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Oscar J Pozo, Josep Marcos, Olha Khymenets, Andy Pranata, Christopher Fitzgerald, Malcolm Donald McLeod, Cedric Shackleton
The steroid disulfates (aka bis-sulfates or bis(sulfates)) are a significant but minor fraction of the urinary steroid metabolome that have not been widely studied because major components are not hydrolyzed by the commercial sulfatases commonly used in steroid metabolomics. In early studies, conjugate fractionation followed by hydrolysis using acidified solvent (solvolysis) was used for the indirect detection of this fraction by GC-MS. This paper describes the application of a specific LC-MS/MS method for the direct identification of disulfates in urine, and their use as markers for the prenatal diagnosis of disorders causing reduced estriol production: STSD (Steroid Sulfatase Deficiency), SLOS (Smith-Lemli-Opitz Syndrome) and PORD (P450 Oxido-Reductase Deficiency)...
February 19, 2018: Journal of Molecular Endocrinology
Sarah E Donoghue, James J Pitt, Avihu Boneh, Susan M White
BACKGROUND: Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive disorder caused by mutations in the DHCR7 gene that result in reduced cholesterol biosynthesis. The aim of the study was to examine the biochemical and clinical features of SLOS in the context of the emerging evidence of the importance of cholesterol in morphogenesis and steroidogenesis. METHODS: We retrospectively reviewed the records of 18 patients (including four fetuses) with confirmed SLOS and documented their clinical and biochemical features...
February 19, 2018: Journal of Pediatric Endocrinology & Metabolism: JPEM
Karen J Gibbins, Uma M Reddy, George R Saade, Robert L Goldenberg, Donald J Dudley, Corette B Parker, Vanessa Thorsten, Halit Pinar, Radek Bukowski, Carol J Hogue, Robert M Silver
OBJECTIVE:  Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive syndrome caused by a defect in cholesterol biosynthesis with mutations in 7-dehydrocholesterol reductase (DHCR7). A total of 3% of Caucasians carry DHCR7 mutations, theoretically resulting in a homozygote frequency of 1/4000. However, SLOS occurs in only 1/20,000 to 60,000 live births. Our objective was to assess DHCR7 mutations in unexplained stillbirths. STUDY DESIGN:  Prospective, multicenter, population-based case-control study of all stillbirths and a representative sample of live births enrolled in five geographic areas...
February 12, 2018: American Journal of Perinatology
Matthew P Bronnimann, Pamela J Skinner, Elizabeth Connick
The majority of HIV replication occurs in secondary lymphoid organs (SLOs) such as the spleen, lymph nodes, and gut-associated lymphoid tissue. Within SLOs, HIV RNA+ cells are concentrated in the B-cell follicle during chronic untreated infection, and emerging data suggest that they are a major source of replication in treated disease as well. The concentration of HIV RNA+ cells in the B-cell follicle is mediated by several factors. Follicular CD4+ T-cell subsets including T-follicular helper cells and T-follicular regulatory cells are significantly more permissive to HIV than extrafollicular subsets...
2018: Frontiers in Immunology
Yifei Yang, Lindsay Yassan, Edward Ki Yun Leung, Kiang-Teck J Yeo
BACKGROUND: Patients with Smith-Lemli-Opitz Syndrome (SLOS) have defective endogenous cholesterol synthesis, and present with decrease cholesterol levels and multiple developmental dysmorphologies. CASE DESCRIPTION: A newborn infant with normal XY karyotype and normal microarray was born with multiple developmental defects and ambiguous genitalia was diagnosed following biochemical genetic analysis of serum 7-DHC concentrations. The clinical course of the patient was further complicated by the comorbidities associated with SLOS and the bacterial infections...
