Mucopolysaccharidosis type I in 21 Czech and Slovak patients: Mutation analysis suggests a functional importance of C-terminus of the IDUA protein

PubMed Central

Vazna, Alzbeta; Beesley, Clare; Berna, Linda; Stolnaja, Larisa; Myskova, Helena; Bouckova, Michaela; Vlaskova, Hana; Poupetova, Helena; Zeman, Jiri; Magner, Martin; Hlavata, Anna; Winchester, Bryan; Hrebicek, Martin; Dvorakova, Lenka

2009-01-01

Abstract Mucopolysaccharidosis type I (MPS I) is an autosomal recessive lysosomal storage disorder that is caused by a deficiency of the enzyme α-l-iduronidase (IDUA). Of the 21 Czech and Slovak patients who have been diagnosed with MPS I in the last 30 years, 16 have a severe clinical presentation (Hurler syndrome), 2 less severe manifestations (Scheie syndrome), and 3 an intermediate severity (Hurler/Scheie phenotype). Mutation analysis was performed in 20 MPS I patients and 39 mutant alleles were identified. There was a high prevalence of the null mutations p.W402X (12 alleles) and p.Q70X (7 alleles) in this cohort. Four of the 13 different mutations were novel: p.V620F (3 alleles), p.W626X (1 allele), c.1727 + 2T > G (1 allele) and c.1918_1927del (2 alleles). The pathogenicity of the novel mutations was verified by transient expression studies in Chinese hamster ovary cells. Seven haplotypes were observed in the patient alleles using 13 intragenic polymorphisms. One of the two haplotypes associated with the mutation p.Q70X was not found in any of the controls. Haplotype analysis showed, that mutations p.Q70X, p.V620F, and p.D315Y probably have more than one ancestor. Missense mutations localized predominantly in the hydrophobic core of the enzyme are associated with the severe phenotype, whereas missense mutations localized to the surface of the enzyme are usually associated with the attenuated phenotypes. Mutations in the 130 C-terminal amino acids lead to clinical manifestations, which indicates a functional importance of the C-terminus of the IDUA protein. © 2009 Wiley-Liss, Inc. PMID:19396826

Neonatal bone marrow transplantation prevents bone pathology in a mouse model of mucopolysaccharidosis type I.

PubMed

Pievani, Alice; Azario, Isabella; Antolini, Laura; Shimada, Tsutomu; Patel, Pravin; Remoli, Cristina; Rambaldi, Benedetta; Valsecchi, Maria Grazia; Riminucci, Mara; Biondi, Andrea; Tomatsu, Shunji; Serafini, Marta

2015-03-05

Neonatal bone marrow transplantation (BMT) could offer a novel therapeutic opportunity for genetic disorders by providing sustainable levels of the missing protein at birth, thus preventing tissue damage. We tested this concept in mucopolysaccharidosis type I (MPS IH; Hurler syndrome), a lysosomal storage disorder caused by deficiency of α-l-iduronidase. MPS IH is characterized by a broad spectrum of clinical manifestations, including severe progressive skeletal abnormalities. Although BMT increases the life span of patients with MPS IH, musculoskeletal manifestations are only minimally responsive if the timing of BMT delays, suggesting already irreversible bone damage. In this study, we tested the hypothesis that transplanting normal BM into newborn MPS I mice soon after birth can prevent skeletal dysplasia. We observed that neonatal BMT was effective at restoring α-l-iduronidase activity and clearing elevated glycosaminoglycans in blood and multiple organs. At 37 weeks of age, we observed an almost complete normalization of all bone tissue parameters, using radiographic, microcomputed tomography, biochemical, and histological analyses. Overall, the magnitude of improvements correlated with the extent of hematopoietic engraftment. We conclude that BMT at a very early stage in life markedly reduces signs and symptoms of MPS I before they appear. © 2015 by The American Society of Hematology.

Hurler syndrome

MedlinePlus

... I Thick, coarse facial features with low nasal bridge Exams and Tests In some states, babies are ... storage disease - mucopolysaccharidosis type I Images Low nasal bridge References Pyeritz RE. Inherited diseases of connective tissue. ...

Mucopolysaccharidosis type III

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... the enzymes needed to break down the heparan sulfate sugar chain are missing or defective. There are ... a large amount of a mucopolysaccharide called heparan sulfate in the urine. Other tests may include: Blood ...

Mucopolysaccharidosis type IV

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... include: Abnormal development of bones, including the spine Bell-shaped chest with ribs flared out at the ... may slip and damage the spinal cord, causing paralysis. Surgery to correct such problems should be done ...

Genetics Home Reference: mucopolysaccharidosis type IV

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... individuals develop various skeletal abnormalities, including short stature, knock knees, and abnormalities of the ribs, chest, spine, ... links) Encyclopedia: Cloudy cornea Encyclopedia: Hypermobile joints Encyclopedia: Knock ... Morquio syndrome Encyclopedia: Mucopolysaccharides Health Topic: ...

Mucopolysaccharidosis type I: Identification and characterization of mutations affecting alpha-L-iduronidase activity.

PubMed

Lee-Chen, Guey-Jen; Lin, Shuan-Pei; Chen, I-Shen; Chang, Jui-Hung; Yang, Chyau-Wen; Chin, Yi-Wen

2002-06-01

Mucopolysaccharidosis type I (MPS I) is caused by a deficiency of the lysosomal enzyme alpha-L-iduronidase (IDUA). MPS I covers a broad spectrum of clinical severity ranging from severe Hurler syndrome through intermediate Hurler/Scheie syndrome to mild Scheie syndrome. Mutation screening was performed in two unrelated Taiwanese MPS I patients. A Hurler/Scheie patient had A79V (C to T transition in codon 79) in exon 2 and R619G (C to G transversion in codon 619) in exon 14. R619G has been shown to cause disease. Expression of A79V in COS-7 cells showed trace amounts of IDUA activity, demonstrating the deleterious nature of the mutation. A79V mutation did not cause a reduction in IDUA mRNA levels. The reduced level of IDUA protein suggests increased degradation of the mutant enzyme. A Hurler patient had 134del12 (in-frame deletion of codons 16-19 in signal peptide) in exon 1 and Q584X (C to T transition in codon 584) in exon 13. Transfection of COS-7 cells with Q584X did not yield active enzyme. Q584X mutation caused an apparent reduction in the IDUA mRNA level and no IDUA protein was detected. Conversely, 134del12 showed 124.6% of normal activity in transfected cells and a 77-kDa precursor protein was observed on Western blot, suggesting biologic activity of precursor IDUA without posttranslational cleavage. These findings provide further evidence of the molecular heterogeneity in mutations in MPS I.

Genetics Home Reference: mucopolysaccharidosis type III

MedlinePlus

... breakdown of a subset of GAGs called heparan sulfate. MPS IIIA is caused by mutations in the ... of these enzymes disrupts the breakdown of heparan sulfate. As a result, partially broken down heparan sulfate ...

Genetics Home Reference: mucopolysaccharidosis type I

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... Arn P, Beck M, Clarke JT, Guffon N, Kaplan P, Muenzer J, Norato DY, Shapiro E, Thomas ... Updated Pages Reviewed : December 2012 Published : June 19, 2018 The resources on this site should not be ...

Genetics Home Reference: mucopolysaccharidosis type II

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... inheritance is that fathers cannot pass X-linked traits to their sons. Related Information What does it ... should consult with a qualified healthcare professional . About Selection Criteria for Links Data Files & API Site Map ...

CNS-directed gene therapy for the treatment of neurologic and somatic mucopolysaccharidosis type II (Hunter syndrome).

PubMed

Motas, Sandra; Haurigot, Virginia; Garcia, Miguel; Marcó, Sara; Ribera, Albert; Roca, Carles; Sánchez, Xavier; Sánchez, Víctor; Molas, Maria; Bertolin, Joan; Maggioni, Luca; León, Xavier; Ruberte, Jesús; Bosch, Fatima

2016-06-16

Mucopolysaccharidosis type II (MPSII) is an X-linked lysosomal storage disease characterized by severe neurologic and somatic disease caused by deficiency of iduronate-2-sulfatase (IDS), an enzyme that catabolizes the glycosaminoglycans heparan and dermatan sulphate. Intravenous enzyme replacement therapy (ERT) currently constitutes the only approved therapeutic option for MPSII. However, the inability of recombinant IDS to efficiently cross the blood-brain barrier (BBB) limits ERT efficacy in treating neurological symptoms. Here, we report a gene therapy approach for MPSII through direct delivery of vectors to the CNS. Through a minimally invasive procedure, we administered adeno-associated virus vectors encoding IDS (AAV9- Ids ) to the cerebrospinal fluid of MPSII mice with already established disease. Treated mice showed a significant increase in IDS activity throughout the encephalon, with full resolution of lysosomal storage lesions, reversal of lysosomal dysfunction, normalization of brain transcriptomic signature, and disappearance of neuroinflammation. Moreover, our vector also transduced the liver, providing a peripheral source of therapeutic protein that corrected storage pathology in visceral organs, with evidence of cross-correction of nontransduced organs by circulating enzyme. Importantly, AAV9- Ids -treated MPSII mice showed normalization of behavioral deficits and considerably prolonged survival. These results provide a strong proof of concept for the clinical translation of our approach for the treatment of Hunter syndrome patients with cognitive impairment.

CNS-directed gene therapy for the treatment of neurologic and somatic mucopolysaccharidosis type II (Hunter syndrome)

PubMed Central

Motas, Sandra; Haurigot, Virginia; Garcia, Miguel; Marcó, Sara; Ribera, Albert; Roca, Carles; Sánchez, Víctor; Molas, Maria; Bertolin, Joan; Maggioni, Luca; León, Xavier; Ruberte, Jesús; Bosch, Fatima

2016-01-01

Mucopolysaccharidosis type II (MPSII) is an X-linked lysosomal storage disease characterized by severe neurologic and somatic disease caused by deficiency of iduronate-2-sulfatase (IDS), an enzyme that catabolizes the glycosaminoglycans heparan and dermatan sulphate. Intravenous enzyme replacement therapy (ERT) currently constitutes the only approved therapeutic option for MPSII. However, the inability of recombinant IDS to efficiently cross the blood-brain barrier (BBB) limits ERT efficacy in treating neurological symptoms. Here, we report a gene therapy approach for MPSII through direct delivery of vectors to the CNS. Through a minimally invasive procedure, we administered adeno-associated virus vectors encoding IDS (AAV9-Ids) to the cerebrospinal fluid of MPSII mice with already established disease. Treated mice showed a significant increase in IDS activity throughout the encephalon, with full resolution of lysosomal storage lesions, reversal of lysosomal dysfunction, normalization of brain transcriptomic signature, and disappearance of neuroinflammation. Moreover, our vector also transduced the liver, providing a peripheral source of therapeutic protein that corrected storage pathology in visceral organs, with evidence of cross-correction of nontransduced organs by circulating enzyme. Importantly, AAV9-Ids-treated MPSII mice showed normalization of behavioral deficits and considerably prolonged survival. These results provide a strong proof of concept for the clinical translation of our approach for the treatment of Hunter syndrome patients with cognitive impairment. PMID:27699273

Deleterious effects of interruption followed by reintroduction of enzyme replacement therapy on a lysosomal storage disorder.

PubMed

Schneider, Ana Paula; Matte, Ursula; Pasqualim, Gabriela; Tavares, Angela Maria Vicente; Mayer, Fabiana Quoos; Martinelli, Barbara; Ribas, Graziela; Vargas, Carmen Regla; Giugliani, Roberto; Baldo, Guilherme

2016-10-01

Temporary interruption of enzyme replacement therapy (ERT) in patients with different lysosomal storage disorders may happen for different reasons (adverse reactions, issues with reimbursement, logistic difficulties, and so forth), and the impact of the interruption is still uncertain. In the present work, we studied the effects of the interruption of intravenous ERT (Laronidase, Genzyme) followed by its reintroduction in mice with the prototypical lysosomal storage disorder mucopolysaccharidosis type I, comparing to mice receiving continuous treatment, untreated mucopolysaccharidosis type I mice, and normal mice. In the animals which treatment was temporarily interrupted, we observed clear benefits of treatment in several organs (liver, lung, heart, kidney, and testis) after reintroduction, but a worsening in the thickness of the aortic wall was detected. Furthermore, these mice had just partial improvements in behavioral tests, suggesting some deterioration in the brain function. Despite worsening is some disease aspects, urinary glycosaminoglycans levels did not increase during interruption, which indicates that this biomarker commonly used to monitor treatment in patients should not be used alone to assess treatment efficacy. The deterioration observed was not caused by the development of serum antienzyme antibodies. All together our results suggest that temporary ERT interruption leads to deterioration of function in some organs and should be avoided whenever possible. Copyright © 2016 Elsevier Inc. All rights reserved.

Genetics Home Reference: mucopolysaccharidosis type VII

MedlinePlus

... This gene provides instructions for producing the beta-glucuronidase (β-glucuronidase) enzyme, which is involved in the breakdown of ... reduce or completely eliminate the function of β-glucuronidase. The shortage (deficiency) of β-glucuronidase leads to ...

Correction of murine mucopolysaccharidosis VII by a human. beta. -glucuronidase transgene

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kyle, J.W.; Vogler, C.; Hoffmann, J.W.

1990-05-01

The authors recently described a murine model for mucopolysaccharidosis VII in mice that have an inherited deficiency of {beta}-glucuronidase. Affected mice, of genotype gus{sup mps}/gus{sup mps}, present clinical manifestations similar to those of humans with mucopolysaccharidosis VII (Sly syndrome) and are shown here to have secondary elevations of other lysosomal enzymes. The mucopolysaccharidosis VII phenotype in both species includes dwarfism, skeletal deformities, and premature death. Lysosome storage is visualized within enlarged vesicles and correlates biochemically with accumulation of undegraded and partially degraded glycosaminoglycans. In this report they describe the consequences of introducing the human {beta}-glucuronidase gene, GUSB, into gus{sup mps}/gus{supmore » mps} mice that produce virtually no murine {beta}-glucuronidase. Transgenic mice homozygous for the mucopolysaccharidosis VII mutation expressed high levels of human {beta}-glucuronidase activity in all tissues examined and were phenotypically normal. Biochemically, both the intralysosomal storage of glycosaminoglycans and the secondary elevation of other acid hydrolases were corrected. These findings demonstrate that the GUSB transgene is expressed in gus{sup mps}/gus{sup mps} mice and that human {beta}-glucuronidase corrects the murine mucopolysaccharidosis storage disease.« less

Neonatal Screening Tests.

ERIC Educational Resources Information Center

Vigue, Charles L.

1986-01-01

Describes several laboratory experiments that are adaptations of clinical tests for certain genetic diseases in babies. Information and procedures are provided for tests for phenylketonuria (PKU), galactosemia, tyrosinemia, cystinuria, and mucopolysaccharidosis. Discusses the effects of each disease on the infants' development. (TW)

Pharmaceutical Approval Update.

PubMed

Kaufman, Michele B

2018-02-01

Benznidazole for pediatric patients with Chagas disease; vestronidase alfa-vjbk (Mepsevii) for adults and children with mucopolysaccharidosis type VII; and hepatitis B vaccine (recombinant), adjuvanted (Heplisav-B), for the prevention of infection caused by all known subtypes of hepatitis B virus in adults.

Identification of age-dependent motor and neuropsychological behavioural abnormalities in a mouse model of Mucopolysaccharidosis Type II

PubMed Central

Gleitz, Hélène F. E.; O’Leary, Claire; Holley, Rebecca J.

