings (MeSH) and key words related to pregnancy, fetal monitoring, fetal movement, stillbirth, pregnancy complications, and fetal sonography. This document represents an abstraction of the evidence rather than a methodological review. VALIDATION METHODS: The authors rated the quality of evidence and strength of recommendations using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. See online Appendix A (Tables A1 for definitions and A2 for interpretations of strong and weak recommendations). INTENDED AUDIENCE: All health care team members who provide care for or education to obstetrical patients, including maternal fetal medicine specialists, obstetricians, family physicians, midwives, nurses, nurse practitioners, and radiologists. SUMMARY STATEMENTS: RECOMMENDATIONS.

Directive clinique no 441 : Surveillance prénatale du bien-être fœtal.

OBJECTIF: Résumer les données probantes actuelles et formuler des recommandations pour la surveillance prénatale du bien-être fœtal afin de détecter les facteurs de risque périnatal et toute potentielle décompensation fœtale et de permettre une intervention rapide en prévention de la morbidité et la mortalité périnatales. POPULATION CIBLE: Personnes enceintes avec ou sans facteurs maternels, fœtaux ou gravidiques associés à des risques périnataux et à la décompensation fœtale. OPTIONS: Utiliser des examens prénataux par technologie de base et/ou avancée en fonction des facteurs de risque de décompensation fœtale. RéSULTATS: La reconnaissance précoce de toute décompensation fœtale potentielle permet d'intervenir de façon à favoriser l'adaptation fœtale pour maintenir le bien-être ou à accélérer l'accouchement. BéNéFICES, RISQUES ET COûTS: Chez les personnes enceintes ayant des facteurs de risque périnatal confirmés, la surveillance du bien-être fœtal contribue à réduire le risque d'issue défavorable. Compte tenu du taux élevé de faux positifs, la surveillance du bien-être fœtal peut augmenter le risque d'interventions inutiles, ce qui peut avoir des effets nuisibles, dont l'anxiété parentale, l'accouchement prématuré ou assisté et l'utilisation accrue des ressources de soins de santé. L'optimisation des protocoles de surveillance d'après des pratiques fondées sur des données probantes peut améliorer les issues périnatales et réduire les effets nuisibles. DONNéES PROBANTES: Des recherches ont été effectuées dans les bases de données Medline, PubMed, Embase et Cochrane Library, de leur création jusqu'à janvier 2022, à partir de termes MeSH et de mots clés liés à la grossesse, à la surveillance fœtale, aux mouvements fœtaux, à la mortinaissance, aux complications de grossesse et à l'échographie fœtale. Le présent document est un résumé des données probantes et non pas une revue méthodologique. MéTHODES DE VALIDATION: Les auteurs ont évalué la qualité des données probantes et la force des recommandations en utilisant le cadre méthodologique GRADE (Grading of Recommendations Assessment, Development and Evaluation). Voir l'annexe A en ligne (tableau A1 pour les définitions et tableau A2 pour l'interprétation des recommandations fortes et faibles). PROFESSIONNELS CONCERNéS: Tous les membres de l'équipe de soins qui prodiguent des soins ou donnent de l'information aux patientes en obstétrique, notamment les spécialistes en médecine fœto-maternelle, les obstétriciens, les médecins de famille, les sages-femmes, les infirmières, les infirmières praticiennes et les radiologistes. DÉCLARATIONS SOMMAIRES: RECOMMANDATIONS.

Leflunomide exposure through second trimester of pregnancy: A case report.

Leflunomide is a commonly used disease modifying antirheumatic agent. However, its use is contraindicated in pregnancy. The American College of Rheumatology (ACR) guidelines recommend discontinuing Leflunomide at least 24 months before conception. If a woman is found to be pregnant while on Leflunomide, ACR suggests close monitoring and cholestyramine washout. We describe a case of a patient with a history of juvenile idiopathic arthritis who was on Leflunomide throughout the first and second trimester of her pregnancy. A cholestyramine washout regimen was started but not completed. The patient was induced at 37 weeks of gestation due to non-reassuring fetal heart rate. She ultimately delivered a healthy baby via emergency cesarian section.