January 16, 2018: Clinica Chimica Acta; International Journal of Clinical Chemistry
Steven J Fliesler, Neal S Peachey, Josi Herron, Kelly M Hines, Nadav I Weinstock, Sriganesh Ramachandra Rao, Libin Xu
Smith-Lemli-Opitz Syndrome (SLOS) is a recessive human disease caused by defective cholesterol (CHOL) synthesis at the level of DHCR7 (7-dehydrocholesterol reductase), which normally catalyzes the conversion of 7-dehydrocholesterol (7DHC) to CHOL. Formation and abnormal accumulation of 7DHC and 7DHC-derived oxysterols occur in SLOS patients and in rats treated with the DHCR7 inhibitor AY9944. The rat SLOS model exhibits progressive and irreversible retinal dysfunction and degeneration, which is only partially ameliorated by dietary CHOL supplementation...
January 19, 2018: Scientific Reports
Aurélie Durand, Alexandra Audemard-Verger, Vincent Guichard, Raphaël Mattiuz, Arnaud Delpoux, Pauline Hamon, Nelly Bonilla, Matthieu Rivière, Jérôme Delon, Bruno Martin, Cédric Auffray, Alexandre Boissonnas, Bruno Lucas
Despite being implicated in non-lymphoid tissues, non-recirculating T cells may also exist in secondary lymphoid organs (SLO). However, a detailed characterization of this lymphoid-resident T cell pool has not yet been done. Here we show that a substantial proportion of CD4 regulatory (Treg) and memory (Tmem) cells establish long-term residence in the SLOs of specific pathogen-free mice. Of these SLOs, only T cell residence within Peyer's patches is affected by microbiota. Resident CD4 Treg and CD4 Tmem cells from lymph nodes and non-lymphoid tissues share many phenotypic and functional characteristics...
January 4, 2018: Nature Communications
Yunhui Peng, Rebecca Myers, Wenxing Zhang, Emil Alexov
Smith-Lemli-Opitz syndrome (SLOS) is a cholesterol synthesis disorder characterized by physical, mental, and behavioral symptoms. It is caused by mutations in 7-dehydroxycholesterolreductase gene (DHCR7) encoding DHCR7 protein, which is the rate-limiting enzyme in the cholesterol synthesis pathway. Here we demonstrate that pathogenic mutations in DHCR7 protein are located either within the transmembrane region or are near the ligand-binding site, and are highly conserved among species. In contrast, non-pathogenic mutations observed in the general population are located outside the transmembrane region and have different effects on the conformational dynamics of DHCR7...
January 4, 2018: International Journal of Molecular Sciences
An N Dang Do, Eva H Baker, Katherine E Warren, Simona E Bianconi, Forbes D Porter
Smith-Lemli-Opitz syndrome (SLOS) is a metabolic disorder caused by an inborn error of cholesterol synthesis that affects the development of many organ systems. Malformations in the central nervous system typically involve midline structures and reflect abnormal growth and differentiation of neurons and supporting cells. Despite these defects in central nervous system development, brain tumor formation has only rarely been reported in association with SLOS. We present three individuals with SLOS and lesions in the basal ganglia or brainstem detected by MRI that were concerning for tumor formation...
February 2018: American Journal of Medical Genetics. Part A
Jawaher Alsughayyir, Gavin J Pettigrew, Reza Motallebzadeh
Tertiary lymphoid organs (TLOs) develop at ectopic sites within chronically inflamed tissues, such as in autoimmunity and rejecting organ allografts. TLOs differ structurally from canonical secondary lymphoid organs (SLOs), in that they lack a mantle zone and are not encapsulated, suggesting that they may provide unique immune function. A notable feature of TLOs is the frequent presence of structures typical of germinal centers (GCs). However, little is known about the role of such GCs, and in particular, it is not clear if the B cell response within is autonomous, or whether it synergizes with concurrent responses in SLOs...