2017-01-01

Severe mucopolysaccharidosis type II (MPS II) is a progressive lysosomal storage disease caused by mutations in the IDS gene, leading to a deficiency in the iduronate-2-sulfatase enzyme that is involved in heparan sulphate and dermatan sulphate catabolism. In constitutive form, MPS II is a multi-system disease characterised by progressive neurocognitive decline, severe skeletal abnormalities and hepatosplenomegaly. Although enzyme replacement therapy has been approved for treatment of peripheral organs, no therapy effectively treats the cognitive symptoms of the disease and novel therapies are in development to remediate this. Therapeutic efficacy and subsequent validation can be assessed using a variety of outcome measures that are translatable to clinical practice, such as behavioural measures. We sought to consolidate current knowledge of the cognitive, skeletal and motor abnormalities present in the MPS II mouse model by performing time course behavioural examinations of working memory, anxiety, activity levels, sociability and coordination and balance, up to 8 months of age. Cognitive decline associated with alterations in spatial working memory is detectable at 8 months of age in MPS II mice using spontaneous alternation, together with an altered response to novel environments and anxiolytic behaviour in the open-field. Coordination and balance on the accelerating rotarod were also significantly worse at 8 months, and may be associated with skeletal changes seen in MPS II mice. We demonstrate that the progressive nature of MPS II disease is also seen in the mouse model, and that cognitive and motor differences are detectable at 8 months of age using spontaneous alternation, the accelerating rotarod and the open-field tests. This study establishes neurological, motor and skeletal measures for use in pre-clinical studies to develop therapeutic approaches in MPS II. PMID:28207863

Clinical course of sly syndrome (mucopolysaccharidosis type VII)

PubMed Central

Montaño, Adriana M; Lock-Hock, Ngu; Steiner, Robert D; Graham, Brett H; Szlago, Marina; Greenstein, Robert; Pineda, Mercedes; Gonzalez-Meneses, Antonio; Çoker, Mahmut; Bartholomew, Dennis; Sands, Mark S; Wang, Raymond; Giugliani, Roberto; Macaya, Alfons; Pastores, Gregory; Ketko, Anastasia K; Ezgü, Fatih; Tanaka, Akemi; Arash, Laila; Beck, Michael; Falk, Rena E; Bhattacharya, Kaustuv; Franco, José; White, Klane K; Mitchell, Grant A; Cimbalistiene, Loreta; Holtz, Max; Sly, William S

2016-01-01

Background Mucopolysaccharidosis VII (MPS VII) is an ultra-rare disease characterised by the deficiency of β-glucuronidase (GUS). Patients’ phenotypes vary from severe forms with hydrops fetalis, skeletal dysplasia and mental retardation to milder forms with fewer manifestations and mild skeletal abnormalities. Accurate assessments on the frequency and clinical characteristics of the disease have been scarce. The aim of this study was to collect such data. Methods We have conducted a survey of physicians to document the medical history of patients with MPS VII. The survey included anonymous information on patient demographics, family history, mode of diagnosis, age of onset, signs and symptoms, severity, management, clinical features and natural progression of the disease. Results We collected information on 56 patients from 11 countries. Patients with MPS VII were classified based on their phenotype into three different groups: (1) neonatal non-immune hydrops fetalis (NIHF) (n=10), (2) Infantile or adolescent form with history of hydrops fetalis (n=13) and (3) Infantile or adolescent form without known hydrops fetalis (n=33). Thirteen patients with MPS VII who had the infantile form with history of hydrops fetalis and survived childhood, had a wide range of clinical manifestations from mild to severe. Five patients underwent bone marrow transplantation and one patient underwent enzyme replacement therapy with recombinant human GUS. Conclusions MPS VII is a pan-ethnic inherited lysosomal storage disease with considerable phenotypical heterogeneity. Most patients have short stature, skeletal dysplasia, hepatosplenomegaly, hernias, cardiac involvement, pulmonary insufficiency and cognitive impairment. In these respects it resembles MPS I and MPS II. In MPS VII, however, one unique and distinguishing clinical feature is the unexpectedly high proportion of patients (41%) that had a history of NIHF. Presence of NIHF does not, by itself, predict the eventual severity of the clinical course, if the patient survives infancy. PMID:26908836

Open field locomotor activity and anxiety-related behaviors in mucopolysaccharidosis type IIIA mice.

PubMed

Lau, Adeline A; Crawley, Allison C; Hopwood, John J; Hemsley, Kim M

2008-08-05

Mucopolysaccharidosis (MPS) IIIA, or Sanfilippo syndrome, is a lysosomal storage disorder characterized by severe and progressive neuropathology. Following an asymptomatic period, patients may present with sleep disturbances, cognitive decline, aggressive tendencies and hyperactivity. A naturally-occurring mouse model of MPS IIIA also exhibits many of these behavioral features and has been recently back-crossed onto a C57BL/6 genetic background. To more thoroughly characterize the behavioral phenotype of congenic MPS IIIA mice, we assessed exploratory activity and unconditioned anxiety-related behavior in the elevated plus maze (EPM) and open field locomotor activity. Although MPS IIIA male mice were less active in the EPM at 18 and 20 weeks of age, they were more likely to explore the open arms than their normal counter-parts suggesting reduced anxiety. Repeated EPM testing reduced exploration of the open arms in MPS IIIA mice. In the open field test, significant reductions in activity were evident in naïve-tested male MPS IIIA mice from 10 weeks of age. Female normal and MPS IIIA mice displayed similar exploratory activity in the open field test. These differences in anxiety and locomotor activity will allow us to evaluate the efficacy of therapeutic regimes for MPS IIIA as a forerunner to developing safe and effective therapies for Sanfilippo patients.

Central Nervous System Delivery of Helper-Dependent Canine Adenovirus Corrects Neuropathology and Behavior in Mucopolysaccharidosis Type VII Mice

PubMed Central

Ariza, Lorena; Giménez-Llort, Lydia; Cubizolle, Aurélie; Pagès, Gemma; García-Lareu, Belén; Serratrice, Nicolas; Cots, Dan; Thwaite, Rosemary; Chillón, Miguel; Kremer, Eric J.

2014-01-01

Abstract Canine adenovirus type 2 vectors (CAV-2) are promising tools to treat global central nervous system (CNS) disorders because of their preferential transduction of neurons and efficient retrograde axonal transport. Here we tested the potential of a helper-dependent CAV-2 vector expressing β-glucuronidase (HD-RIGIE) in a mouse model of mucopolysaccharidosis type VII (MPS VII), a lysosomal storage disease caused by deficiency in β-glucuronidase activity. MPS VII leads to glycosaminoglycan accumulation into enlarged vesicles in peripheral tissues and the CNS, resulting in peripheral and neuronal dysfunction. After intracranial administration of HD-RIGIE, we show long-term expression of β-glucuronidase that led to correction of neuropathology around the injection site and in distal areas. This phenotypic correction correlated with a decrease in secondary-elevated lysosomal enzyme activity and glycosaminoglycan levels, consistent with global biochemical correction. Moreover, HD-RIGIE-treated mice show significant cognitive improvement. Thus, injections of HD-CAV-2 vectors in the brain allow a global and sustained expression and may have implications for brain therapy in patients with lysosomal storage disease. PMID:24299455

Mucopolysaccharidosis type IVA: Common double deletion in the N-Acetylgalactosamine-6-sulfatase gene (GALNS)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hori, Toshinori; Tomatsu, Shunji; Fukuda, Seiji

1995-04-10

Mucopolysaccharidosis IVA (MPS IVA) is an autosomal recessive disorder caused by a deficiency in N-acetylgalactosamine-6-sulfatase (GALNS). We found two separate deletions of nearly 8.0 and 6.0 kb in the GALNS gene, including some exons. There are Alu repetitive elements near the breakpoints of the 8.0-kb deletion, and this deletion resulted from an Alu-Alu recombination. The other 6.0-kb deletion involved illegitimate recombinational events between incomplete short direct repeats of 8 bp at deletion breakpoints. The same rearrangement has been observed in a heteroallelic state in four unrelated patients. This is the first documentation of a common double deletion a gene thatmore » is not a member of a gene cluster. 39 refs., 5 figs.« less

Retrovirally mediated correction of bone marrow-derived mesenchymal stem cells from patients with mucopolysaccharidosis type I.

PubMed

Baxter, Melissa A; Wynn, Robert F; Deakin, Jonathan A; Bellantuono, Ilaria; Edington, Kirsten G; Cooper, Alan; Besley, Guy T N; Church, Heather J; Wraith, J Ed; Carr, Trevor F; Fairbairn, Leslie J

2002-03-01

We have investigated the utility of bone marrow-derived mesenchymal stem cells (MSCs) as targets for gene therapy of the autosomal recessive disorder mucopolysaccharidosis type IH (MPS-IH, Hurler syndrome). Cultures of MSCs were initially exposed to a green fluorescent protein-expressing retrovirus. Green fluorescent protein-positive cells maintained their proliferative and differentiation capacity. Next we used a vector encoding alpha-L-iduronidase (IDUA), the enzyme that is defective in MPS-IH. Following transduction, MPS-IH MSCs expressed high levels of IDUA and secreted supernormal levels of this enzyme into the extracellular medium. Exogenous IDUA expression led to a normalization of glycosaminoglycan storage in MPS-IH cells, as evidenced by a dramatic decrease in the amount of (35)SO(4) sequestered within the heparan sulfate and dermatan sulfate compartments of these cells. Finally, gene-modified MSCs were able to cross-correct the enzyme defect in untransduced MPS-IH fibroblasts via protein transfer.

Molecular analysis of patients with {Beta}-glucuronidase deficiency presenting as hydrops fetalis or as early mucopolysaccharidosis VII

DOE Office of Scientific and Technical Information (OSTI.GOV)

Vervoort, R.; Liebaers, I.; Lissens, W.

1996-03-01

Although not all mucopolysaccharidosis type VII (MPS VII) neonates present with hydrops fetalis or with related symptoms, hydrops fetalis is a common form of presentation of this mucopolysaccharidosis. We used reverse-transcription-PCR-SSCP and direct sequencing to screen for mutations in the human {beta}-glucuronidase cDNA of 17 MPS VII patients with severe presentation of the disease. Mutations resulting in an unstable mRNA were detected in genomic DNA with direct sequencing of the PCR-amplified {beta}-glucuronidase exons. We found extensive genetic heterogeneity in MPS VII alleles: in addition to 6 of 12 previously reported mutations (L176F, R216W, R357X, R382C, W507X, and W627C), we detectedmore » 14 undescribed mutations in the {beta}-glucuronidase coding region that produce MPS VII alleles (G136R, E150K, S312X, Y320S, Y320C, H351Y, R382H, R374C, R435P, R477W, G572D, Y508C, K606N, and 1900{Delta}GA). The mutations in hydropic fetuses were widely scattered in the {beta}-glucuronidase gene. Analysis of three polymorphic sites of the mutant alleles (1766T/C, 1972C/T, and a new 1091+27C/G polymorphism) allowed exclusion of identity by descent for some recurrent mutations. Three of four mutations introducing a premature translation stop codon were found to affect mRNA abundance and/or structure. Expression studies provided evidence for the causal relationship between each of the mutations found in MPS VII alleles and the enzyme deficiency, in that all mutations identified exhibited markedly reduced enzyme activity expressed in COS7 cells following transfection with the mutant cDNA. 52 refs., 4 figs., 5 tabs.« less

Molecular analysis of patients with beta-glucuronidase deficiency presenting as hydrops fetalis or as early mucopolysaccharidosis VII.

PubMed Central

Vervoort, R.; Islam, M. R.; Sly, W. S.; Zabot, M. T.; Kleijer, W. J.; Chabas, A.; Fensom, A.; Young, E. P.; Liebaers, I.; Lissens, W.

1996-01-01

Although not all mucopolysaccharidosis type VII (MPS VII) neonates present with hydrops fetalis or with related symptoms, hydrops fetalis is a common form of presentation of this mucopolysaccharidosis. We used reverse-transcription-PCR-SSCP and direct sequencing to screen for mutations in the human beta-glucuronidase cDNA of 17 MPS VII patients with severe presentation of the disease. Mutations resulting in an unstable mRNA were detected in genomic DNA with direct sequencing of the PCR-amplified beta-glucuronidase exons. We found extensive genetic heterogeneity in MPS VII alleles: in addition to 6 or 12 previously reported mutations (L176F, R216W, R357X, R382C, W507X, and W627C), we detected 14 undescribed mutations in the beta-glucuronidase coding region that produce MPS VII alleles (G136R, E150K, S312X, Y320S, Y320C, H351Y, R382H, R374C, R435P, R477W, G572D, Y508C, K606N and 1900 delta GA). The mutations in hydropic fetuses were widely scattered in the beta-glucuronidase gene. Analysis of three polymorphic sites of the mutant alleles (1766T/C, 1972C/T and a new 1091+27C/G polymorphism) allowed exclusion of identity by descent for some recurrent mutations. Three of four mutations introducing a premature translation stop codon were found to affect mRNA abundance and/or structure. Expression studies provided evidence for the causal relationship between each of the mutations found in MPS VII alleles and the enzyme deficiency, in that all mutations identified exhibited markedly reduced enzyme activity expressed in COS7 cells following transfection with the mutant cDNA. Images Figure 2 Figure 3A Figure 3BC Figure 4 PMID:8644704

Ocular lesions in canine mucopolysaccharidosis I and response to enzyme replacement therapy.

PubMed

Newkirk, Kim M; Atkins, Rosalie M; Dickson, Patti I; Rohrbach, Barton W; McEntee, Michael F

2011-07-11

Mucopolysaccharidosis I (MPS I) is an inherited metabolic disorder resulting from deficiency of α-L-iduronidase and lysosomal accumulation of glycosaminoglycans (GAG) in multiple tissues. Accumulation of GAG in corneal stromal cells causes corneal opacity and reduced vision. The purpose of this study was to determine the extent of ocular GAG accumulation and investigate the effectiveness of intravenous enzyme replacement therapy (ERT) on corneal GAG accumulation in dogs. Ocular tissues were obtained from 58 dogs with mucopolysaccharidosis I and four unaffected controls. Affected dogs received either low-dose ERT, high-dose ERT, or no treatment; some low-dose dogs also received intrathecal treatments. Histologic severity of corneal stromal GAG accumulation was scored. Accumulation of GAG was found in corneal stromal cells and scleral fibroblasts but not in corneal epithelium, endothelium, ciliary epithelium, choroid, retina, retinal pigment epithelium, or optic nerve. Corneal GAG accumulation increased in severity with increasing age. Although low-dose ERT did not significantly reduce corneal stromal GAG accumulation in comparison with untreated animals, high-dose ERT did result in significantly less GAG accumulation compared with the untreated dogs (adjusted P = 0.0143) or the low-dose ERT group (adjusted P = 0.0031). Intrathecal treatments did not significantly affect GAG accumulation. Dogs that began ERT shortly after birth also had significantly less (P < 0.0001) GAG accumulation in the corneal stroma than dogs with a later onset of treatment. These data suggest that high-dose, intravenous ERT is effective at preventing and/or clearing corneal stromal GAG accumulation, particularly if initiated early after birth.

Intrafamilial variability in the clinical manifestations of mucopolysaccharidosis type II: Data from the Hunter Outcome Survey (HOS)

PubMed Central

Giugliani, Roberto; Harmatz, Paul; Mendelsohn, Nancy J.; Jego, Virginie; Parini, Rossella

2017-01-01

Several cases of phenotypic variability among family members with mucopolysaccharidosis type II (MPS II) have been reported, but the data are limited. Data from patients enrolled in the Hunter Outcome Survey (HOS) were used to investigate intrafamilial variability in male siblings with MPS II. As of July 2015, data were available for 78 patients aged ≥5 years at last visit who had at least one affected sibling (39 sibling pairs). These patients were followed prospectively (i.e., they were alive at enrollment in HOS). The median age at the onset of signs and symptoms was the same for the elder and younger brothers (2.0 years); however, the younger brothers were typically diagnosed at a younger age than the elder brothers (median age, 2.5 and 5.1 years, respectively). Of the 39 pairs, eight pairs were classified as being discordant (the status of four or more signs and symptoms differed between the siblings); 21 pairs had one, two, or three signs and symptoms that differed between the siblings, and 10 pairs had none. Regression status of the majority of the developmental milestones studied was generally concordant among siblings. Functional classification, a measure of central nervous system involvement, was the same in 24/28 pairs, although four pairs were considered discordant as functional classification differed between the siblings. Overall, this analysis revealed similarity in the clinical manifestations of MPS II among siblings. This information should help to improve our understanding of the clinical presentation of the disease, including phenotype prediction in affected family members. PMID:29210515

Symptoms of Autism Spectrum Disorder (ASD) in Individuals with Mucopolysaccharide Disease Type III (Sanfilippo Syndrome): A Systematic Review

ERIC Educational Resources Information Center

Wolfenden, C.; Wittkowski, A.; Hare, D. J.

2017-01-01

The prevalence of autism spectrum disorder (ASD) in many genetic disorders is well documented but not as yet in Mucopolysaccharidosis type III (MPS III). MPS III is a recessively inherited metabolic disorder and evidence suggests that symptoms of ASD present in MPS III. This systematic review examined the extant literature on the symptoms of ASD…

Treatment of lysosomal storage disease in MPS VII mice using a recombinant adeno-associated virus.

PubMed

Watson, G L; Sayles, J N; Chen, C; Elliger, S S; Elliger, C A; Raju, N R; Kurtzman, G J; Podsakoff, G M

1998-12-01

Mucopolysaccharidosis type VII (MPS VII) is a lysosomal storage disease caused by a genetic deficiency of beta-glucuronidase (GUS). We used a recombinant adeno-associated virus vector (AAV-GUS) to deliver GUS cDNA to MPS VII mice. The route of vector administration had a dramatic effect on the extent and distribution of GUS activity. Intramuscular injection of AAV-GUS resulted in high, localized production of GUS, while intravenous administration produced low GUS activity in several tissues. This latter treatment of MPS VII mice reduced glycosaminoglycan levels in the liver to normal and reduced storage granules dramatically. We show that a single administration of AAV-GUS can provide sustained expression of GUS in a variety of cell types and is sufficient to reverse the disease phenotype at least in the liver.