Getting on with life: a qualitative evaluation of an independent living skills education program for people with physical disabilities.

Background: The Independent Living Movement seeks to promote independence for people living with disabilities by encouraging them to direct their own care. Programs exist that strive to teach individuals the necessary skills to live independently; however, these programs have not been widely researched.Purpose: The purpose of this paper is to explore alumni perceptions of a long-duration, immersive, independent living program and its influence on community independent living.Methods: Nine individuals who had previously attended the Gage Transition to Independent Living program in urban Toronto were interviewed to ascertain their perceptions on the program and how it assisted with independent community living, as well as their feedback for program improvement.Results: Most participants reported a positive impact from the program, and five main themes were developed: (i) referral source and expectations, (ii) perspectives of program and staff, (iii) navigating housing, (iv) benefits to transition and (v) recommendations for program improvement.Conclusions: Independent living skills education programs seem to have a positive impact on the participants who complete them. Further research should target direct comparisons of program models and effect on quality of life as measured by validated constructs.IMPLICATIONS FOR REHABILITATIONIncorporating a life skills component for individuals with physical disabilities can improve their transition to independent living.Skills such as self-advocacy, directing attendant services, and completing instrumental activities of daily living are found to be the most efficacious components taught within an independent living skills program.Greater awareness of independent living skills educational programs are needed amongst healthcare professionals to inform individuals who could benefit from such interventions.

RAC1 activation drives pathologic interactions between the epidermis and immune cells.

Interactions between the epidermis and the immune system govern epidermal tissue homeostasis. These epidermis-immune interactions are altered in the inflammatory disease psoriasis; however, the pathways that underlie this aberrant immune response are not well understood. Here, we determined that Ras-related C3 botulinum toxin substrate 1 (RAC1) is a key mediator of epidermal dysfunction. RAC1 activation was consistently elevated in psoriatic epidermis and primary psoriatic human keratinocytes (PHKCs) exposed to psoriasis-related stimuli, but not in skin from patients with basal or squamous cell carcinoma. Expression of a constitutively active form of RAC1 (RACV12) in mice resulted in the development of lesions similar to those of human psoriasis that required the presence of an intact immune system. RAC1V12-expressing mice and human psoriatic skin showed similar RAC1-dependent signaling as well as transcriptional overlap of differentially expressed epidermal and immune pathways. Coculture of PHKCs with immunocytes resulted in the upregulation of RAC1-dependent proinflammatory cytokines, an effect that was reproduced by overexpressing RAC1 in normal human keratinocytes. In keratinocytes, modulating RAC1 activity altered differentiation, proliferation, and inflammatory pathways, including STAT3, NFκB, and zinc finger protein 750 (ZNF750). Finally, RAC1 inhibition in xenografts composed of human PHKCs and immunocytes abolished psoriasiform hyperplasia and inflammation in vivo. These studies implicate RAC1 as a potential therapeutic target for psoriasis and as a key orchestrator of pathologic epidermis-immune interactions.

Autoantigens in vitiligo identified by the serological selection of a phage-displayed melanocyte cDNA expression library.

Vitiligo is an acquired idiopathic hypomelanotic disorder characterized by circumscribed depigmented macules resulting from the loss of cutaneous melanocytes. Although the exact cause of vitiligo remains obscure, autoimmunity may play a role in the development of the disease. The present study was undertaken to investigate the applicability of phage display technology to identify B-cell autoantigens in vitiligo. A melanocyte cDNA phage display library was subjected to rounds of enrichment with vitiligo patient IgG. Subsequently, enriched IgG-binding peptides representing putative autoantigens were identified by sequencing their encoding cDNAs. Radioimmunoassays were used to confirm the immunoreactivity of vitiligo patient (n=61) and control (n=28) sera to several of the putative autoantigens. Non-segmental vitiligo patient sera (n=53) were positive for antibody (Ab) reactivity to gamma-enolase (8%); alpha-enolase (9%); heat-shock protein 90 (13%); osteopontin (4%); ubiquitin-conjugating enzyme (15%); translation-initiation factor 2 (6%); and GTP-binding protein, Rab38 (15%). Ab reactivity to at least one of the previously unknown autoantigens was detected in 51% of patients with non-segmental vitiligo. In contrast, Ab reactivity in a group of patients with segmental vitiligo (n=8) was not demonstrated. Overall, the study indicated that the targets of autoantibodies in vitiligo patients can be revealed by employing the methodology of phage display.

