Refining the phenotype associated with biallelic DNAJC21 mutations

Accepted manuscriptInherited bone marrow failure syndromes (IBMFS) are caused by mutations in genes involved in genomic stability. Although they may be recognized by the association of typical clinical features, variable penetrance and expressivity are common, and clinical diagnosis is often challenging. DNAJC21, which is involved in ribosome biogenesis, was recently linked to bone marrow failure. However, the specific phenotype and natural history remain to be defined. We correlate molecular data, phenotype, and clinical history of 5 unreported affected children and all individuals reported in the literature. All patients present features consistent with IBMFS: bone marrow failure, growth retardation, failure to thrive, developmental delay, recurrent infections, and skin, teeth or hair abnormalities. Additional features present in some individuals include retinal abnormalities, pancreatic insufficiency, liver cirrhosis, skeletal abnormalities, congenital hip dysplasia, joint hypermobility, and cryptorchidism. We suggest that DNAJC21-related diseases constitute a distinct IBMFS, with features overlapping Shwachman-Diamond syndrome and Dyskeratosis congenita, and additional characteristics that are specific to DNAJC21 mutations. The full phenotypic spectrum, natural history, and optimal management will require more reports. Considering the aplastic anemia, the possible increased risk for leukemia, and the multisystemic features, we provide a checklist for clinical evaluation at diagnosis and regular follow-up.FCT—Fundação para a Ciência e a Tecnologia (SFRH/BD/84650/2010)info:eu-repo/semantics/publishedVersio

Clinical Practice Guidelines for Childbearing Female Candidates for Bariatric Surgery, Pregnancy, and Post-partum Management After Bariatric Surgery

Emerging evidence suggests that bariatric surgery improves pregnancy outcomes of women with obesity by reducing the rates of gestational diabetes, pregnancy-induced hypertension, and macrosomia. However, it is associated with an increased risk of a small-for-gestational-age fetus and prematurity. Based on the work of a multidisciplinary task force, we propose clinical practice recommendations for pregnancy management following bariatric surgery. They are derived from a comprehensive review of the literature, existing guidelines, and expert opinion covering the preferred type of surgery for women of childbearing age, timing between surgery and pregnancy, contraception, systematic nutritional support and management of nutritional deficiencies, screening and management of gestational diabetes, weight gain during pregnancy, gastric banding management, surgical emergencies, obstetrical management, and specific care in the postpartum period and for newborns

Clusterin, a haploinsufficient tumor suppressor gene in neuroblastomas

This article is available open access through the publisher’s website. Copyright @ 2009 The Authors.Background - Clusterin expression in various types of human cancers may be higher or lower than in normal tissue, and clusterin may promote or inhibit apoptosis, cell motility, and inflammation. We investigated the role of clusterin in tumor development in mouse models of neuroblastoma. Methods - We assessed expression of microRNAs in the miR-17-92 cluster by real-time reverse transcription–polymerase chain reaction in MYCN-transfected SH-SY5Y and SH-EP cells and inhibited expression by transfection with microRNA antisense oligonucleotides. Tumor development was studied in mice (n = 66) that were heterozygous or homozygous for the MYCN transgene and/or for the clusterin gene; these mice were from a cross between MYCN-transgenic mice, which develop neuroblastoma, and clusterin-knockout mice. Tumor growth and metastasis were studied in immunodeficient mice that were injected with human neuroblastoma cells that had enhanced (by clusterin transfection, four mice per group) or reduced (by clusterin short hairpin RNA [shRNA] transfection, eight mice per group) clusterin expression. All statistical tests were two-sided. Results - Clusterin expression increased when expression of MYCN-induced miR-17-92 microRNA cluster in SH-SY5Y neuroblastoma cells was inhibited by transfection with antisense oligonucleotides compared with scrambled oligonucleotides. Statistically significantly more neuroblastoma-bearing MYCN-transgenic mice were found in groups with zero or one clusterin allele than in those with two clusterin alleles (eg, 12 tumor-bearing mice in the zero-allele group vs three in the two-allele group, n = 22 mice per group; relative risk for neuroblastoma development = 4.85, 95% confidence interval [CI] = 1.69 to 14.00; P = .005). Five weeks after injection, fewer clusterin-overexpressing LA-N-5 human neuroblastoma cells than control cells were found in mouse liver or bone marrow, but statistically significantly more clusterin shRNA-transfected HTLA230 cells (3.27%, with decreased clusterin expression) than control-transfected cells (1.53%) were found in the bone marrow (difference = 1.74%, 95% CI = 0.24% to 3.24%, P = .026). Conclusions - We report, to our knowledge, the first genetic evidence that clusterin is a tumor and metastasis suppressor gene.Sport Aiding Medical Research for Kids (SPARKS), Great Ormond Street Hospital/National Health Service, the National Cancer Institute and University of Parma