Klüver–Bucy syndrome associated with a recessive variant in HGSNAT in two siblings with Mucopolysaccharidosis type IIIC (Sanfilippo C)

PubMed Central

Hu, Hao; Hübner, Christoph; Lukacs, Zoltan; Musante, Luciana; Gill, Esther; Wienker, Thomas F; Ropers, Hans-Hilger; Knierim, Ellen; Schuelke, Markus

2017-01-01

Klüver–Bucy syndrome (KBS) comprises a set of neurobehavioral symptoms with psychic blindness, hypersexuality, disinhibition, hyperorality, and hypermetamorphosis that were originally observed after bilateral lobectomy in Rhesus monkeys. We investigated two siblings with KBS from a consanguineous family by whole-exome sequencing and autozygosity mapping. We detected a homozygous variant in the heparan-α-glucosaminidase-N-acetyltransferase gene (HGSNAT; c.518G>A, p.(G173D), NCBI ClinVar RCV000239404.1), which segregated with the phenotype. Disease-causing variants in this gene are known to be associated with autosomal recessive Mucopolysaccharidosis type IIIC (MPSIIIC, Sanfilippo C). This lysosomal storage disease is due to deficiency of the acetyl-CoA:α-glucosaminidase-N-acetyltransferase, which was shown to be reduced in patient fibroblasts. Our report extends the phenotype associated with MPSIIIC. Besides MPSIIIA and MPSIIIB, due to variants in SGSH and NAGLU, this is the third subtype of Sanfilippo disease to be associated with KBS. MPSIII should be included in the differential diagnosis of young patients with KBS. PMID:27827379

Klüver-Bucy syndrome associated with a recessive variant in HGSNAT in two siblings with Mucopolysaccharidosis type IIIC (Sanfilippo C).

PubMed

Hu, Hao; Hübner, Christoph; Lukacs, Zoltan; Musante, Luciana; Gill, Esther; Wienker, Thomas F; Ropers, Hans-Hilger; Knierim, Ellen; Schuelke, Markus

2017-02-01

Klüver-Bucy syndrome (KBS) comprises a set of neurobehavioral symptoms with psychic blindness, hypersexuality, disinhibition, hyperorality, and hypermetamorphosis that were originally observed after bilateral lobectomy in Rhesus monkeys. We investigated two siblings with KBS from a consanguineous family by whole-exome sequencing and autozygosity mapping. We detected a homozygous variant in the heparan-α-glucosaminidase-N-acetyltransferase gene (HGSNAT; c.518G>A, p.(G173D), NCBI ClinVar RCV000239404.1), which segregated with the phenotype. Disease-causing variants in this gene are known to be associated with autosomal recessive Mucopolysaccharidosis type IIIC (MPSIIIC, Sanfilippo C). This lysosomal storage disease is due to deficiency of the acetyl-CoA:α-glucosaminidase-N-acetyltransferase, which was shown to be reduced in patient fibroblasts. Our report extends the phenotype associated with MPSIIIC. Besides MPSIIIA and MPSIIIB, due to variants in SGSH and NAGLU, this is the third subtype of Sanfilippo disease to be associated with KBS. MPSIII should be included in the differential diagnosis of young patients with KBS.

Clinical characterization of cardiovascular abnormalities associated with feline mucopolysaccharidosis I and VI.

PubMed

Sleeper, M M; Kusiak, C M; Shofer, F S; O'Donnell, P; Bryan, C; Ponder, K P; Haskins, M E

2008-06-01

The purpose of this study was to define the cardiovascular abnormalities present in young and adult cats affected with the lysosomal storage diseases mucopolysaccharidosis (MPS) I and MPS VI. Eighteen cats affected with MPS I and 10 cats affected with MPS VI were evaluated by physical examination, electrocardiography and echocardiography. Electrocardiography (ECG) was performed on all MPS I and 9 of the MPS VI cats. Twelve unaffected cats underwent complete examinations for comparison purposes. No cardiovascular abnormalities were noted on physical examination. Measured ECG intervals were normal in affected cats; however, sinus arrhythmia was noted more frequently than in the unaffected cats. Significant echocardiographic abnormalities included aortic valve thickening, regurgitation and aortic root dilation. Significant mitral valve thickening was also noted. The severity of changes increased in older affected cats. As affected animals increased in age, more cardiac abnormalities were found with increasing severity. Significant lesions included the mitral and aortic valves and ascending aorta, but myocardial changes were not recognized. MPS I and MPS VI cats have similar cardiovascular findings to those seen in children and constitute important models for testing new MPS therapies.

Hyperactive behaviour in the mouse model of mucopolysaccharidosis IIIB in the open field and home cage environments.

PubMed

Langford-Smith, A; Malinowska, M; Langford-Smith, K J; Wegrzyn, G; Jones, S; Wynn, R; Wraith, J E; Wilkinson, F L; Bigger, B W

2011-08-01

Mucopolysaccharidosis IIIB (MPS IIIB) is a lysosomal storage disorder characterized by severe behavioural disturbances and progressive loss of cognitive and motor function. There is no effective treatment, but behavioural testing is a valuable tool to assess neurodegeneration and the effect of novel therapies in mouse models of disease. Several groups have evaluated behaviour in this model, but the data are inconsistent, often conflicting with patient natural history. We hypothesize that this discrepancy could be due to differences in open field habituation and home cage behaviour. Eight-month-old wild-type and MPS IIIB mice were tested in a 1-h open field test, performed 1.5 h after lights on, and a 24-h home cage behaviour test performed after 24 h of acclimatization. In the 1-h test, MPS IIIB mice were hyperactive, with increased rapid exploratory behaviour and reduced immobility time. No differences in anxiety were seen. Over the course of the test, differences became more pronounced with maximal effects at 1 h. The 24-hour home cage test was less reliable. There was evidence of increased hyperactivity in MPS IIIB mice, however, immobility was also increased, suggesting a level of inconsistency in this test. Performance of open field analysis within 1-2 h after lights on is probably critical to achieving maximal success as MPS IIIB mice have a peak in activity around this time. The open field test effectively identifies hyperactive behaviour in MPS IIIB mice and is a significant tool for evaluating effects of therapy on neurodegeneration. © 2011 The Authors. Genes, Brain and Behavior © 2011 Blackwell Publishing Ltd and International Behavioural and Neural Genetics Society.

Low Bone Mineral Content and Challenges in Interpretation of Dual-Energy X-Ray Absorptiometry in Children With Mucopolysaccharidosis Types I, II, and VI

PubMed Central

Polgreen, Lynda E.; Thomas, William; Fung, Ellen; Viskochil, David; Stevenson, David A.; Steinberger, Julia; Orchard, Paul; Whitley, Chester B.; Ensrud, Kristine E.

2013-01-01

Osteoporosis has been described in animal models of mucopolysaccharidosis (MPS). Whether clinically significant osteoporosis is common among children with MPS is unknown. Therefore, cross-sectional data from whole body (WB; excluding head) and lumbar spine (LS) bone mineral density (BMD) compared with sex-, chronologic age–, and ethnicity-matched healthy individuals (Zage), height-for-age (HAZ) Z-score (ZHAZ) and bone mineral content (BMC) measured by dual-energy X-ray absorptiometry (DXA) in 40 children with MPS were analyzed. A subset of these children (n = 24) was matched 1:3 by age and sex to a group of healthy children (n = 72) for comparison of BMC adjusted for Tanner stage, race, lean body mass, height, and bone area. Low BMD Z-score was defined as Z-score of −2 or less. In children with MPS, 15% had low WB Zage and 48% had low LS Zage; 0% and 6% had low WB ZHAZ and low LS ZHAZ, respectively. Adjusted WB BMC was lower in MPS participants (p = 0.009). In conclusion, children with MPS had deficits in WB BMC after adjustments for stature and bone area. HAZ adjustment underestimated bone deficits (i.e., overestimated WB BMD Z-scores) in children with MPS likely owing to their abnormal bone shape. The influence of severe short stature and bone geometry on DXA measurements must be considered in children with MPS to avoid unnecessary exposure to antiresorptive treatments. PMID:23562131

Hyperactivity, unexplained speech delay, and coarse facies--is it Sanfilippo syndrome?

PubMed

Saini, Arushi Gahlot; Singhi, Pratibha; Sahu, Jitendra Kumar; Ganesan, Saptharishi L; Vyas, Sameer; Rao, Sandeep; Sachdeva, Man Updesh Singh

2014-08-01

Mucopolysaccharidosis-IIIB or Sanfilippo-B syndrome is caused by deficiency of lysosomal α-N-acetylglucosaminidase that leads to accumulation of heparan-sulphate and degeneration of central nervous system with progressive dementia, hyperactivity, and aggressive behavior. Mucopolysaccharidosis-III remains underdiagnosed as a cause of developmental delay and hyperactivity both in adults and children because in contrast to other mucopolysaccharidoses, they have little somatic disease, coarse facial features, hepatosplenomegaly or skeletal changes, and a high incidence of false-negative results on the urinary screening tests. We describe here a girl with the classic phenotype of mucopolysaccharidosis-IIIB to alert pediatricians to the possibility of this disorder in children with unexplained speech delay and hyperactivity and prevent unnecessary investigations. © The Author(s) 2013.

Systemic and Central Nervous System Correction of Lysosomal Storage in Mucopolysaccharidosis Type VII Mice

PubMed Central

Stein, Colleen S.; Ghodsi, Abdi; Derksen, Todd; Davidson, Beverly L.

1999-01-01

Mucopolysaccharidosis (MPS) type VII patients lack functional β-glucuronidase, leading to systemic and central nervous system dysfunction. In this study we tested whether recombinant adenovirus that encodes β-glucuronidase (Adβgluc), delivered intravenously and into the brain parenchyma of MPS type VII mice, could provide long-term transgene expression and correction of lysosomal distension. We also tested whether systemic treatment with the immunosuppressive anti-CD40 ligand antibody, MR-1, affected transgene expression. We found substantial plasma β-glucuronidase activity for over 9 weeks after gene transfer in the MR-1- treated group, with subsequent decline in activity corresponding to a delayed anti-β-glucuronidase antibody response. At 16 weeks, near wild-type amounts of β-glucuronidase activity and striking reduction of lysosomal pathology were detected in livers from mice that had received either MR-1 cotreatment or control antibody. In the lung and kidney, β-glucuronidase activity was markedly higher for the MR-1-treated group. β-Glucuronidase activity in the brain persisted independently of MR-1 treatment. Activity was intense in the injected hemisphere and was also evident in the noninjected cortex and striatum, with dramatic improvements in storage deposits in areas of both hemispheres. These results indicate that prolonged enzyme expression from transgenes delivered to deficient liver and brain can mediate pervasive correction and illustrate the potential for gene therapy of MPS and other lysosomal storage diseases. PMID:10074197

Developmental Outcome in Five Children with Hurler Syndrome after Stem Cell Transplantation: A Pilot Study

ERIC Educational Resources Information Center

Lucke, Thomas; Das, Anibh M.; Hartmann, Hans; Sykora, Karl-Walter; Donnerstag, Frank; Schmid-Ott, Gerhard; Grigull, Lorenz

2007-01-01

Hurler syndrome (mucopolysaccharidosis type 1H; MPS1H) is a lysosomal storage disease caused by a deficiency of [alpha]-L-iduronidase activity. The natural course of this neurodegenerative disease inevitably leads to premature death within the first 10 years of life. Enzyme replacement therapy is effective in correcting the enzymatic deficiency of…

Identifying the need for a multidisciplinary approach for early recognition of mucopolysaccharidosis VI (MPS VI).

PubMed

Choy, Yew Sing; Bhattacharya, Kaustuv; Balasubramaniam, Shanti; Fietz, Michael; Fu, Antony; Inwood, Anita; Jin, Dong-Kyu; Kim, Ok-Hwa; Kosuga, Motomichi; Kwun, Young Hee; Lin, Hsiang-Yu; Lin, Shuan-Pei; Mendelsohn, Nancy J; Okuyama, Torayuki; Samion, Hasri; Tan, Adeline; Tanaka, Akemi; Thamkunanon, Verasak; Thong, Meow-Keong; Toh, Teck-Hock; Yang, Albert D; McGill, Jim

2015-05-01

Mucopolysaccharidosis VI (MPS VI, Maroteaux-Lamy syndrome) is caused by deficient activity of the enzyme, N-acetylgalactosamine-4-sulfatase, resulting in impaired degradation of the glycosaminoglycan dermatan sulfate. Patients experience a range of manifestations including joint contractures, short stature, dysostosis multiplex, coarse facial features, decreased pulmonary function, cardiac abnormalities, corneal clouding and shortened life span. Recently, clinicians from institutions in the Asia-Pacific region met to discuss the occurrence and implications of delayed diagnosis and misdiagnosis of MPS VI in the patients they have managed. Eighteen patients (44% female) were diagnosed. The most common sign presented by the patients was bone deformities in 11 patients (65%). Delays to diagnosis occurred due to the lack of or distance to diagnostic facilities for four patients (31%), alternative diagnoses for two patients (15%), and misleading symptoms experienced by two patients (15%). Several patients experienced manifestations that were subtler than would be expected and were subsequently overlooked. Several cases highlighted the unique challenges associated with diagnosing MPS VI from the perspective of different specialties and provide insights into how these patients initially present, which may help to elucidate strategies to improve the diagnosis of MPS VI. Copyright © 2015 Elsevier Inc. All rights reserved.

Clinical characterization of cardiovascular abnormalities associated with feline mucopolysaccharidosis I and VI

PubMed Central

Sleeper, Meg M.; Kusiak, Catherine M.; Shofer, Frances S.; O’Donnell, Patricia; Bryan, Caroline; Ponder, Katherine P.; Haskins, Mark E.

2009-01-01

Summary Objective The purpose of this study was to define the cardiovascular abnormalities present in young and adult cats affected with the lysosomal storage diseases mucopolysaccharidosis (MPS) I and MPS VI. Method Eighteen cats affected with MPS I and fifteen cats affected with MPS VI were evaluated by physical examination, electrocardiography and echocardiography. Electrocardiograms were performed on all MPS I and all but 7 of the MPS VI cats. Ten unaffected cats underwent complete examinations for comparison purposes. Results No cardiovascular physical examination abnormalities were noted. ECG intervals were normal in affected cats; however, changes consistent with aberrant conduction were noted more frequently than in unaffected cats. Significant echocardiographic abnormalities included valve thickening and regurgitation (aortic and mitral) and aortic root dilation, particularly in the older cats. Conclusion As affected animals increased in age, more cardiac abnormalities were found with increasing severity. MPS I and MPS VI cats have similar cardiovascular findings to those seen in children and MPS VII dogs. PMID:18509743

Multimodal image analysis of the retina in Hunter syndrome (mucopolysaccharidosis type II): Case report.

PubMed

Salvucci, Isadora Darriba Macedo; Finzi, Simone; Oyamada, Maria Kiyoko; Kim, Chong Ae; Pimentel, Sérgio Luis Gianotti

2018-01-01

We report a case of retinal and posterior ocular findings in a 33-year-old man diagnosed with Hunter syndrome (Mucopolysaccharidosis type II) in a multimodal imaging way. Our patient was complaining of blurred night vision for the past 3 years. He had not received any systemic treatment for Hunter syndrome. Vision acuity was 20/20 in both eyes and corneas were clear. Fundus examination revealed bilateral crowded and hyperemic optic nerve heads (elevated in the ocular ultrasound) and areas of subretinal hypopigmentation. There was hyperautofluorescence at the central fovea and perifovea, and a diffuse bilateral choroidal fluorescence in angiography. Macular SD-OCT showed a thinning of the external retina at the perifovea in both eyes. Visual field testing showed a bilateral ring scotoma. The full field ERG was subnormal, with a negative response in the scotopic phase. Visual Evoked Potencial test and cranial MRI were normal. Our multimodal analysis reported here attempted to contribute to the knowledge of the natural history of GAG deposition in the eye, focusing on the retina and retinal pigment epithelium. Defining this natural history is essential for a proper comparison with Hunter patients receiving systemic treatment, thus determining if it can or cannot improve retinal function in humans with this disorder.

A novel, long-lived, and highly engraftable immunodeficient mouse model of mucopolysaccharidosis type I.