Evidence of a role for osteoprotegerin in the pathogenesis of pulmonary arterial hypertension.

Pulmonary artery smooth muscle cell (PA-SMC) migration and proliferation are key processes in the pathogenesis of pulmonary arterial hypertension (PAH). Recent information suggests that abnormalities in the bone morphogenetic protein (BMP) receptor 2 (BMP-R2) signaling pathway are important in PAH pathogenesis. It remains unclear whether and how this pathway interacts with, for example, serotonin (5-HT) and inflammation to trigger and/or sustain the development of PAH. The secreted glycoprotein osteoprotegerin (OPG) is emerging as an important regulatory molecule in vascular biology and is modulated by BMPs, 5-HT, and interleukin-1 in other cell types. However, whether OPG is expressed by PA-SMCs within PAH lesions and plays a role in PAH is unknown. Immunohistochemistry of human PAH lesions demonstrated increased OPG expression, and OPG was significantly increased in idiopathic PAH patient serum. Recombinant OPG stimulated proliferation and migration of PA-SMCs in vitro, and BMP-R2 RNA interference increased OPG secretion. Additionally, both 5-HT and interleukin-1 also increased OPG secretion. These data are the first to demonstrate that OPG is increased in PAH and that it can regulate PA-SMC proliferation and migration. OPG may provide a common link between the different pathways associated with the disease, potentially playing an important role in the pathogenesis of PAH.

The antibody MAB8051 directed against osteoprotegerin detects carbonic anhydrase II: implications for association studies with human cancers.

A commonly used monoclonal antibody targeting osteoprotegerin (OPG), MAB8051, detects a truncated protein species in breast and prostate cancer cell lysates. OPG expression has been reported to contribute to cell survival of both of these cancers. We hypothesised that the truncated protein represented a unique tumour-associated OPG isoform. However, here we show that the truncated protein identified by MAB8051 in cancer cell lines is carbonic anhydrase II (CA II), also implicated in tumour biology. We clearly demonstrate cross-reactivity of this OPG antibody in western blots. OPG and CA II RNA-interference studies confirmed the identity of the bands. We show almost identical staining patterns between MAB8051 and CA II immunohistochemistry of different human tissue types and human tumour types using serial sections. We conclude that care should be exercised using this antibody for immunohistochemistry studies, without additional in situ hybridisation, or parallel use of other OPG-specific antibodies.

A laminin-collagen complex drives human epidermal carcinogenesis through phosphoinositol-3-kinase activation.

Laminin-332 (formerly laminin-5) and collagen VII are basement membrane proteins expressed at the invasive front of human squamous cell carcinoma (SCC) tumors. These proteins have protumorigenic properties, but whether laminin-332 and collagen VII promote SCC tumors by providing adhesion or other nonadhesive extracellular cues, or whether laminin-332 and collagen VII interact together in this process remains unknown. In this study, we examined the role of these molecules by a structural approach using an in vivo model of human SCC tumorigenesis. Here, we show that individual domains (VI and V-III) on the laminin-332 beta3 chain provide distinct and highly divergent cell adhesion and tumor-promoting functions. We found that laminin beta3 domain VI provided a critical role in the assembly of stable adhesion complexes, but this domain was not required in SCC tumors. Instead, we found that laminin beta3 domain V-III played an essential role in SCC carcinogenesis/invasion through binding to collagen VII, which in turn, led to phosphoinositol-3-kinase activation and protection from apoptosis. Overexpression of constitutively active p110 phosphoinositol-3-kinase subunit was sufficient to restore invasion and tumorigenesis in transformed cells lacking laminin-332/collagen VII interaction in a manner independent of cellular adhesion. These studies show distinctive adhesive and signaling functions in individual domains of laminin-332, one which is required for normal epithelial adhesion and one which is required for SCC tumorigenesis. This uncoupling of stable adhesion from tumor progression in our studies suggests that laminin-332/collagen VII interaction promotes epidermal carcinogenesis through signaling rather than adhesion.