2017: Frontiers in Immunology
Tapas Mukherjee, Budhaditya Chatterjee, Atika Dhar, Sachendra S Bais, Meenakshi Chawla, Payel Roy, Anna George, Vineeta Bal, Satyajit Rath, Soumen Basak
Lymphotoxin-beta receptor (LTβR) present on stromal cells engages the noncanonical NF-κB pathway to mediate RelB-dependent expressions of homeostatic chemokines, which direct steady-state ingress of naïve lymphocytes to secondary lymphoid organs (SLOs). In this pathway, NIK promotes partial proteolysis of p100 into p52 that induces nuclear translocation of the RelB NF-κB heterodimers. Microbial infections often deplete homeostatic chemokines; it is thought that infection-inflicted destruction of stromal cells results in the downregulation of these chemokines...
December 1, 2017: EMBO Journal
Ahmad Alkhalil, Harveen Lamba, Salil Deo, Hiram G Bezerra, Sandeep M Patel, Alan Markowitz, Daniel I Simon, Marco A Costa, Angela C Davis, Guilherme F Attizzani
OBJECTIVE: Determine the feasibility and predictors of early discharge after minimalist transcatheter aortic valve replacement (TAVR). BACKGROUND: Duration of hospitalization has a direct impact on overall cost of care, but the clinical impact of length of stay (LOS) in patients undergoing minimalist TAVR remains unclear. METHODS: We studied 268 patients who underwent minimalist TAVR. Short LOS (sLOS) was defined as post-procedural LOS ≤ 3 days and observed in 163 patients...
August 24, 2017: Catheterization and Cardiovascular Interventions
Georgios L Moschovakis, Anja Bubke, Michaela Friedrichsen, Christine S Falk, Regina Feederle, Reinhold Förster
The chemokine receptor CXCR5 is primarily expressed on B cells and Tfh cells and facilitates their migration towards B cell follicles. In the present study we investigated the role of the CXCL13/CXCR5 axis in the pathogenesis of rheumatoid arthritis (RA) and specifically addressed the impact of CXCR5-mediated T and B cell migration in this disease. Employing collagen-induced arthritis (CIA) we identify CXCR5 as an absolutely essential factor for the induction of inflammatory autoimmune arthritis. Cxcr5-deficient mice and mice selectively lacking Cxcr5 on T cells were completely resistant to CIA, showed impaired germinal center responses and failed to mount an IgG1 antibody response to collagen II...
August 21, 2017: Scientific Reports
André Travessa, Patrícia Dias, Pedro Rocha, Ana Berta Sousa
OBJECTIVE: To show the importance of measuring cholesterol precursor levels in amniotic fluid in all pregnancies with ultrasound features (such as holoprosencephaly) suggestive of Smith-Lemli-Opitz syndrome (SLOS), after exclusion of chromosomal anomalies. CASE REPORT: A 28-year-old woman, gravida 1 para 0, performed chorionic villus sampling for fetal karyotyping at 13 weeks of gestation due to positive combined first trimester screening in a fetus with increased nuchal translucency and suspected holoprosencephaly...
August 2017: Taiwanese Journal of Obstetrics & Gynecology
Barbara Dema, Yasmine Lamri, Christophe Pellefigues, Emeline Pacreau, Fanny Saidoune, Caroline Bidault, Hajime Karasuyama, Karim Sacré, Eric Daugas, Nicolas Charles
Lupus nephritis (LN), one of the most severe outcomes of systemic lupus erythematosus (SLE), is initiated by glomerular deposition of immune-complexes leading to an inflammatory response and kidney failure. Autoantibodies to nuclear antigens and autoreactive B and T cells are central in SLE pathogenesis. Immune mechanisms amplifying this autoantibody production drive flares of the disease. We previously showed that basophils were contributing to LN development in a spontaneous lupus-like mouse model (constitutive Lyn (-/-) mice) and in SLE subjects through their activation and migration to secondary lymphoid organs (SLOs) where they amplify autoantibody production...