E-Cadherin mediates UVR- and calcium-induced melanin transfer in human skin cells

yesSkin pigmentation is directed by epidermal-melanin units, characterized by long-lived and dendritic epidermal melanocytes (MC) that interact with viable keratinocytes (KC) to contribute melanin to the epidermis. Previously we reported that MC:KC contact is required for melanosome transfer, that this can be enhanced by filopodial and by UVR/UVA irradiation, which can up-regulate melanosome transfer via Myosin X-mediated control of MC filopodia. Both MC and KC express Ca2+-dependent E-cadherins. These homophilic adhesion contacts induce transient increases in intra-KC Ca2+, while ultraviolet radiation (UVR) raises intra-MC Ca2+ via calcium selective ORAI1 ion channels; both are associated with regulating melanogenesis. However, how Ca2+ triggers melanin transfer remains unclear, and here we evaluated the role of E-Cadherin in UVR-mediated melanin transfer in human skin cells. MC and KC in human epidermis variably express filopodia-associated E-Cadherin, Cdc42, VASP and β-catenin, all of which were upregulated by UVR/UVA in human MC in vitro. Knockdown of E-cadherin revealed that this cadherin is essential for UVR-induced MC filopodia formation and melanin transfer. Moreover, Ca2+ induced a dose-dependent increase in filopodia formation and melanin transfer, as well as increased β-catenin, Cdc42, Myosin X, and E-Cadherin expression in these skin cells. Together these data suggest that filopodial proteins and E-Cadherin, which are upregulated by intracellular (UVR-stimulated) and extracellular Ca2+ availability, are required for filopodia formation and melanin transfer. This may open new avenues to explore how Ca2+ signalling influences human pigmentation

Pessaries in multiple pregnancy as a prevention of preterm birth: the ProTwin Trial

Contains fulltext : 79491.pdf (publisher's version ) (Open Access)BACKGROUND: Multiple pregnancies are at high risk for preterm birth, and therefore an important cause of infant mortality and morbidity. A pessary is a simple and potentially effective measure for the prevention of preterm birth. Small studies have indicated its effectiveness, but large studies with sufficient power on the subject are lacking. Despite this lack of evidence, the treatment is at present applied by some gynaecologists in The Netherlands. METHODS/DESIGN: We aim to investigate the hypothesis that prophylactic use of a cervical pessary will be effective in the prevention of preterm delivery and the neonatal mortality and morbidity resulting from preterm delivery in multiple pregnancy. We will evaluate the costs and effects of this intervention. At study entry, cervical length will be measured. Eligible women will be randomly allocated to receive either a cervical pessary or no intervention. The cervical pessary will be placed in situ at 16 to 20 weeks, and will stay in situ up to 36 weeks gestation or until delivery, whatever comes first.The primary outcome is composite bad neonatal condition (perinatal death or severe morbidity). Secondary outcome measures are time to delivery, preterm birth rate before 32 and 37 weeks, days of admission in neonatal intensive care unit, maternal morbidity, maternal admission days for preterm labour and costs. We need to include 660 women to indicate a reduction in bad neonatal outcome from 7.2% without to 3.9% with a cervical pessary, using a two-sided test with an alpha of 0.05 and a power of 0.80. DISCUSSION: This trial will provide evidence on whether a cervical pessary will decrease the incidence of early preterm birth and its concomitant bad neonatal outcome in multiple pregnancies. TRIAL REGISTRATION: Current Controlled Trials: NTR 1858

Women's perceptions of homebirths in two rural medical districts in Burkina Faso: a qualitative study