Autoantibodies in vitiligo patients recognize multiple domains of the melanin-concentrating hormone receptor.

Previously, we reported the identification of autoantibodies against the melanin-concentrating hormone receptor 1 in patients with vitiligo. In this study, the B cell epitopes on melanin-concentrating hormone receptor 1 that are recognized by these autoantibodies have been identified. Deletion derivatives of melanin-concentrating hormone receptor 1 complementary DNA were constructed and then translated in vitro with the concomitant incorporation of [35S]-methionine into the protein products. The [35S]-labeled melanin-concentrating hormone receptor 1 derivatives were subsequently used in radio-binding assays to investigate the reactivity of sera from nine vitiligo patients that were known to contain antibodies to the receptor. Analysis of the results obtained in the radio-binding assays suggested the existence of multiple antibody binding sites on melanin-concentrating hormone receptor 1, including regions between amino acids 1 to 138 and 139 to 298. Several patients exhibited autoantibodies to more than one melanin-concentrating hormone receptor 1 epitope indicating a heterogeneous humoral response to the receptor. Computer prediction of the potential B cell epitopes on melanin-concentrating hormone receptor 1 revealed that the epitope domains identified overlapped, at least in part, with regions predicted to be highly antigenic.

Hydralazine for treatment of severe hypertension in pregnancy: meta-analysis.

OBJECTIVE: To review outcomes in randomised controlled trials comparing hydralazine against other antihypertensives for severe hypertension in pregnancy. STUDY DESIGN: Meta-analysis of randomised controlled trials (published between 1966 and September 2002) of short acting antihypertensives for severe hypertension in pregnancy. Independent data abstraction by two reviewers. Data were entered into RevMan software for analysis (fixed effects model, relative risk and 95% confidence interval); in a secondary analysis, risk difference was also calculated. RESULTS: Of 21 trials (893 women), eight compared hydralazine with nifedipine and five with labetalol. Hydralazine was associated with a trend towards less persistent severe hypertension than labetalol (relative risk 0.29 (95% confidence interval 0.08 to 1.04); two trials), but more severe hypertension than nifedipine or isradipine (1.41 (0.95 to 2.09); four trials); there was significant heterogeneity in outcome between trials and differences in methodological quality. Hydralazine was associated with more maternal hypotension (3.29 (1.50 to 7.23); 13 trials); more caesarean sections (1.30 (1.08 to 1.59); 14 trials); more placental abruption (4.17 (1.19 to 14.28); five trials); more maternal oliguria (4.00 (1.22 to 12.50); three trials); more adverse effects on fetal heart rate (2.04 (1.32 to 3.16); 12 trials); and more low Apgar scores at one minute (2.70 (1.27 to 5.88); three trials). For all but Apgar scores, analysis by risk difference showed heterogeneity between trials. Hydralazine was associated with more maternal side effects (1.50 (1.16 to 1.94); 12 trials) and with less neonatal bradycardia than labetalol (risk difference -0.24 (-0.42 to -0.06); three trials). CONCLUSIONS: The results are not robust enough to guide clinical practice, but they do not support use of hydralazine as first line for treatment of severe hypertension in pregnancy. Adequately powered clinical trials are needed, with a comparison of labetalol and nifedipine showing the most promise.

Alpha 6 beta 4 integrin regulates keratinocyte chemotaxis through differential GTPase activation and antagonism of alpha 3 beta 1 integrin.