PubMed

Mendez, Daniel C; Stover, Alexander E; Rangel, Anthony D; Brick, David J; Nethercott, Hubert E; Torres, Marissa A; Khalid, Omar; Wong, Andrew Ms; Cooper, Jonathan D; Jester, James V; Monuki, Edwin S; McGuire, Cian; Le, Steven Q; Kan, Shih-Hsin; Dickson, Patricia I; Schwartz, Philip H

2015-01-01

Mucopolysaccharidosis type I (MPS I) is an inherited α-L-iduronidase (IDUA, I) deficiency in which glycosaminoglycan (GAG) accumulation causes progressive multisystem organ dysfunction, neurological impairment, and death. Current MPS I mouse models, based on a NOD/SCID (NS) background, are short-lived, providing a very narrow window to assess the long-term efficacy of therapeutic interventions. They also develop thymic lymphomas, making the assessment of potential tumorigenicity of human stem cell transplantation problematic. We therefore developed a new MPS I model based on a NOD/SCID/Il2rγ (NSG) background. This model lives longer than 1 year and is tumor-free during that time. NSG MPS I (NSGI) mice exhibit the typical phenotypic features of MPS I including coarsened fur and facial features, reduced/abnormal gait, kyphosis, and corneal clouding. IDUA is undetectable in all tissues examined while GAG levels are dramatically higher in most tissues. NSGI brain shows a significant inflammatory response and prominent gliosis. Neurological MPS I manifestations are evidenced by impaired performance in behavioral tests. Human neural and hematopoietic stem cells were found to readily engraft, with human cells detectable for at least 1 year posttransplantation. This new MPS I model is thus suitable for preclinical testing of novel pluripotent stem cell-based therapy approaches.

Inner ear changes in mucopolysaccharidosis type I/Hurler syndrome.

PubMed

Kariya, Shin; Schachern, Patricia A; Nishizaki, Kazunori; Paparella, Michael M; Cureoglu, Sebahattin

2012-10-01

Mucopolysaccharidosis type I/Hurler syndrome is an autosomal recessive disease caused by a deficiency of α-L-iduronidase activity. Recurrent middle ear infections and hearing loss are common complications in Hurler syndrome. Although sensorineural and conductive components occur, the mechanism of sensorineural hearing loss has not been determined. The purpose of this study is to evaluate the quantitative inner ear histopathology of the temporal bones of patients with Hurler syndrome. Eleven temporal bones from 6 patients with Hurler syndrome were examined. Age-matched healthy control samples consisted of 14 temporal bones from 7 cases. Temporal bones were serially sectioned in the horizontal plane and stained with hematoxylin and eosin. The number of spiral ganglion cells, loss of cochlear hair cells, area of stria vascularis, and cell density of spiral ligament were evaluated using light microscopy. There was no significant difference between Hurler syndrome and healthy controls in the number of spiral ganglion cells, area of stria vascularis, or cell density of spiral ligament. The number of cochlear hair cells in Hurler syndrome was significantly decreased compared with healthy controls. Auditory pathophysiology in the central nerve system in Hurler syndrome remains unknown; however, decreased cochlear hair cells may be one of the important factors for the sensorineural component of hearing loss.

A novel, long-lived, and highly engraftable immunodeficient mouse model of mucopolysaccharidosis type I

PubMed Central

Mendez, Daniel C; Stover, Alexander E; Rangel, Anthony D; Brick, David J; Nethercott, Hubert E; Torres, Marissa A; Khalid, Omar; Wong, Andrew MS; Cooper, Jonathan D; Jester, James V; Monuki, Edwin S; McGuire, Cian; Le, Steven Q; Kan, Shih-hsin; Dickson, Patricia I; Schwartz, Philip H

2015-01-01

Mucopolysaccharidosis type I (MPS I) is an inherited α-L-iduronidase (IDUA, I) deficiency in which glycosaminoglycan (GAG) accumulation causes progressive multisystem organ dysfunction, neurological impairment, and death. Current MPS I mouse models, based on a NOD/SCID (NS) background, are short-lived, providing a very narrow window to assess the long-term efficacy of therapeutic interventions. They also develop thymic lymphomas, making the assessment of potential tumorigenicity of human stem cell transplantation problematic. We therefore developed a new MPS I model based on a NOD/SCID/Il2rγ (NSG) background. This model lives longer than 1 year and is tumor-free during that time. NSG MPS I (NSGI) mice exhibit the typical phenotypic features of MPS I including coarsened fur and facial features, reduced/abnormal gait, kyphosis, and corneal clouding. IDUA is undetectable in all tissues examined while GAG levels are dramatically higher in most tissues. NSGI brain shows a significant inflammatory response and prominent gliosis. Neurological MPS I manifestations are evidenced by impaired performance in behavioral tests. Human neural and hematopoietic stem cells were found to readily engraft, with human cells detectable for at least 1 year posttransplantation. This new MPS I model is thus suitable for preclinical testing of novel pluripotent stem cell-based therapy approaches. PMID:26052536

Sanfilippo syndrome: Overall review.

PubMed

Andrade, Fernando; Aldámiz-Echevarría, Luis; Llarena, Marta; Couce, María Luz

2015-06-01

Mucopolysaccharidosis type III (MPS III, Sanfilippo syndrome) is a lysosomal storage disorder, caused by a deficiency in one of the four enzymes involved in the catabolism of glycosaminoglycan heparan sulfate. It is characterized by progressive cognitive decline and severe hyperactivity, with relatively mild somatic features. This review focuses on clinical features, diagnosis, treatment, and follow-up of MPS III, and provides information about supplementary tests and differential diagnosis. Given that few reviews of MPS III have been published, several studies were compiled to establish diagnostic recommendations. Quantitative urinary glycosaminoglycan analysis is strongly recommended, and measurement of disaccharides, heparin cofactor II-thrombin complex and gangliosides is also used. Enzyme activity of the different enzymes in blood serum, leukocytes or fibroblasts, and mutational analysis for SGSH, NAGLU, HGSNAT or GNS genes are required to confirm diagnosis and differentiate four subtypes of MPS III. Although there is no global consensus for treatment, enzyme replacement therapy and gene therapy can provide appropriate results. In this regard, recent publications on treatment and follow-up are discussed. © 2015 Japan Pediatric Society.

Metabolic Syndrome and Cardiovascular Risk Factors after Hematopoietic Cell Transplantation in Severe Mucopolysaccharidosis Type I (Hurler Syndrome).

PubMed

Braunlin, Elizabeth; Steinberger, Julia; DeFor, Todd; Orchard, Paul; Kelly, Aaron S

2018-06-01

Hematopoietic cell transplantation is a life-saving procedure, but one associated with increasing long-term cardiovascular risk requiring frequent long-term follow-up. This therapy has significantly lengthened survival in mucopolysaccharidosis type IH (Hurler syndrome), a disease with known coronary artery involvement. Metabolic syndrome-a constellation of central obesity, high blood pressure, low high-density lipoprotein cholesterol, elevated triglycerides, and fasting blood glucose-is associated with increased cardiovascular risk, and occurs when any 3 or more of these 5 components is present within a single individual. The incidence of metabolic syndrome and its components is poorly defined after transplantation for Hurler syndrome. Chart review of all long-term survivors of hematopoietic cell transplantation for Hurler syndrome ≥9 years of age for factors comprising the metabolic syndrome: obesity, high blood pressure, low high-density lipoprotein cholesterol, elevated triglycerides, and fasting blood glucose. Sixty-three patients were evaluated, 20 of whom had components of the metabolic syndrome available for review. There was no significant difference in age at transplantation, sex, number of transplants, pretransplant radiation, or percent engraftment between those with and without these data. Median follow-up after transplantation for the 20 patients with data was 14.3 years. Only 1 (5%) patient of this group fulfilled the criteria for metabolic syndrome. Fifty-three percent of the patients had 1 or more components of metabolic syndrome: the most common was high blood pressure occurring in 40%. Metabolic syndrome is uncommon in this cohort of long-term survivors of hematopoietic cell transplantation for Hurler syndrome but almost half of the patients had 1 or more components of the syndrome, with high blood pressure being the most common. Further studies are needed to develop guidelines in this diagnosis as well as other nonmalignant diseases of children. Copyright © 2018 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Molecular analysis of mucopolysaccharidosis IVA: Common mutations and racial difference

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tomatsu, S.; Hori, T.; Nakashima, Y.

1994-09-01

Mucopolysaccharidosis IVA (MPS IVA) is an autosomal recessive disorder caused by a deficiency in N-acetylgalactosamine -6-sulfate sulfatase (GALNS). Studies on the molecular basis of MPS IVA have been facilitated following cloning of the full-length cDNA and genomic DNA. In this study we detected mutations from 20 Caucasian and 19 Japanese MPS IVA patients using SSCP system and compared mutations of Caucasian origin with those of Japanese origin. The results showed the presence of 16 various mutations (3 small, deletions, 2 nonsense and 11 missense mutations) for Caucasian patients and 15 (1 deletion, 1 large alteration and 13 missense mutations) formore » Japanese. Moreover, two common mutations existed; one is double gene deletion characteristic for Japanese (6 alleles; 15%) and the other is a point mutation (1113F A{yields}T transition) characteristic for Caucasian (9 alleles; 22.5%). And the clear genotype/phenotype relationship among 1342delCA, IVS1(-2), P151S, Q148X, R386C, I113F, Q473X, W220G, P151L, A291T, R90W, and P77R, for a severe type, G96B N204K and V138A for a milder type, was observed. Only R386 mutation was seen in both of the populations. Further, the precise DNA analysis for double gene deletion of a common double gene deletion has been performed by defining the breakpoints and the results showed that one deletion was caused by homologous recombination due to Alu repetitive sequences and the other was due to nonhomologous recombination of short direct repeat. Haplotype analysis for six alleles with double deletion were different, indicating the different origin of this mutation or the frequent recombination events before a mutational event. Thus the mutations in GALNS gene are very heterogeneous and the racial difference is characteristic.« less

The Murine Model of Mucopolysaccharidosis IIIB Develops Cardiopathies over Time Leading to Heart Failure

PubMed Central

De Pasquale, Valeria; Cocchiaro, Pasquale; Paciello, Orlando; Avallone, Luigi; Belfiore, Maria Paola; Iacobellis, Francesca; Di Napoli, Daniele; Magliulo, Fabio; Perrino, Cinzia; Trimarco, Bruno; Esposito, Giovanni; Di Natale, Paola; Pavone, Luigi Michele

2015-01-01

Mucopolysaccharidosis (MPS) IIIB is a lysosomal disease due to the deficiency of the enzyme α-N-acetylglucosaminidase (NAGLU) required for heparan sulfate (HS) degradation. The disease is characterized by mild somatic features and severe neurological disorders. Very little is known on the cardiac dysfunctions in MPS IIIB. In this study, we used the murine model of MPS IIIB (NAGLU knockout mice, NAGLU-/-) in order to investigate the cardiac involvement in the disease. Echocardiographic analysis showed a marked increase in left ventricular (LV) mass, reduced cardiac function and valvular defects in NAGLU-/- mice as compared to wild-type (WT) littermates. The NAGLU-/- mice exhibited a significant increase in aortic and mitral annulus dimension with a progressive elongation and thickening of anterior mitral valve leaflet. A severe mitral regurgitation with reduction in mitral inflow E-wave-to-A-wave ratio was observed in 32-week-old NAGLU-/- mice. Compared to WT mice, NAGLU-/- mice exhibited a significantly lower survival with increased mortality observed in particular after 25 weeks of age. Histopathological analysis revealed a significant increase of myocardial fiber vacuolization, accumulation of HS in the myocardial vacuoles, recruitment of inflammatory cells and collagen deposition within the myocardium, and an increase of LV fibrosis in NAGLU-/- mice compared to WT mice. Biochemical analysis of heart samples from affected mice showed increased expression levels of cardiac failure hallmarks such as calcium/calmodulin-dependent protein kinase II, connexin43, α-smooth muscle actin, α-actinin, atrial and brain natriuretic peptides, and myosin heavy polypeptide 7. Furthermore, heart samples from NAGLU-/- mice showed enhanced expression of the lysosome-associated membrane protein-2 (LAMP2), and the autophagic markers Beclin1 and LC3 isoform II (LC3-II). Overall, our findings demonstrate that NAGLU-/- mice develop heart disease, valvular abnormalities and cardiac failure associated with an impaired lysosomal autophagic flux. PMID:26147524

MT2013-31: Allo HCT for Metabolic Disorders and Severe Osteopetrosis

ClinicalTrials.gov

2018-01-19

Mucopolysaccharidosis Disorders; Hurler Syndrome; Hunter Syndrome; Maroteaux Lamy Syndrome; Sly Syndrome; Alpha-Mannosidosis; Fucosidosis; Aspartylglucosaminuria; Glycoprotein Metabolic Disorders; Sphingolipidoses; Recessive Leukodystrophies; Globoid Cell Leukodystrophy; Metachromatic Leukodystrophy; Niemann-Pick B; Niemann-Pick C Subtype 2; Sphingomyelin Deficiency; Peroxisomal Disorders; Adrenoleukodystrophy With Cerebral Involvement; Zellweger Syndrome; Neonatal Adrenoleukodystrophy; Infantile Refsum Disease; Acyl-CoA Oxidase Deficiency; D-Bifunctional Enzyme Deficiency; Multifunctional Enzyme Deficiency; Alpha-methylacyl-CoA Racmase Deficiency; Mitochondrial Neurogastrointestingal Encephalopathy; Severe Osteopetrosis; Hereditary Leukoencephalopathy With Axonal Spheroids (HDLS; CSF1R Mutation); Inherited Metabolic Disorders

Cardiovascular studies in the mucopolysaccharidoses.

PubMed Central

Nelson, J; Shields, M D; Mulholland, H C

1990-01-01

Cardiovascular studies were performed on 22 patients with mucopolysaccharidosis ascertained from an epidemiological study on the mucopolysaccharidoses in Northern Ireland. None of the patients had attended a cardiologist before the study. The main echocardiographical findings were thickening of the interventricular septum and left ventricular posterior wall in the absence of ECG evidence of ventricular hypertrophy. Moreover, reduced QRS voltages were present in the majority of the patients (77%) and some had reduced shortening fraction (33%). These findings suggest an infiltrative cardiomyopathy owing to mucopolysaccharide deposition as a cause of the cardiac thickening rather than true ventricular hypertrophy. Thickening of the mitral valve was present in one case and thickening of the aortic valve in two cases. Involvement of the other heart valves was minimal and aortic valve disease was not found in any of the cases of Morquio's disease type A. In conclusion, the clinical, ECG, and chest x ray findings and echocardiographical evidence for valvular involvement were significantly less than in other studies. Hence, the incidence of clinically significant cardiovascular disease in patients with mucopolysaccharidosis has probably been overestimated. PMID:2108248

An overview of Korean patients with mucopolysaccharidosis and collaboration through the Asia Pacific MPS Network.

PubMed

Cho, Sung Yoon; Sohn, Young Bae; Jin, Dong-Kyu

2014-08-01

Mucopolysaccharidosis (MPS) is a constellation of disorders characterized by the accumulation of mucopolysaccharides in tissues and organs. This accumulation results in the deterioration and degeneration of multiple organs. This paper describes the general distribution of types of MPS in patients, their clinical characteristics and genotypes, the development of animal studies and preclinical studies, enzyme replacement therapy in South Korea, and the development of idursulfase beta and clinical trials on idursulfase beta in South Korea. In addition, this paper discusses academic collaboration among specialists in MPS care in the Asia-Pacific region, which includes Japan, Taiwan, Malaysia, and South Korea, through an organization called the Asia-Pacific MPS Network (APMN). The Asia-Pacific MPS Registry, an electronic remote data entry system, has been developed by key doctors in the APMN. Rare diseases require international cooperation and collaboration to elucidate their mechanisms and carry out clinical trials; therefore, an organization such as the APMN is required. Furthermore, international collaboration among Asian countries and countries around the world will be of utmost importance in the future.

An overview of Korean patients with mucopolysaccharidosis and collaboration through the Asia Pacific MPS Network

PubMed Central

Cho, Sung Yoon; Sohn, Young Bae; Jin, Dong-Kyu

2014-01-01

Summary Mucopolysaccharidosis (MPS) is a constellation of disorders characterized by the accumulation of mucopolysaccharides in tissues and organs. This accumulation results in the deterioration and degeneration of multiple organs. This paper describes the general distribution of types of MPS in patients, their clinical characteristics and genotypes, the development of animal studies and preclinical studies, enzyme replacement therapy in South Korea, and the development of idursulfase beta and clinical trials on idursulfase beta in South Korea. In addition, this paper discusses academic collaboration among specialists in MPS care in the Asia-Pacific region, which includes Japan, Taiwan, Malaysia, and South Korea, through an organization called the Asia-Pacific MPS Network (APMN). The Asia-Pacific MPS Registry, an electronic remote data entry system, has been developed by key doctors in the APMN. Rare diseases require international cooperation and collaboration to elucidate their mechanisms and carry out clinical trials; therefore, an organization such as the APMN is required. Furthermore, international collaboration among Asian countries and countries around the world will be of utmost importance in the future. PMID:25364648

Natural history of echocardiographic abnormalities in mucopolysaccharidosis III.