<p>Abstract</p> <p>Background</p> <p>In developing countries, most childbirth occurs at home and is not assisted by skilled attendants. The situation increases the risk of death for both mother and child and has severe maternal complications. The purpose of this study was to describe women's perceptions of homebirths in the medical districts of Ouargaye and Diapaga.</p> <p>Methods</p> <p>A qualitative approach was used to gather information. This information was collected by using focus group discussions and individual interviews with 30 women. All the interviews were tape recorded and managed by using QSR NVIVO 2.0, qualitative data management software.</p> <p>Results</p> <p>The findings show that homebirths are frequent because of prohibitive distance to health facilities, fast labour and easy labour, financial constraints, lack of decision making power to reach health facilities.</p> <p>Conclusion</p> <p>The study echoes the need for policy makers to make health facilities easily available to rural inhabitants to forestall maternal and child deaths in the two districts.</p

The effect of high tibial osteotomy on the results of total knee arthroplasty: a matched case control study

BACKGROUND: We performed a matched case control study to assess the effect of prior high tibia valgus producing osteotomy on results and complications of total knee arthroplasty (TKA). METHODS: From 1996 until 2003 356 patients underwent all cemented primary total knee replacement in our institution. Twelve patients with a history of 14 HTO were identified and matched to a control group of 12 patients with 14 primary TKA without previous HTO. The match was made for gender, age, date of surgery, body mass index, aetiology and type of prosthesis. Clinical and radiographic outcome were evaluated after a median duration of follow-up of 3.7 years (minimum, 2.3 years). The SPSS program was used for statistical analyses. RESULTS: The index group had more perioperative blood loss and exposure difficulties with one tibial tuberosity osteotomy and three patients with lateral retinacular releases. No such procedures were needed in the control group. Mid-term HSS, KSS and WOMAC scores were less favourable for the index group, but these differences were not significant. The tibial slope of patients with prior HTO was significantly decreased after this procedure. The tibial posterior inclination angle was corrected during knee replacement but posterior inclination was significantly less compared to the control group. No deep infection or knee component loosening were seen in the group with prior HTO. CONCLUSION: We conclude that TKA after HTO seems to be technically more demanding than a primary knee arthroplasty, but clinical outcome was almost identical to a matched group that had no HTO previously

Proportional lumbar spine inter-vertebral motion patterns: a comparison of patients with chronic, non-specific low back pain and healthy controls

Introduction: Identifying biomechanical subgroups in chronic, non-specific low back pain (CNSLBP) populations from inter-vertebral displacements has proven elusive. Quantitative fluoroscopy (QF) has excellent repeatability and provides continuous standardised inter-vertebral kinematic data from fluoroscopic sequences allowing assessment of mid-range motion. The aim of this study was to determine whether proportional continuous IV rotational patterns were different in patients and controls. A secondary aim was to update the repeatability of QF measurement of range of motion (RoM) for inter-vertebral (IV) rotation

Evaluation of short‐term safety of ultrasound‐guided foetal fluid sampling in the dog (Canis lupus familiaris)

Background: In humans, analysis of amniotic fluid is widely used for diagnostic and prognostic purposes. Amniocentesis has scarcely been used in veterinary medicine to date, despite a tremendous potential for clinical and research applications in dogs. Our study aimed to establish a safe method for foetal fluid sampling in female dogs. Methods: Two transabdominal ultrasound-guided methods were assessed: the "free hand" and the needle-guided bracket sampling. In addition, through a subsequent routinely scheduled ovariohysterectomy, fluid was directly collected. Samples from 98 conceptuses were collected at day 46.7 +/- 7.5 of pregnancy. Results: The amount of fluid retrieved varied between 0.5 and 5.0 ml per collection. Macroscopic examination of the uterus and conceptuses identified 53% of the puncture sites. Neither fluid leakage nor foetal injury was detected, and six hematomas (5.8%) were visible. Ultrasound-guided foetal fluid collection was found to be potentially safe, and it can be performed by using either transabdominal method. Conclusion: Foetal fluid collection is possible with relative ease and low short-term risk, and may open paths for diagnostic, therapeutic and research purposes in dogs. The procedure can provide new insights into prenatal clinical medicine, including diagnostics of foetal deaths, early identification of heritable diseases and so on