August 11, 2017: Scientific Reports
Miyad Movassaghi, Simona Bianconi, Richard Feinn, Christopher A Wassif, Forbes D Porter
Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive congenital malformation syndrome caused by mutations in the 7-dehydrocholesterol reductase gene. This inborn error of cholesterol synthesis leads to elevated concentrations of 7-dehydrocholesterol (7-DHC). 7-DHC also serves as the precursor for vitamin D synthesis. Limited data is available on vitamin D levels in individuals with SLOS. Due to elevated concentrations of 7-DHC, we hypothesized that vitamin D status would be abnormal and possibly reach toxic levels in patients with SLOS...
October 2017: American Journal of Medical Genetics. Part A
Anna K Bird, Martin Chang, Jennifer Barnard, Bruce I Goldman, Nida Meednu, Javier Rangel-Moreno, Jennifer H Anolik
Neutrophils are well characterized as mediators of peripheral tissue damage in lupus, but it remains unclear whether they influence loss of self-tolerance in the adaptive immune compartment. Lupus neutrophils produce elevated levels of factors known to fuel autoantibody production, including IL-6 and B cell survival factors, but also reactive oxygen intermediates, which can suppress lymphocyte proliferation. To assess whether neutrophils directly influence the progression of autoreactivity in secondary lymphoid organs (SLOs), we characterized the localization and cell-cell contacts of splenic neutrophils at several stages in the progression of disease in the NZB/W murine model of lupus...
July 15, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
Masayuki Fujino, Hirotaka Sato, Tomotaka Okamura, Akihiko Uda, Satoshi Takeda, Nursarat Ahmed, Shigeyuki Shichino, Teiichiro Shiino, Yohei Saito, Satoru Watanabe, Chie Sugimoto, Marcelo J Kuroda, Manabu Ato, Yoshiyuki Nagai, Shuji Izumo, Kouji Matsushima, Masaaki Miyazawa, Aftab A Ansari, Francois Villinger, Kazuyasu Mori
Glycosylation of Env defines pathogenic properties of simian immunodeficiency virus (SIV). We previously demonstrated that pathogenic SIVmac239 and a live-attenuated, quintuple deglycosylated Env mutant (Δ5G) virus target CD4+ T cells residing in different tissues during acute infection. SIVmac239 and Δ5G preferentially infected distinct CD4+ T cells in secondary lymphoid organs (SLOs) and within the lamina propria of the small intestine, respectively (C. Sugimoto et al., J Virol 86:9323-9336, 2012, https://doi...
July 1, 2017: Journal of Virology
Yasemen Eroglu, Mina Nguyen-Driver, Robert D Steiner, Louise Merkens, Mark Merkens, Jean-Baptiste Roullet, Ellen Elias, Geeta Sarphare, Forbes D Porter, Chumei Li, Elaine Tierney, Małgorzata J Nowaczyk, Kurt A Freeman
Children with Smith-Lemli-Opitz syndrome (SLOS) are typically reported to have moderate to severe intellectual disability. This study aims to determine whether normal cognitive function is possible in this population and to describe clinical, biochemical and molecular characteristics of children with SLOS and normal intelligent quotient (IQ). The study included children with SLOS who underwent cognitive testing in four centers. All children with at least one IQ composite score above 80 were included in the study...
August 2017: American Journal of Medical Genetics. Part A
Joern Pezoldt, Fabio Pisano, Wiebke Heine, Maria Pasztoi, Maik Rosenheinrich, Aaron M Nuss, Marina C Pils, Immo Prinz, Reinhold Förster, Jochen Huehn, Petra Dersch
Background: To successfully limit pathogen dissemination, an immunological link between the entry tissue of the pathogen and the underlying secondary lymphoid organs (SLOs) needs to be established to prime adaptive immune responses. Here, the prerequisite of CCR7 to mount host immune responses within SLOs during gastrointestinal Yersinia pseudotuberculosis infection to limit pathogen spread was investigated. Methods: Survival, bacterial dissemination, and intestinal and systemic pathology of wild-type and CCR7-/- mice were assessed and correlated to the presence of immune cell subsets and cytokine responses throughout the course of infection...
September 15, 2017: Journal of Infectious Diseases
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