PubMed

Wilhelm, Carolyn M; Truxal, Kristen V; McBride, Kim L; Kovalchin, John P; Flanigan, Kevin M

2018-06-01

Mucopolysaccharidosis (MPS) type III, Sanfilippo Syndrome, is an autosomal recessive lysosomal storage disorder. MPS I and II patients often develop cardiac involvement leading to early mortality, however there are limited data in MPS III. The objective of this study is to describe cardiac abnormalities in a large group of MPS III patients followed in a longitudinal natural history study designed to determine outcome measures for gene transfer trials. A single center study of MPS III patients who were enrolled in the Nationwide Children's Hospital natural history study in 2014. Two cardiologists reviewed all patient echocardiograms for anatomic, valvular, and functional abnormalities. Valve abnormalities were defined as abnormal morphology, trivial mitral regurgitation (MR) with abnormal morphology or at least mild MR, and any aortic regurgitation (AR). Abnormal left ventricular (LV) function was defined as ejection fraction < 50%. Group comparisons were assessed using two-sample t-tests or Wilcoxon rank sum tests for continuous variables and chi-square or Fisher's exact tests for categorical variables. Twenty-five patients, 15 Type A and 10 Type B MPS III, underwent 45 echocardiograms. Fifteen patients (60%) demonstrated an abnormal echocardiographic finding with age at first abnormal echocardiogram within the study being 6.8 ± 2.8 years. Left-sided valve abnormalities were common over time: 7 mitral valve thickening, 2 mitral valve prolapse, 16 MR (8 mild, 8 trivial), 3 aortic valve thickening, and 9 AR (7 mild, 2 trivial). Two patients had asymmetric LV septal hypertrophy. No valvular stenosis or ventricular function abnormalities were noted. Incidental findings included: mild aortic root dilation (2), bicommissural aortic valve (1), and mild tricuspid regurgitation (3). Individuals with Sanfilippo A and B demonstrate a natural history of cardiac involvement with valvular abnormalities most common. In short-term follow up, patients demonstrated only mild progression of abnormalities, none requiring intervention. Valvular disease prevalence is similar to MPS I and II, but appears less severe. These findings raise no specific concerns for gene transfer trials in patients in this age range. Copyright © 2018 Elsevier Inc. All rights reserved.

Determination of genotypic and clinical characteristics of Colombian patients with mucopolysaccharidosis IVA

PubMed Central

Tapiero-Rodriguez, Sandra M; Acosta Guio, Johanna C; Porras-Hurtado, Gloria Liliana; García, Natalia; Solano, Martha; Pachajoa, Harry; Velasco, Harvy M

2018-01-01

Background As mucopolysaccharidosis IVA (MPS IVA) is the most frequent MPS in Colombia, this paper aims to describe its clinical and mutational characteristics in 32 diagnosed patients included in this study. Methods Genotyping was completed by amplification and Sanger sequencing of the GALNS gene. The SWISS-model platform was used for bioinformatic analysis, and mutant proteins were generated by homology from the wild-type GALNS code 4FDI template from the Protein Data Bank (PDB) database. Docking was performed using the GalNAc6S ligand (PubChem CID: 193456) by AutoDock Vina 1.0 and visualized in PyMOL and LigPlot+. Results Eleven variants were identified, and one new pathogenic variant was described in the heterozygous state, which is consistent with genotype c. 319 G> T or p.Ala107Ser. The pathogenic variant c.901G>T or p.Gly301Cys was the most frequent mutation with 51.6% of alleles. Docking revealed affinity energy of −5.9 Kcal/mol between wild-type GALNS and the G6S ligand. Some changes were evidenced at the intermolecular interaction level, and affinity energy for each mutant decreased. Conclusion Clinical variables and genotypic analysis were similar to those reported for other world populations. Genotypic data showed greater allelic heterogeneity than those previously reported. Bioinformatics tools showed differences in the binding interactions of mutant proteins with the G6S ligand, in regard the wild-type GALNS. PMID:29731656

Observational Prospective Natural History of Patients with Sanfilippo Syndrome Type B.

PubMed

Whitley, Chester B; Cleary, Maureen; Eugen Mengel, Karl; Harmatz, Paul; Shapiro, Elsa; Nestrasil, Igor; Haslett, Patrick; Whiteman, David; Alexanderian, David

2018-06-01

To evaluate the natural course of disease progression in patients with Sanfilippo syndrome type B (mucopolysaccharidosis type IIIB), identify potential end points for future therapy trials, and characterize biomarkers related to the disease. A prospective, multicenter study was conducted. Baseline, 6-month, and 12-month assessments included neurodevelopmental status (Bayley Scales of Infant Development, Third edition), adaptive status (Vineland Adaptive Behavior Scales, Second Edition), volumetric brain magnetic resonance imaging, cerebrospinal fluid heparan sulfate, and urine glycosaminoglycan (GAG) measurements. Nineteen patients aged 1.6-31.7 years were enrolled. Over 12 months, cognition, adaptive behavior, and cortical gray matter volume (GMV) declined in most patients. For patients diagnosed at <6 years, although there was no overall mean change over 12 months, there were 10%-48%, 3%-66%, and 1%-14% decreases in cognitive development quotient score, Vineland Adaptive Behavior Scales, Second Edition development quotient score, and cortical GMV in 8/12, 9/11, and 10/11 patients, respectively. Mean urine GAG and cerebrospinal fluid heparan sulfate levels were stable, but patients diagnosed at <6 years (n = 14) had higher levels than those ≥6 years at diagnosis (n = 4), which was likely associated with age as they also were generally younger. Cognition, adaptive behavior, and cortical GMV measures sensitively tracked deterioration in patients with mucopolysaccharidosis type IIIB aged ≤8.6 years. Biomarkers may have prognostic value, but their sensitivity to disease progression requires further investigation. These findings should help evaluate enzyme replacement and gene therapy agents for this rare, devastating, neurodegenerative disease. ClinicalTrials.gov: NCT01509768. Copyright © 2018 Elsevier Inc. All rights reserved.

Radiographic evaluation of bones and joints in mucopolysaccharidosis I and VII dogs after neonatal gene therapy.

PubMed

Herati, Ramin Sedaghat; Knox, Van W; O'Donnell, Patricia; D'Angelo, Marina; Haskins, Mark E; Ponder, Katherine P

2008-11-01

Mucopolysaccharidosis I (MPS I) and MPS VII are due to deficient activity of the glycosaminoglycan-degrading lysosomal enzymes alpha-L-iduronidase and beta-glucuronidase, respectively, and result in abnormal bones and joints. Here, the severity of skeletal disease in MPS I and MPS VII dogs and the effects of neonatal gene therapy were evaluated. For untreated MPS VII dogs, the lengths of the second cervical vertebrae (C2) and the femur were only 56% and 84% of normal, respectively, and bone dysplasia and articular erosions, and joint subluxation were severe. Previously, we reported that neonatal intravenous injection of a retroviral vector (RV) with the appropriate gene resulted in expression in liver and blood cells, and high serum enzyme activity. In this study, we demonstrate that C2 and femurs of RV-treated MPS VII dogs were longer at 82% and 101% of normal, respectively, and there were partial improvements of qualitative abnormalities. For untreated MPS I dogs, the lengths of C2 and femurs (91% and 96% of normal, respectively) were not significantly different from normal dogs. Qualitative changes in MPS I bones and joints were generally modest and were partially improved with RV treatment, although cervical spine disease was severe and was difficult to correct with gene therapy in both models. The greater severity of skeletal disease in MPS VII than in MPS I dogs may reflect accumulation of chondroitin sulfate in cartilage in MPS VII, or could relate to the specific mutations. Neonatal RV-mediated gene therapy ameliorates, but does not prevent, skeletal disease in MPS I and MPS VII dogs.

Corrective GUSB transfer to the canine mucopolysaccharidosis VII cornea using a helper-dependent canine adenovirus vector

PubMed Central

Serratrice, Nicolas; Cubizolle, Aurelie; Ibanes, Sandy; Mestre-Francés, Nadine; Bayo-Puxan, Neus; Creyssels, Sophie; Gennetier, Aurelie; Bernex, Florence; Verdier, Jean-Michel; Haskins, Mark E.; Couderc, Guilhem; Malecaze, Francois; Kalatzis, Vasiliki; Kremer, Eric J.

2015-01-01

Corneal transparency is maintained, in part, by specialized fibroblasts called keratocytes, which reside in the fibrous lamellae of the stroma. Corneal clouding, a condition that impairs visual acuity, is associated with numerous diseases, including mucopolysaccharidosis (MPS) type VII. MPS VII is due to deficiency in β-glucuronidase (β-glu) enzymatic activity, which leads to accumulation of glycosaminoglycans (GAGs), and secondary accumulation of gangliosides. Here, we tested the efficacy of canine adenovirus type 2 (CAV-2) vectors to transduce keratocyte in vivo in mice and nonhuman primates, and ex vivo in dog and human corneal explants. Following efficacy studies, we asked if we could treat corneal clouding by the injection a helper-dependent (HD) CAV-2 vector (HD-RIGIE) harboring the human cDNA coding for β-glu (GUSB) in the canine MPS VII cornea. β-Glu activity, GAG content, and lysosome morphology and physiopathology were analyzed. We found that HD-RIGIE injections efficiently transduced coxsackievirus adenovirus receptor-expressing keratocytes in the four species and, compared to mock-injected controls, improved the pathology in the canine MPS VII cornea. The key criterion to corrective therapy was the steady controlled release of β-glu and its diffusion throughout the collagen-dense stroma. These data support the continued evaluation of HD CAV-2 vectors to treat diseases affecting corneal keratocytes. PMID:24607662

Association between brain structural anomalies, electroencephalogram and history of seizures in Mucopolysaccharidosis type II (Hunter syndrome).

PubMed

Jiménez-Arredondo, Ramón Ernesto; Brambila-Tapia, Aniel Jessica Leticia; Mercado-Silva, Francisco Miguel; Ortiz-Aranda, Martha; Benites-Godinez, Verónica; Olmos-García-de-Alba, Graciela; Figuera, Luis Eduardo

2017-03-01

Mucopolysaccharidosis type II or Hunter syndrome (MPS II) is a genetic disease that can course with intellectual impairment and central nervous system (CNS) alterations. To date, no report has documented electroencephalogram (EEG) measures associated with CNS alterations, detected by imaging studies, and the history of seizures in patients with MPS II. Therefore, we decided to search this association. We included 9 patients with MPS II and performed imaging studies of the brain to detect the presence of cortico-subcortical atrophy, enlarged subarachnoid space and supratentorial ventricular size. Additionally, we performed EEG studies in sleep and awake conditions and a complete clinical description. Five out of the nine patients presented history of seizures and all except one patient (88.9%) presented some CNS structural alteration in the imaging studies, being the most frequent the cortico-subcortical atrophy (77.8%). The EEG results showed low amplitude in all patients and low voltage in sleep condition in eight patients with interhemispheric asymmetry in six patients during awake and sleep conditions. Although the five patients with history of seizures did not present a distinctive EEG anomaly, four of them presented some structural alteration in the imaging studies. In conclusion, most patients presented structural alterations in the CNS; likewise, all of them presented EEG anomalies mainly during sleep conditions. However, a clear association between EEG, CNS and the history of seizures was not established.

The impact of laronidase treatment in otolaryngological manifestations of patients with mucopolysaccharidosis.

PubMed

Dualibi, Ana Paula Fiuza Funicello; Martins, Ana Maria; Moreira, Gustavo Antônio; de Azevedo, Marisa Frasson; Fujita, Reginaldo Raimundo; Pignatari, Shirley Shizue Nagata

2016-01-01

Mucopolysaccharidosis (MPS) is a lysosomal storage disease caused by deficiency of α-l-iduronidase. The otolaryngological findings include hearing loss, otorrhea, recurrent otitis, hypertrophy of tonsils and adenoid, recurrent rhinosinusitis, speech disorders, snoring, oral breathing and nasal obstruction. To evaluate the impact of enzymatic replacement therapy with laronidase (Aldurazyme(®)) in patients with mucopolysaccharidosis (MPS I), regarding sleep and hearing disorders, and clinical manifestations in the upper respiratory tract (URT). Nine patients with MPS I (8 Hurler-Scheie, and 1 Scheie phenotypes) of both sexes, ages ranging between 3 and 20 years, were included in this study. Patients were evaluated between seven and 11 months before the treatment and between 16 and 22 months after the onset of the enzymatic replacement. They were all submitted to a clinical and otolaryngological evaluation, including nasofibroscopical, polysomnographic and audiologic exams. The results' data showed decreasing of the frequency of ear, nose and throat infections, with improvement of the rhinorrhea and respiratory quality. No remarkable changes were observed regarding macroglossia and tonsil and adenoid hypertrophy. Audiometric and polysomnographic evaluations did not show statistical significance. Enzymatic replacement therapy in patients with mucopolysaccharidosis I provides control of recurrent URT infections, rhinorrhea and respiratory quality, however it is does not seem to improve audiologic and polisomnographic parameters, with no effect on adenoid and tonsils hypertrophy and macroglossia. Copyright © 2015 Associação Brasileira de Otorrinolaringologia e Cirurgia Cérvico-Facial. Published by Elsevier Editora Ltda. All rights reserved.

Physical performance testing in mucopolysaccharidosis I: a pilot study.

PubMed

Dumas, Helene M; Fragala, Maria A; Haley, Stephen M; Skrinar, Alison M; Wraith, James E; Cox, Gerald F

2004-01-01

To develop and field-test a physical performance measure (MPS-PPM) for individuals with Mucopolysaccharidosis I (MPS I), a rare genetic disorder. Motor performance and endurance items were developed based on literature review, clinician feedback, feasibility, and equipment and training needs. A standardized testing protocol and scoring rules were created. The MPS-PPM includes: Arm Function (7 items), Leg Function (5 items), and Endurance (2 items). Pilot data were collected for 10 subjects (ages 5-29 years). We calculated Spearman's rho correlations between age, severity and summary z-scores on the MPS-PPM. Subjects had variable presentations, as correlations among the three sub-test scores were not significant. Increasing age was related to greater severity in physical performance (r = 0.72, p<0.05) and lower scores on the Leg Function (r = -0.67, p<0.05) and Endurance (r = -0.65, p<0.05) sub-tests. The MPS-PPM was sensitive to detecting physical performance deficits, as six subjects could not complete the full battery of Arm Function items and eight subjects were unable to complete all Leg Function items. Subjects walked more slowly and expended more energy than typically developing peers. Individuals with MPS I have difficulty with arm and leg function and reduced endurance. The MPS-PPM is a clinically feasible measure that detects limitations in physical performance and may have potential to quantify changes in function following intervention. Copyright 2004 Taylor and Francis Ltd.

Storage vesicles in neurons are related to Golgi complex alterations in mucopolysaccharidosis IIIB.

PubMed

Vitry, Sandrine; Bruyère, Julie; Hocquemiller, Michaël; Bigou, Stéphanie; Ausseil, Jérôme; Colle, Marie-Anne; Prévost, Marie-Christine; Heard, Jean Michel

2010-12-01

The accumulation of intracellular storage vesicles is a hallmark of lysosomal storage diseases. Neither the identity nor origin of these implicated storage vesicles have yet been established. The vesicles are often considered as lysosomes, endosomes, and/or autophagosomes that are engorged with undigested materials. Our studies in the mouse model of mucopolysaccharidosis type IIIB, a lysosomal storage disease that induces neurodegeneration, showed that large storage vesicles in cortical neurons did not receive material from either the endocytic or autophagy pathway, which functioned normally. Storage vesicles expressed GM130, a Golgi matrix protein, which mediates vesicle tethering in both pre- and cis-Golgi compartments. However, other components of the tethering/fusion complex were not associated with GM130 on storage vesicles, likely accounting for both the resistance of the vesicles to brefeldin A and the alteration of Golgi ribbon architecture, which comprised distended cisterna connected to LAMP1-positive storage vesicles. We propose that alteration in the GM130-mediated control of vesicle trafficking in pre-Golgi and Golgi compartments affects Golgi biogenesis and gives rise to a dead-end storage compartment. Vesicle accumulation, Golgi disorganization, and alterations of other GM130 functions may account for neuron dysfunction and death.

[The thesis of judicialization of health care by the elites: medication for mucopolysaccharidosis].

PubMed

Medeiros, Marcelo; Diniz, Debora; Schwartz, Ida Vanessa Doederlein

2013-04-01

This paper evaluates the hypothesis that the judicialization of medicine for mucopolysaccharidosis in Brazil is an action promoted by economic elites. Previous studies upholding the thesis of judicialization by elites in the case of other types of medication that are more costly for the Unified Health Service are discussed. An analysis of all 196 processes containing information about judicial processes brought to court between February 2006 and December 2010 that ended by determining that the State should provide such medication free of charge to patients was conducted. There is evidence that attorneys' fees were covered by entities interested in the results of judicialization, such as the distributors or pharmaceutical industries. Patients may also be migrating for diagnosis and treatment to university centers that are a benchmark for medical innovation in the country, as the option for public health services is related to their higher technical and scientific capacity. Therefore, the resort to private lawyers, indicators of social exclusion based on the address of patients and the use of public health services, are not adequate class information to corroborate or refute the thesis of judicialization by the elites.