Growth factor-induced cell migration and proliferation are essential for epithelial wound repair. Cell migration during wound repair also depends upon expression of laminin-5, a ligand for alpha 6 beta 4 integrin. We investigated the role of alpha 6 beta 4 integrin in laminin-5-dependent keratinocyte migration by re-expressing normal or attachment-defective beta 4 integrin in beta 4 integrin null keratinocytes. We found that expression of beta 4 integrin in either a ligand bound or ligand unbound state was necessary and sufficient for EGF-induced cell migration. In a ligand bound state, beta 4 integrin supported EGF-induced cell migration though sustained activation of Rac1. In the absence of alpha 6 beta 4 integrin ligation, Rac1 activation became tempered and EGF chemotaxis proceeded through an alternate mechanism that depended upon alpha 3 beta 1 integrin and was characterized by cell scattering. alpha 3 beta 1 integrin also relocalated from cell-cell contacts to sites of basal clustering where it displayed increased conformational activation. The aberrant distribution and activation of alpha 3 beta 1 integrin in attachment-defective beta 4 cells could be reversed by the activation of Rac1. Conversely, in WT beta 4 cells the normal cell-cell localization of alpha 3 beta 1 integrin became aberrant after the inhibition of Rac1. These studies indicate that the extracellular domain of beta 4 integrin, through its ability to bind ligand, functions to integrate the divergent effects of growth factors on the cytoskeleton and adhesion receptors so that coordinated keratinocyte migration can be achieved.

Immunoscreening of phage-displayed cDNA-encoded polypeptides identifies B cell targets in autoimmune disease.

Characterisation of self-antigens can contribute to an understanding of the aetiology of autoimmune disorders as well as to the development of new therapies and diagnostic methods. The present study was undertaken to investigate the applicability of complementary DNA (cDNA) phage-display technology to the identification of autoantigens recognised by the humoral response in autoimmune disease. Using systemic lupus erythematosus (SLE) as a model system, a pool of patient immunoglobulin G (IgG) was biopanned on a fibroblast cDNA phage-display library constructed in the vector pJuFo. Following three rounds of biopanning, recovered cDNAs were sequenced and then identified using BLAST comparisons with international databases. Both previously reported SLE autoantigens, for example, alpha-enolase and U1 small nuclear ribonucleoprotein-C (U1snRNP-C), and novel autoantibody targets, including ribosomal protein S20 (RPS20), ribosomal protein S13 (RPS13), ubiquitin-like protein PIC1 (PIC1), and transcription factor-like protein MRG15 (MRG15), were recovered from the biopanning procedure. Radiobinding assays were used subsequently to confirm the reactivity of some putative autoantigens to panels of sera from SLE patients, control patient groups, and healthy individuals. SLE patient sera were positive for reactivity to: U1snRNP-C, 4/15 (27%); alpha-enolase, 1/15 (7%); RPS20, 3/15 (20%); RPS13, 1/15 (7%); PIC1, 1/15 (7%); and MRG15, 2/15 (13%). Overall, cDNA phage-display technology appears to be applicable to the identification of autoantigens in autoimmune disease.

The melanin-concentrating hormone receptor 1, a novel target of autoantibody responses in vitiligo.

Vitiligo is a common depigmenting disorder resulting from the loss of melanocytes in the skin. The pathogenesis of the disease remains obscure, although autoimmune mechanisms are thought to be involved. Indeed, autoantibodies and autoreactive T lymphocytes that target melanocytes have been reported in some vitiligo patients. The objective of this study was to identify pigment cell antigens that are recognized by autoantibodies in vitiligo. Using IgG from vitiligo patients to screen a melanocyte cDNA phage-display library, we identified the melanin-concentrating hormone receptor 1 (MCHR1) as a novel autoantigen related to this disorder. Immunoreactivity against the receptor was demonstrated in vitiligo patient sera by using radiobinding assays. Among sera from healthy controls and from patients with autoimmune disease, none exhibited immunoreactivity to MCHR1, indicating a high disease specificity for Ab's against the receptor. Inhibition of MCH binding to its receptor by IgG from vitiligo patients was also shown.