Intranasal Adeno-Associated Virus Mediated Gene Delivery and Expression of Human Iduronidase in the Central Nervous System: A Noninvasive and Effective Approach for Prevention of Neurologic Disease in Mucopolysaccharidosis Type I.

PubMed

Belur, Lalitha R; Temme, Alexa; Podetz-Pedersen, Kelly M; Riedl, Maureen; Vulchanova, Lucy; Robinson, Nicholas; Hanson, Leah R; Kozarsky, Karen F; Orchard, Paul J; Frey, William H; Low, Walter C; McIvor, R Scott

2017-07-01

Mucopolysaccharidosis type I (MPS I) is a progressive, multi-systemic, inherited metabolic disease caused by deficiency of α-L-iduronidase (IDUA). Current treatments for this disease are ineffective in treating central nervous system (CNS) disease due to the inability of lysosomal enzymes to traverse the blood-brain barrier. A noninvasive and effective approach was taken in the treatment of CNS disease by intranasal administration of an IDUA-encoding adeno-associated virus serotype 9 (AAV9) vector. Adult IDUA-deficient mice aged 3 months were instilled intranasally with AAV9-IDUA vector. Animals sacrificed 5 months post instillation exhibited IDUA enzyme activity levels that were up to 50-fold that of wild-type mice in the olfactory bulb, with wild-type levels of enzyme restored in all other parts of the brain. Intranasal treatment with AAV9-IDUA also resulted in the reduction of tissue glycosaminoglycan storage materials in the brain. There was strong IDUA immunofluorescence staining of tissue sections observed in the nasal epithelium and olfactory bulb, but there was no evidence of the presence of transduced cells in other portions of the brain. This indicates that reduction of storage materials most likely occurred as a result of enzyme diffusion from the olfactory bulb and the nasal epithelium into deeper areas of the brain. At 8 months of age, neurocognitive testing using the Barnes maze to assess spatial navigation demonstrated that treated IDUA-deficient mice were no different from normal control animals, while untreated IDUA-deficient mice exhibited significant learning and navigation deficits. This novel, noninvasive strategy for intranasal AAV9-IDUA instillation could potentially be used to treat CNS manifestations of human MPS I.

Large scale analysis of the mutational landscape in β-glucuronidase: A major player of mucopolysaccharidosis type VII.

PubMed

Khan, Faez Iqbal; Shahbaaz, Mohd; Bisetty, Krishna; Waheed, Abdul; Sly, William S; Ahmad, Faizan; Hassan, Md Imtaiyaz

2016-01-15

The lysosomal storage disorders are a group of 50 unique inherited diseases characterized by unseemly lipid storage in lysosomes. These malfunctions arise due to genetic mutations that result in deficiency or reduced activities of the lysosomal enzymes, which are responsible for catabolism of biological macromolecules. Sly syndrome or mucopolysaccharidosis type VII is a lysosomal storage disorder associated with the deficiency of β-glucuronidase (EC 3.2.1.31) that catalyzes the hydrolysis of β-D-glucuronic acid residues from the non-reducing terminal of glycosaminoglycan. The effects of the disease causing mutations on the framework of the sequences and structure of β-glucuronidase (GUSBp) were analyzed utilizing a variety of bioinformatic tools. These analyses showed that 211 mutations may result in alteration of the biological activity of GUSBp, including previously experimentally validated mutations. Finally, we refined 90 disease causing mutations, which presumably cause a significant impact on the structure, function, and stability of GUSBp. Stability analyses showed that mutations p.Phe208Pro, p.Phe539Gly, p.Leu622Gly, p.Ile499Gly and p.Ile586Gly caused the highest impact on GUSBp stability and function because of destabilization of the protein structure. Furthermore, structures of wild type and mutant GUSBp were subjected to molecular dynamics simulation to examine the relative structural behaviors in the explicit conditions of water. In a broader view, the use of in silico approaches provided a useful understanding of the effect of single point mutations on the structure-function relationship of GUSBp. Copyright © 2015 Elsevier B.V. All rights reserved.

Radiographic Evaluation of Bones and Joints in Mucopolysaccharidosis I and VII Dogs After Neonatal Gene Therapy

PubMed Central

Herati, Ramin Sedaghat; Knox, Van W.; O’Donnell, Patricia; D’Angelo, Marina; Haskins, Mark E.; Ponder, Katherine P.

2009-01-01

Mucopolysaccharidosis I (MPS I) and MPS VII are due to deficient activity of the glycosaminoglycan-degrading lysosomal enzymes α-L-iduronidase and β-glucuronidase, respectively, and result in abnormal bones and joints. Here, the severity of skeletal disease in MPS I and MPS VII dogs and the effects of neonatal gene therapy were evaluated. For untreated MPS VII dogs, the lengths of the second cervical vertebrae (C2) and the femur were only 56% and 84% of normal, respectively, and bone dysplasia and articular erosions, and joint subluxation were severe. Previously, we reported that neonatal intravenous injection of a retroviral vector (RV) with the appropriate gene resulted in expression in liver and blood cells, and high serum enzyme activity. In this study, we demonstrate that C2 and femurs of RV-treated MPS VII dogs were longer at 82% and 101% of normal, respectively, and there were partial improvements of qualitative abnormalities. For untreated MPS I dogs, the lengths of C2 and femurs (91% and 96% of normal, respectively) were not significantly different from normal dogs. Qualitative changes in MPS I bones and joints were generally modest and were partially improved with RV treatment, although cervical spine disease was severe and was difficult to correct with gene therapy in both models. The greater severity of skeletal disease in MPS VII than in MPS I dogs may reflect accumulation of chondroitin sulfate in cartilage in MPS VII, or could relate to the specific mutations. Neonatal RV-mediated gene therapy ameliorates, but does not prevent, skeletal disease in MPS I and MPS VII dogs. PMID:18707908

Features of Brain MRI in Dogs with Treated and Untreated Mucopolysaccharidosis Type I

PubMed Central

Vite, Charles H; Nestrasil, Igor; Mlikotic, Anton; Jens, Jackie K; Snella, Elizabeth M; Gross, William; Shapiro, Elsa G; Kovac, Victor; Provenzale, James M; Chen, Steven; Le, Steven Q; Kan, Shih-hsin; Banakar, Shida; Wang, Raymond Y; Haskins, Mark E; Ellinwood, N Matthew; Dickson, Patricia I

2013-01-01

The mucopolysaccharidosis type I (MPS I) dog model has been important in the development of therapies for human patients. We treated dogs with enzyme replacement therapy (ERT) by various approaches. Dogs assessed included untreated MPS I dogs, heterozygous carrier dogs, and MPS I dogs treated with intravenous ERT as adults (beginning at age 13 to 16 mo), intrathecal and intravenous ERT as adults (beginning at age 13 to 16 mo), or intrathecal ERT as juveniles (beginning at age 4 mo). We then characterized the neuroimaging findings of 32 of these dogs (age, 12 to 30 mo). Whole and midsagittal volumes of the corpus callosum, measured from brain MRI, were significantly smaller in affected dogs compared with unaffected heterozygotes. Corpus callosum volumes in dogs that were treated with intrathecal ERT from 4 mo until 21 mo of age were indistinguishable from those of age-matched carrier controls. Dogs with MPS I showed cerebral ventricular enlargement and cortical atrophy as early as 12 mo of age. Ventricular enlargement was greater in untreated MPS I dogs than in age-matched dogs treated with intrathecal ERT as juveniles or adults. However, treated dogs still showed some ventricular enlargement or cortical atrophy (or both). Understanding the progression of neuroimaging findings in dogs with MPS I and their response to brain-directed therapy may improve preclinical studies for new human-directed therapies. In particular, corpus callosum volumes may be useful quantitative neuroimaging markers for MPS-related brain disease and its response to therapy. PMID:23582423

Liver-directed gene therapy corrects cardiovascular lesions in feline mucopolysaccharidosis type I.

PubMed

Hinderer, Christian; Bell, Peter; Gurda, Brittney L; Wang, Qiang; Louboutin, Jean-Pierre; Zhu, Yanqing; Bagel, Jessica; O'Donnell, Patricia; Sikora, Tracey; Ruane, Therese; Wang, Ping; Haskins, Mark E; Wilson, James M

2014-10-14

Patients with mucopolysaccharidosis type I (MPS I), a genetic deficiency of the lysosomal enzyme α-l-iduronidase (IDUA), exhibit accumulation of glycosaminoglycans in tissues, with resulting diverse clinical manifestations including neurological, ocular, skeletal, and cardiac disease. MPS I is currently treated with hematopoietic stem cell transplantation or weekly enzyme infusions, but these therapies have significant drawbacks for patient safety and quality of life and do not effectively address some of the most critical clinical sequelae, such as life-threatening cardiac valve involvement. Using the naturally occurring feline model of MPS I, we tested liver-directed gene therapy as a means of achieving long-term systemic IDUA reconstitution. We treated four MPS I cats at 3-5 mo of age with an adeno-associated virus serotype 8 vector expressing feline IDUA from a liver-specific promoter. We observed sustained serum enzyme activity for 6 mo at ∼ 30% of normal levels in one animal, and in excess of normal levels in three animals. Remarkably, treated animals not only demonstrated reductions in glycosaminoglycan storage in most tissues, but most also exhibited complete resolution of aortic valve lesions, an effect that has not been previously observed in this animal model or in MPS I patients treated with current therapies. These data point to clinically meaningful benefits of the robust enzyme expression achieved with hepatic gene transfer that extend beyond the economic and quality of life advantages over lifelong enzyme infusions.

Lentiviral-mediated gene therapy results in sustained expression of β-glucuronidase for up to 12 months in the gus(mps/mps) and up to 18 months in the gus(tm(L175F)Sly) mouse models of mucopolysaccharidosis type VII.

PubMed

Derrick-Roberts, Ainslie L K; Pyragius, Carmen E; Kaidonis, Xenia M; Jackson, Matilda R; Anson, Donald S; Byers, Sharon

2014-09-01

A number of mucopolysaccharidosis type VII (MPS VII) mouse models with different levels of residual enzyme activity have been created replicating the range of clinical phenotypes observed in human MPS VII patients. In this study, a lentivirus encoding murine β-glucuronidase was administered intravenously at birth to both the severe (Gus(mps/mps) strain) and attenuated (Gus(tm(L175F)Sly) strain) mouse models of MPS VII. Circulating enzyme levels were normalized in the Gus(mps/mps) mice and were 3.5-fold higher than normal in the Gus(tm(L175F)Sly) mouse 12 and 18 months after administration. Tissue β-glucuronidase activity increased over untreated levels in all tissues evaluated in both strains at 12 months, and the elevated level was maintained in Gus(tm(L175F)Sly) tissues at 18 months. These elevated enzyme levels reduced glycosaminoglycan storage in the liver, spleen, kidney, and heart in both models. Bone mineral volume decreased toward normal in both models after 12 months of therapy and after 18 months in the Gus(tm(L175F)Sly) mouse. Open-field exploration was improved in 18-month-old treated Gus(tm(L175F)Sly) mice, while spatial learning improved in both 12- and 18-month-old treated Gus(tm(L175F)Sly) mice. Overall, neonatal administration of lentiviral gene therapy resulted in sustained enzyme expression for up to 18 months in murine models of MPS VII. Significant improvements in biochemistry and enzymology as well as functional improvement of bone and behavior deficits in the Gus(tm(L175F)Sly) model were observed. Therapy significantly increased the lifespan of Gus(mps/mps) mice, with 12 months being the longest reported lentiviral treatment for this strain. It is important to assess the long-term outcome on enzyme levels and effect on pathology for lentiviral gene therapy to be a potential therapy for MPS patients.

Does early use of enzyme replacement therapy alter the natural history of mucopolysaccharidosis I? Experience in three siblings.

PubMed

Laraway, Sarah; Breen, Catherine; Mercer, Jean; Jones, Simon; Wraith, James E

2013-07-01

Enzyme replacement therapy is widely used as treatment for mucopolysaccharidosis I (MPS I), and there is evidence that this produces improvement in certain clinical domains. There does appear to be variation in the response of clinical features to treatment once these are established. In a reported sibling pair, when enzyme replacement therapy was commenced pre-symptomatically in the younger child, the natural history of the condition appeared to be affected. We present data from three siblings treated with enzyme replacement therapy at different ages which supports this finding. Copyright © 2013 Elsevier Inc. All rights reserved.

Genetic and other diseases in the pottery of Tumaco-La Tolita culture in Colombia-Ecuador.

PubMed

Bernal, J E; Briceno, I

2006-09-01

The people of Tumaco-La Tolita culture inhabited the borders of present-day Colombia and Ecuador. Already extinct by the time of the Spaniards arrival, they left a huge collection of pottery artifacts depicting everyday life; among these, disease representations were frequently crafted. In this article, we present the results of the personal examination of the largest collections of Tumaco-La Tolita pottery in Colombia and Ecuador; cases of Down syndrome, achondroplasia, mucopolysaccharidosis I H, mucopolysaccharidosis IV, a tumor of the face and a benign tumor in an old woman were found. We believe these to be among the earliest artistic representations of disease.

Screening of lysosomal storage disorders: application of the online trapping-and-cleanup liquid chromatography/mass spectrometry method for mucopolysaccharidosis I.

PubMed

Ombrone, Daniela; Malvagia, Sabrina; Funghini, Silvia; Giocaliere, Elisa; Della Bona, Maria Luisa; Forni, Giulia; De Luca, Alessio; Villanelli, Fabio; Casetta, Bruno; Guerrini, Renzo; la Marca, Giancarlo

2013-01-01

In recent years, new treatments have become available to treat some lysosomal storage disorders (LSDs) and many studies suggest that there is a benefit with starting therapy early. Newborn screening should detect diseases early enough for prompt treatment. Some countries include additional conditions, such as some LSDs, into their newborn screening panels. Mucopolysaccharidosis Type I (MPS I) is an autosomal recessive disorder caused by the deficiency of α-L-iduronidase (IDUA) activity. Currently, enzyme replacement therapy (ERT) or bone marrow transplantation is available and this has raised a growing interest for the development of a newborn screening test. In 2009, we reported a new fast and simplified tandem mass spectrometry-based method for quantifying five enzyme activities on dried blood spots. Here, we describe the inclusion of IDUA activity determination for the simultaneous detection of six lysosomal storage diseases. We have defined reference normal ranges by testing 680 healthy newborns and 240 adults. The assay was checked through three confirmed MPS I patients whose IDUA activity was below the normal range. Reproducibility of the assays has been established by assessing the intra-day and inter-day assay imprecisions. This quick assay has been devised to be implemented in newborn screening by liquid chromatography tandem mass spectrometry.

Mucopolysaccharidosis-like phenotype in feline Sandhoff disease and partial correction after AAV gene therapy.

PubMed

Gray-Edwards, Heather L; Brunson, Brandon L; Holland, Merrilee; Hespel, Adrien-Maxence; Bradbury, Allison M; McCurdy, Victoria J; Beadlescomb, Patricia M; Randle, Ashley N; Salibi, Nouha; Denney, Thomas S; Beyers, Ronald J; Johnson, Aime K; Voyles, Meredith L; Montgomery, Ronald D; Wilson, Diane U; Hudson, Judith A; Cox, Nancy R; Baker, Henry J; Sena-Esteves, Miguel; Martin, Douglas R

2015-01-01

Sandhoff disease (SD) is a fatal neurodegenerative disease caused by a mutation in the enzyme β-N-acetylhexosaminidase. Children with infantile onset SD develop seizures, loss of motor tone and swallowing problems, eventually reaching a vegetative state with death typically by 4years of age. Other symptoms include vertebral gibbus and cardiac abnormalities strikingly similar to those of the mucopolysaccharidoses. Isolated fibroblasts from SD patients have impaired catabolism of glycosaminoglycans (GAGs). To evaluate mucopolysaccharidosis-like features of the feline SD model, we utilized radiography, MRI, echocardiography, histopathology and GAG quantification of both central nervous system and peripheral tissues/fluids. The feline SD model exhibits cardiac valvular and structural abnormalities, skeletal changes and spinal cord compression that are consistent with accumulation of GAGs, but are much less prominent than the severe neurologic disease that defines the humane endpoint (4.5±0.5months). Sixteen weeks after intracranial AAV gene therapy, GAG storage was cleared in the SD cat cerebral cortex and liver, but not in the heart, lung, skeletal muscle, kidney, spleen, pancreas, small intestine, skin, or urine. GAG storage worsens with time and therefore may become a significant source of pathology in humans whose lives are substantially lengthened by gene therapy or other novel treatments for the primary, neurologic disease. Published by Elsevier Inc.

Cassava diet--a cause for mucopolysaccharidosis?

PubMed

Sreeja, V G; Leelamma, S

2002-01-01

Studies were carried out to determine the changes in glycosaminnoglycan (GAG) metabolism in rats fed cassava with varying cyanoglucoside levels and two levels of protein. Results indicated that there was an enhancement in the level of total and individual GAG with a corresponding reduction in the activity of enzymes involved in the degradation of glycosaminoglycan. These changes were significant for rats given a cassava diet (raw and boiled cassava) and low protein. The changes in total and individual GAG and the decrease in the activity of degrading enzymes was more for high cyanide (raw cassava) groups compared with other groups showing that consumption of untreated cassava is an additive factor for the promotion of mucopolysaccharidosis.

Whole body correction of mucopolysaccharidosis IIIA by intracerebrospinal fluid gene therapy

PubMed Central

Haurigot, Virginia; Marcó, Sara; Ribera, Albert; Garcia, Miguel; Ruzo, Albert; Villacampa, Pilar; Ayuso, Eduard; Añor, Sònia; Andaluz, Anna; Pineda, Mercedes; García-Fructuoso, Gemma; Molas, Maria; Maggioni, Luca; Muñoz, Sergio; Motas, Sandra; Ruberte, Jesús; Mingozzi, Federico; Pumarola, Martí; Bosch, Fatima

2013-01-01

For most lysosomal storage diseases (LSDs) affecting the CNS, there is currently no cure. The BBB, which limits the bioavailability of drugs administered systemically, and the short half-life of lysosomal enzymes, hamper the development of effective therapies. Mucopolysaccharidosis type IIIA (MPS IIIA) is an autosomic recessive LSD caused by a deficiency in sulfamidase, a sulfatase involved in the stepwise degradation of glycosaminoglycan (GAG) heparan sulfate. Here, we demonstrate that intracerebrospinal fluid (intra-CSF) administration of serotype 9 adenoassociated viral vectors (AAV9s) encoding sulfamidase corrects both CNS and somatic pathology in MPS IIIA mice. Following vector administration, enzymatic activity increased throughout the brain and in serum, leading to whole body correction of GAG accumulation and lysosomal pathology, normalization of behavioral deficits, and prolonged survival. To test this strategy in a larger animal, we treated beagle dogs using intracisternal or intracerebroventricular delivery. Administration of sulfamidase-encoding AAV9 resulted in transgenic expression throughout the CNS and liver and increased sulfamidase activity in CSF. High-titer serum antibodies against AAV9 only partially blocked CSF-mediated gene transfer to the brains of dogs. Consistently, anti-AAV antibody titers were lower in CSF than in serum collected from healthy and MPS IIIA–affected children. These results support the clinical translation of this approach for the treatment of MPS IIIA and other LSDs with CNS involvement. PMID:23863627

Whole body correction of mucopolysaccharidosis IIIA by intracerebrospinal fluid gene therapy.

PubMed

Haurigot, Virginia; Marcó, Sara; Ribera, Albert; Garcia, Miguel; Ruzo, Albert; Villacampa, Pilar; Ayuso, Eduard; Añor, Sònia; Andaluz, Anna; Pineda, Mercedes; García-Fructuoso, Gemma; Molas, Maria; Maggioni, Luca; Muñoz, Sergio; Motas, Sandra; Ruberte, Jesús; Mingozzi, Federico; Pumarola, Martí; Bosch, Fatima

2013-07-01

For most lysosomal storage diseases (LSDs) affecting the CNS, there is currently no cure. The BBB, which limits the bioavailability of drugs administered systemically, and the short half-life of lysosomal enzymes, hamper the development of effective therapies. Mucopolysaccharidosis type IIIA (MPS IIIA) is an autosomic recessive LSD caused by a deficiency in sulfamidase, a sulfatase involved in the stepwise degradation of glycosaminoglycan (GAG) heparan sulfate. Here, we demonstrate that intracerebrospinal fluid (intra-CSF) administration of serotype 9 adenoassociated viral vectors (AAV9s) encoding sulfamidase corrects both CNS and somatic pathology in MPS IIIA mice. Following vector administration, enzymatic activity increased throughout the brain and in serum, leading to whole body correction of GAG accumulation and lysosomal pathology, normalization of behavioral deficits, and prolonged survival. To test this strategy in a larger animal, we treated beagle dogs using intracisternal or intracerebroventricular delivery. Administration of sulfamidase-encoding AAV9 resulted in transgenic expression throughout the CNS and liver and increased sulfamidase activity in CSF. High-titer serum antibodies against AAV9 only partially blocked CSF-mediated gene transfer to the brains of dogs. Consistently, anti-AAV antibody titers were lower in CSF than in serum collected from healthy and MPS IIIA-affected children. These results support the clinical translation of this approach for the treatment of MPS IIIA and other LSDs with CNS involvement.

Long Circulating Enzyme Replacement Therapy Rescues Bone Pathology in Mucopolysaccharidosis VII Murine Model

PubMed Central

Rowan, Daniel J.; Tomatsu, Shunji; Grubb, Jeffrey H.; Haupt, Bisong; Montaño, Adriana M.; Oikawa, Hirotaka; Sosa, Catalina; Chen, Anping; Sly, William S.

2012-01-01

Mucopolysaccharidosis (MPS) type VII is a lysosomal storage disease caused by deficiency of the lysosomal enzyme β-glucuronidase (GUS), leading to accumulation of glycosaminoglycans (GAGs). Enzyme replacement therapy (ERT) effectively clears GAG storage in the viscera. Recent studies showed that a chemically modified form of GUS (PerT-GUS), which escaped clearance by mannose 6-phosphate and mannose receptors and showed prolonged circulation, reduced CNS storage more effectively than native GUS. Clearance of storage in bone has been limited due to the avascularity of the growth plate. To evaluate the effectiveness of long-circulating PerT-GUS in reducing the skeletal pathology, we treated MPS VII mice for 12 weeks beginning at 5 weeks of age with PerT-GUS or native GUS and used micro-CT, radiographs, and quantitative histopathological analysis for assessment of bones. Micro-CT findings showed PerT-GUS treated mice had a significantly lower BMD. Histopathological analysis also showed reduced storage material and a more organized growth plate in PerT-GUS treated mice compared with native GUS treated mice. Long term treatment with PerT-GUS from birth up to 57 weeks also significantly improved bone lesions demonstrated by micro-CT, radiographs and quantitative histopathological assay. In conclusion, long-circulating PerT-GUS provides a significant impact to rescue of bone lesions and CNS involvement. PMID:22902520

Allogeneic Bone Marrow Transplant for Inherited Metabolic Disorders

ClinicalTrials.gov

2018-01-09

Mucopolysaccharidosis; Hurler Syndrome; Hunter Syndrome; Maroteaux-Lamy Syndrome; Sly Syndrome; Alpha Mannosidosis; Fucosidosis; Aspartylglucosaminuria; Adrenoleukodystrophy (ALD); Krabbe Disease; Metachromatic Leukodystrophy (MLD); Sphingolipidoses; Peroxisomal Disorders

Spine malformation complex in 3 diverse syndromic entities: Case reports.

PubMed

Kaissi, Ali Al; van Egmond-Fröhlich, Andreas; Ryabykh, Sergey; Ochirov, Polina; Kenis, Vladimir; Hofstaetter, Jochen G; Grill, Franz; Ganger, Rudolf; Kircher, Susanne Gerit

2016-12-01

Clinical and radiographic phenotypic characterizations were the base line tool of diagnosis in 3 syndromic disorders in which congenital cervico-thoracic kyphosis was the major deformity. Directing maximal care toward the radiographic analysis is not only the axial malformation but also toward the appendicular abnormalities was our main concern. We fully documented the diversity of the spine phenotypic malformation complex via the clinical and radiographic phenotypes. We established the diagnosis via phenotypic/genotypic confirmation in 3 diverse syndromic entities namely acampomelic campomelic dysplasia, Larsen syndrome and Morquio syndrome type A (mucopolysaccharidosis type IV A). Surgical interventions have been carried out in the Larsen syndrome and Morquio syndrome type A, resepectively. The earliest the diagnosis is, the better the results are. The necessity to diagnose children in their first year of life has many folds, firstly the management would be in favor of the child's growth and development and secondly, the prognosis could be clearer to the family and the medical staff as well. Our current paper is to sensitize paediatricians, physicians and orthopedic surgeons regarding the necessity to detect the aetiological understanding in every child who manifests a constellation of malformation complex. Scoliosis and kyphosis/kyphoscoliosis are not a diagnosis in themselves. Such deformities are mostly a symptom complex correlated to dozens of types of syndromic associations. The rate curve progression and the final severity of congenital spine tilting are related to 3 factors: (a) the type of vertebral malformation present, (b) the patient's phenotype, and (c) the diagnosis.

Clinical characteristics and surgical history of Taiwanese patients with mucopolysaccharidosis type II: data from the hunter outcome survey (HOS).

PubMed

Lin, Hsiang-Yu; Chuang, Chih-Kuang; Chen, Ming-Ren; Lin, Shio Jean; Chiu, Pao Chin; Niu, Dau-Ming; Tsai, Fuu-Jen; Hwu, Wuh-Liang; Chien, Yin-Hsiu; Lin, Ju-Li; Lin, Shuan-Pei

2018-06-04

Mucopolysaccharidosis type II (MPS II) is the most frequently occurring MPS in Taiwan, with an incidence of 2.05 per 100,000 live male births, but little is known about clinical characteristics and surgical history in Taiwanese patients. Medical history, demographics, signs and symptoms, and surgical history were analysed in all patients from Taiwanese centres in the Hunter Outcome Survey (HOS; NCT 03292887), a global, multicentre registry that collects real-world data on patients with MPS II. As of January 2016, 61 male Taiwanese patients were enrolled; 49% (24/49) had received at least one infusion of idursulfase. Median (10th, 90th percentiles) ages at signs and symptom onset and at diagnosis were 2.5 (0.2, 5.5) years (n = 55) and 3.5 (1.2, 11.9) years (n = 56), respectively. Hernia, facial features consistent with MPS II and claw hands were the earliest presenting signs and symptoms (median ages of 3.2 [0.4, 12.0] years, 4.3 [1.1, 12.0] years and 4.7 [2.5, 12.2] years [n = 45, 53 and 50], respectively). More than 75% of patients had undergone a surgical procedure, most commonly hernia repair (57% of patients). Median age at first surgery for hernia repair was 4.2 (0.5, 9.8) years (n = 35). Almost one-third (31.1%) of patients had at least one surgical procedure before diagnosis, and of the 20 procedures before diagnosis, 16 were hernia repair. This information from patients in HOS highlights the importance of both medical and surgical history in diagnosing MPS II in Taiwanese patients.

Biochemical, histological and functional correction of mucopolysaccharidosis type IIIB by intra-cerebrospinal fluid gene therapy.

PubMed

Ribera, Albert; Haurigot, Virginia; Garcia, Miguel; Marcó, Sara; Motas, Sandra; Villacampa, Pilar; Maggioni, Luca; León, Xavier; Molas, Maria; Sánchez, Víctor; Muñoz, Sergio; Leborgne, Christian; Moll, Xavier; Pumarola, Martí; Mingozzi, Federico; Ruberte, Jesús; Añor, Sònia; Bosch, Fatima

2015-04-01

Gene therapy is an attractive tool for the treatment of monogenic disorders, in particular for lysosomal storage diseases (LSD) caused by deficiencies in secretable lysosomal enzymes in which neither full restoration of normal enzymatic activity nor transduction of all affected cells are necessary. However, some LSD such as Mucopolysaccharidosis Type IIIB (MPSIIIB) are challenging because the disease's main target organ is the brain and enzymes do not efficiently cross the blood-brain barrier even if present at very high concentration in circulation. To overcome these limitations, we delivered AAV9 vectors encoding for α-N-acetylglucosaminidase (NAGLU) to the Cerebrospinal Fluid (CSF) of MPSIIIB mice with the disease already detectable at biochemical, histological and functional level. Restoration of enzymatic activity in Central Nervous System (CNS) resulted in normalization of glycosaminoglycan content and lysosomal physiology, resolved neuroinflammation and restored the pattern of gene expression in brain similar to that of healthy animals. Additionally, transduction of the liver due to passage of vectors to the circulation led to whole-body disease correction. Treated animals also showed reversal of behavioural deficits and extended lifespan. Importantly, when the levels of enzymatic activity were monitored in the CSF of dogs following administration of canine NAGLU-coding vectors to animals that were either naïve or had pre-existing immunity against AAV9, similar levels of activity were achieved, suggesting that CNS efficacy would not be compromised in patients seropositive for AAV9. Our studies provide a strong rationale for the clinical development of this novel therapeutic approach as the treatment for MPSIIIB. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Multimodal detection of GM2 and GM3 lipid species in the brain of mucopolysaccharidosis type II mouse by serial imaging mass spectrometry and immunohistochemistry.

PubMed

Dufresne, Martin; Guneysu, Daniel; Patterson, Nathan Heath; Marcinkiewicz, Mieczyslaw Martin; Regina, Anthony; Demeule, Michel; Chaurand, Pierre

2017-02-01

Mucopolysaccharidosis type II (Hunter's disease) mouse model (IdS-KO) was investigated by both imaging mass spectrometry (IMS) and immunohistochemistry (IHC) performed on the same tissue sections. For this purpose, IdS-KO mice brain sections were coated with sublimated 1,5-diaminonaphtalene and analyzed by high spatial resolution IMS (5 μm) and anti-GM3 IHC on the same tissue sections to characterize the ganglioside monosialated ganglioside (GM) deposits found in Hunter's disease. IMS analysis have found that two species of GM3 and GM2 that are only different due to the length of their fatty acid residue (stearic or arachidic residue) were overexpressed in the IdS-KO mice compared to a control mouse. GM3 and GM2 were characterized by on-tissue exact mass and MS/MS compared to a GM3 standard. Realignment of both IMS and IHC data sets further confirmed the observed regioselective signal previously detected by providing direct correlation of the IMS image for the two GM3 overly expressed MS signals with the anti-GM3 IHC image. Furthermore, these regioselective GM MS signals were also found to have highly heterogeneous distributions within the GM3-IHC staining. Some deposits showed high content in GM3 and GM2 stearic species (r = 0.74) and others had more abundant GM3 and GM2 arachidic species (r = 0.76). Same-section analysis of Hunter's disease mouse model by both high spatial resolution IMS and IHC provides a more in-depth analysis of the composition of the GM aggregates while providing spatial distribution of the observed molecular species. Graphical Abstract Ganglioside imaging mass spectrometry followed by immunohistochemistry performed on the same tissue section.

Mucopolysaccharidosis IVA: Identification of a common missense mutation I113F in the N-Acetylgalactosamine-6-sulfate sulfatase gene

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tomatsu, Shunji; Fukuda, Seiji; Rezvi, Maruf

1995-09-01

Mucopolysaccharidosis IVA is an autosomal recessive lysosomal storage disorder caused by a deficiency of N-acetylgalactosamine-6-sulfate sulfatase (GALNS). The recent isolation and characterization of cDNA and genomic sequences encoding GALNS has facilitated identification of the molecular lesions that cause MPS IVA. We identified a common missense mutation among Caucasian MPS IVA patients. The mutation was originally detected by SSCP, and successive sequencing revealed an A{yields}T transversion at nt 393. This substitution altered the isoleucine at position 113 to phenylalanine (I113F) in the 622 amino acid GALNS protein and was associated with a severe phenotype in a homozygote. Compound heterogzygotes with onemore » I113F-allele mutation have a wide range of clinical phenotypes. Transfection experiments in GALNS-deficient fibroblasts revealed that the mutation drastically reduces the enzyme activity of GALNS. Allele-specific oligonucleotide or SSCP analysis indicated that this mutation accounted for 22.5% (9/40) of unrelated MPS IVA chromosomes from 23 Caucasian patients, including 6 consanguineous cases. Of interest, the I1e 113{yields}Phe substitution occurred in only Caucasian MPS IVA patients and in none of the GALNS alleles of 20 Japanese patients. These findings identify a frequent missense mutation among MPS IVA patients of Caucasian ancestry that results in severe MPS IVA when homoallelic, and will facilitate molecular diagnosis of most such patients and identification of heterozygous carriers. In addition to this common mutation, 10 different point mutations and 2 small deletions were detected, suggesting allelic heterogeneity in GALNS gene. 32 refs., 2 figs., 3 tabs.« less

Guanidinylated Neomycin Conjugation Enhances Intranasal Enzyme Replacement in the Brain.

PubMed

Tong, Wenyong; Dwyer, Chrissa A; Thacker, Bryan E; Glass, Charles A; Brown, Jillian R; Hamill, Kristina; Moremen, Kelley W; Sarrazin, Stéphane; Gordts, Philip L S M; Dozier, Lara E; Patrick, Gentry N; Tor, Yitzhak; Esko, Jeffrey D

2017-12-06

Iduronidase (IDUA)-deficient mice accumulate glycosaminoglycans in cells and tissues and exhibit many of the same neuropathological symptoms of patients suffering from Mucopolysaccharidosis I. Intravenous enzyme-replacement therapy for Mucopolysaccharidosis I ameliorates glycosaminoglycan storage and many of the somatic aspects of the disease but fails to treat neurological symptoms due to poor transport across the blood-brain barrier. In this study, we examined the delivery of IDUA conjugated to guanidinoneomycin (GNeo), a molecular transporter. GNeo-IDUA and IDUA injected intravenously resulted in reduced hepatic glycosaminoglycan accumulation but had no effect in the brain due to fast clearance from the circulation. In contrast, intranasally administered GNeo-IDUA entered the brain rapidly. Repetitive intranasal treatment with GNeo-IDUA reduced glycosaminoglycan storage, lysosome size and number, and neurodegenerative astrogliosis in the olfactory bulb and primary somatosensory cortex, whereas IDUA was less effective. The enhanced efficacy of GNeo-IDUA was not the result of increased nose-to-brain delivery or enzyme stability, but rather due to more efficient uptake into neurons and astrocytes. GNeo conjugation also enhanced glycosaminoglycan clearance by intranasally delivered sulfamidase to the brain of sulfamidase-deficient mice, a model of Mucopolysaccharidosis IIIA. These findings suggest the general utility of the guanidinoglycoside-based delivery system for restoring missing lysosomal enzymes in the brain. Copyright © 2017 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.

A Novel GUSB Mutation in Brazilian Terriers with Severe Skeletal Abnormalities Defines the Disease as Mucopolysaccharidosis VII

PubMed Central

Hytönen, Marjo K.; Arumilli, Meharji; Lappalainen, Anu K.; Kallio, Heli; Snellman, Marjatta; Sainio, Kirsi; Lohi, Hannes

2012-01-01

Hundreds of different human skeletal disorders have been characterized at molecular level and a growing number of resembling dysplasias with orthologous genetic defects are being reported in dogs. This study describes a novel genetic defect in the Brazilian Terrier breed causing a congenital skeletal dysplasia. Affected puppies presented severe skeletal deformities observable within the first month of life. Clinical characterization using radiographic and histological methods identified delayed ossification and spondyloepiphyseal dysplasia. Pedigree analysis suggested an autosomal recessive disorder, and we performed a genome-wide association study to map the disease locus using Illumina’s 22K SNP chip arrays in seven cases and eleven controls. A single association was observed near the centromeric end of chromosome 6 with a genome-wide significance after permutation (pgenome  = 0.033). The affected dogs shared a 13-Mb homozygous region including over 200 genes. A targeted next-generation sequencing of the entire locus revealed a fully segregating missense mutation (c.866C>T) causing a pathogenic p.P289L change in a conserved functional domain of β-glucuronidase (GUSB). The mutation was confirmed in a population of 202 Brazilian terriers (p = 7,71×10−29). GUSB defects cause mucopolysaccharidosis VII (MPS VII) in several species and define the skeletal syndrome in Brazilian Terriers. Our results provide new information about the correlation of the GUSB genotype to phenotype and establish a novel canine model for MPS VII. Currently, MPS VII lacks an efficient treatment and this model could be utilized for the development and validation of therapeutic methods for better treatment of MPS VII patients. Finally, since almost one third of the Brazilian terrier population carries the mutation, breeders will benefit from a genetic test to eradicate the detrimental disease from the breed. PMID:22815736

Symptoms of Autism Spectrum Disorder (ASD) in Individuals with Mucopolysaccharide Disease Type III (Sanfilippo Syndrome): A Systematic Review.

PubMed

Wolfenden, C; Wittkowski, A; Hare, D J

2017-11-01

The prevalence of autism spectrum disorder (ASD) in many genetic disorders is well documented but not as yet in Mucopolysaccharidosis type III (MPS III). MPS III is a recessively inherited metabolic disorder and evidence suggests that symptoms of ASD present in MPS III. This systematic review examined the extant literature on the symptoms of ASD in MPS III and quality assessed a total of 16 studies. Results indicated that difficulties within speech, language and communication consistent with ASD were present in MPS III, whilst repetitive and restricted behaviours and interests were less widely reported. The presence of ASD-like symptoms can result in late diagnosis or misdiagnosis of MPS III and prevent opportunities for genetic counselling and the provision of treatments.

Gene delivery strategies for the treatment of mucopolysaccharidoses.

PubMed

Baldo, Guilherme; Giugliani, Roberto; Matte, Ursula

2014-03-01

Mucopolysaccharidosis (MPS) disorders are genetic diseases caused by deficiencies in the lysosomal enzymes responsible for the degradation of glycosaminoglycans. Current treatments are not able to correct all disease symptoms and are not available for all MPS types, which makes gene therapy especially relevant. Multiple gene therapy approaches have been tested for different types of MPS, and our aim in this study is to critically analyze each of them. In this review, we have included the major studies that describe the use of adeno-associated retroviral and lentiviral vectors, as well as relevant non-viral approaches for MPS disorders. Some protocols such as the use of adeno-associated vectors and lentiviral vectors are approaching the clinic for these disorders and, along with combined approaches, seem to be the future of gene therapy for MPS.

Altered lumbar spine structure, biochemistry and biomechanical properties in a canine model of mucopolysaccharidosis type VII

PubMed Central

Smith, Lachlan J; Martin, John T; Szczesny, Spencer E; Ponder, Katherine P; Haskins, Mark E; Elliott, Dawn M

2010-01-01

Mucopolysaccharidosis VII (MPS VII) is a lysosomal storage disorder characterized by a deficiency in β-glucuronidase activity, leading to systemic accumulation of poorly degraded glycosaminoglycans (GAG). Along with other morbidities, MPS VII is associated with paediatric spinal deformity. The objective of this study was to examine potential associations between abnormal lumbar spine matrix structure and composition in MPS VII, and spine segment and tissue-level mechanical properties, using a naturally occurring canine model with a similar clinical phenotype to the human form of the disorder. Segments from juvenile MPS VII and unaffected dogs were allocated to: radiography, gross morphology, histology, biochemistry, and mechanical testing. MPS VII spines had radiolucent lesions in the vertebral body epiphyses. Histologically, this corresponded to a GAG-rich cartilaginous region in place of bone, and elevated GAG staining was seen in the annulus fibrosus. Biochemically, MPS VII samples had elevated GAG in the outer annulus fibrosus and epiphyses, low calcium in the epiphyses, and high water content in all regions except the nucleus pulposus. MPS VII spine segments had higher range of motion and lower stiffness than controls. Endplate indentation stiffness and failure loads were significantly lower in MPS VII samples, while annulus fibrosus tensile mechanical properties were normal. Vertebral body lesions in MPS VII spines suggest a failure to convert cartilage to bone during development. Low stiffness in these regions likely contributes to mechanical weakness in motion segments and is a potential factor in the progression of spinal deformity. PMID:19918911

Dental findings and oral health status in patients with mucopolysaccharidosis: a case series.

PubMed

Antunes, Lívia Azeredo Alves; Nogueira, Ana Paula Barreto; Castro, Glória Fernanda; Ribeiro, Márcia Gonçalves; de Souza, Ivete Pomarico Ribeiro

2013-01-01

To present a mucopolysaccharidosis (MPS) case series evaluating oral manifestations (clinical and radiographic), oral health status and discussing its implications. All patients with MPS attending the Genetics clinic/Brazil were evaluated by means of anamnesis, clinical and radiographic examinations. The final sample consisted of 12 subjects (nine males and three females), with ages ranging from 3-31 years old. Concerning oral health, it was observed high levels of caries and periodontal problems. About oral manifestations, this study clinically observed more cases of delayed tooth eruption, thickness of alveolar process and thick lips. Radiographically, it was observed alterations on condyle, mandibular ramus and joint fossa. The dental changes in MPS population are high and consequently it is important to know them for differential diagnoses, early treatment intervention, prevention and education of both patients and parents/caregivers about oral health.

Transition from paediatric care to adult care for patients with mucopolysaccharidosis.

PubMed

Couce, M L; Del Toro, M; García-Jiménez, M C; Gutierrez-Solana, L; Hermida-Ameijeiras, Á; López-Rodríguez, M; Pérez-López, J; Torralba, M Á

Mucopolysaccharidosis are multisystem diseases that require large multidisciplinary teams for their care. Specific recommendations are therefore needed for the transition from childhood to adulthood in this patient group. To overcome the barriers that might arise during the transition, the authors consider it essential to implement a flexible plan with a coordinator for the entire process, systematising the information through a standardised paediatric discharge report and educating the patient and their family about the disease, showing the characteristics of the healthcare system in this new stage. The final objective is that, once the transition to adulthood has been completed, the patient's autonomy and potential development are maximised and that the patient receives appropriate healthcare during this transition. Copyright © 2017 Elsevier España, S.L.U. and Sociedad Española de Medicina Interna (SEMI). All rights reserved.

Spine malformation complex in 3 diverse syndromic entities

PubMed Central

Kaissi, Ali Al; van Egmond-Fröhlich, Andreas; Ryabykh, Sergey; Ochirov, Polina; Kenis, Vladimir; Hofstaetter, Jochen G.; Grill, Franz; Ganger, Rudolf; Kircher, Susanne Gerit

2016-01-01

Abstract Rationale: Clinical and radiographic phenotypic characterizations were the base line tool of diagnosis in 3 syndromic disorders in which congenital cervico-thoracic kyphosis was the major deformity. Patients concerns: Directing maximal care toward the radiographic analysis is not only the axial malformation but also toward the appendicular abnormalities was our main concern. We fully documented the diversity of the spine phenotypic malformation complex via the clinical and radiographic phenotypes. Diagnoses: We established the diagnosis via phenotypic/genotypic confirmation in 3 diverse syndromic entities namely acampomelic campomelic dysplasia, Larsen syndrome and Morquio syndrome type A (mucopolysaccharidosis type IV A). Interventions: Surgical interventions have been carried out in the Larsen syndrome and Morquio syndrome type A, resepectively. Outcomes: The earliest the diagnosis is, the better the results are. The necessity to diagnose children in their first year of life has many folds, firstly the management would be in favor of the child's growth and development and secondly, the prognosis could be clearer to the family and the medical staff as well. Our current paper is to sensitize paediatricians, physicians and orthopedic surgeons regarding the necessity to detect the aetiological understanding in every child who manifests a constellation of malformation complex. Lesons: Scoliosis and kyphosis/kyphoscoliosis are not a diagnosis in themselves. Such deformities are mostly a symptom complex correlated to dozens of types of syndromic associations. The rate curve progression and the final severity of congenital spine tilting are related to 3 factors: (a) the type of vertebral malformation present, (b) the patient's phenotype, and (c) the diagnosis. PMID:27977582

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bunge, S.; Steglich, C.; Kleijer, W.J.

Mucopolysaccharidosis type I (MPS I) is caused by alpha-L-iduronidase (IDUA) deficiency. Clinical severity ranges from mild (Scheie) and intermediate (Hurler/Scheie) to severe (Hurler) forms. We investigated 70 patients with various MPS I phenotypes for mutations of the IDUA gene. 28 different mutations on 93% of mutant alleles, defining 90% of the genotypes were characterized. The two common missense mutations Q70X and W402X were found on, respectively, 31% and 28% of mutant alleles. However, Q70X is much more frequent in Scandinavia (64%) than in other European countries (16%). L218P (4.3%) and A327P (6.4%) were also identified in several patients, while allmore » other mutations were found on only one or two alleles each. Of the 11 novel mutations identified in this study, G51D, L218P, D315Y, A327P, R489P, E404X, and R621X were associated with severe phenotypes. Eleven different small deletions and insertions were detected (134del12, 964delC, 1132del6, 1782del11, 1995del11, {Delta}D444/445, 252insC, 396insAC, 682insAC, 974ins12, and 1277ins9), most of them causing severe MPS I. Two novel Hurler/Scheie (M504T and W626R) and two novel Scheie point mutations (R89W and R383H) were also identified. Characterization of the primary genetic defect and establishing genotype/phenotype correlation is important for prognostic predictions, evaluation of therapeutic success, and prenatal diagnosis.« less

An improved purification method for the lysosomal storage disease protein β-glucuronidase produced in CHO cells.

PubMed

Fratz-Berilla, Erica J; Ketcham, Stephanie A; Parhiz, Hamideh; Ashraf, Muhammad; Madhavarao, Chikkathur N

2017-12-01

Human β-glucuronidase (GUS; EC 3.2.1.31) is a lysosomal enzyme that catalyzes the hydrolysis of β-d-glucuronic acid residues from the non-reducing termini of glycosaminoglycans. Impairment in GUS function leads to the metabolic disorder mucopolysaccharidosis type VII, also known as Sly syndrome. We produced GUS from a CHO cell line grown in suspension in a 15 L perfused bioreactor and developed a three step purification procedure that yields ∼99% pure enzyme with a recovery of more than 40%. The method can be completed in two days and has the potential to be integrated into a continuous manufacturing scheme. Published by Elsevier Inc.

UCB Transplant of Inherited Metabolic Diseases With Administration of Intrathecal UCB Derived Oligodendrocyte-Like Cells

ClinicalTrials.gov

2018-03-15

Adrenoleukodystrophy; Batten Disease; Mucopolysaccharidosis II; Leukodystrophy, Globoid Cell; Leukodystrophy, Metachromatic; Neimann Pick Disease; Pelizaeus-Merzbacher Disease; Sandhoff Disease; Tay-Sachs Disease; Brain Diseases, Metabolic, Inborn; Alpha-Mannosidosis; Sanfilippo Mucopolysaccharidoses

Nocturnal frontal lobe epilepsy in mucopolysaccharidosis.

PubMed

Bonanni, Paolo; Volzone, Anna; Randazzo, Giovanna; Antoniazzi, Lisa; Rampazzo, Angelica; Scarpa, Maurizio; Nobili, Lino

2014-10-01

Nocturnal frontal lobe epilepsy (NFLE) is an epileptic syndrome that is primarily characterized by seizures with motor signs occurring almost exclusively during sleep. We describe 2 children with mucopolysaccharidosis (MPS) who were referred for significant sleep disturbance. Long term video-EEG monitoring (LT-VEEGM) demonstrated sleep-related hypermotor seizures consistent with NFLE. No case of sleep-related hypermotor seizures has ever been reported to date in MPS. However, differential diagnosis with parasomnias has been previously discussed. The high frequency of frontal lobe seizures causes sleep fragmentation, which may result in sleep disturbances observed in at least a small percentage of MPS patients. We suggest monitoring individuals with MPS using periodic LT-VEEGM, particularly when sleep disorder is present. Moreover, our cases confirm that NFLE in lysosomal storage diseases may occur, and this finding extends the etiologic spectrum of NFLE. Copyright © 2014 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

Assessment of bone dysplasia by micro-CT and glycosaminoglycan levels in mouse models for mucopolysaccharidosis type I, IIIA, IVA, and VII

PubMed Central

Rowan, Daniel J.; Tomatsu, Shunji; Grubb, Jeffrey H.; Montaño, Adriana M.; Sly, William S.

2012-01-01

Summary Mucopolysaccharidoses (MPS) are a group of lysosomal storage diseases caused by mutations in lysosomal enzymes involved in degradation of glycosaminoglycans (GAGs). Patients with MPS grow poorly and become physically disabled due to systemic bone disease. While many of the major skeletal effects in mouse models for MPS have been described, no detailed analysis that compares GAGs levels and characteristics of bone by micro-CT has been done. The aims of this study were to assess severity of bone dysplasia among four MPS mouse models (MPS I, IIIA, IVA and VII), to determine the relationship between severity of bone dysplasia and serum keratan sulfate (KS) and heparan sulfate (HS) levels in those models, and to explore the mechanism of KS elevation in MPS I, IIIA, and VII mouse models. Clinically, MPS VII mice had the most severe bone pathology; however, MPS I and IVA mice also showed skeletal pathology. MPS I and VII mice showed severe bone dysplasia, higher bone mineral density, narrowed spinal canal, and shorter sclerotic bones by micro-CT and radiographs. Serum KS and HS levels were elevated in MPS I, IIIA, and VII mice. Severity of skeletal disease displayed by micro-CT, radiographs and histopathology correlated with the level of KS elevation. We showed that elevated HS levels in MPS mouse models could inhibit N-acetylgalactosamine-6-sulfate sulfatase enzyme. These studies suggest that KS could be released from chondrocytes affected by accumulation of other GAGs and that KS could be useful as a biomarker for severity of bone dysplasia in MPS disorders. PMID:22971960

Biodistribution and Pharmacodynamics of Recombinant Human Alpha-L-Iduronidase (rhIDU) in Mucopolysaccharidosis Type I-Affected Cats Following Multiple Intrathecal Administrations

PubMed Central

Vite, Charles H.; Wang, Ping; Patel, Reema T.; Walton, Raquel M.; Walkley, Steven U.; Sellers, Rani S.; Ellinwood, N. Matthew; Cheng, Alphonsus S.; White, Joleen T.; O’Neill, Charles A.; Haskins, Mark

2011-01-01

The storage disorder mucopolysaccharidosis type I (MPS I) is caused by a deficiency in lysosomal α-L-iduronidase activity. The inability to degrade glycosaminoglycans (GAG) results in lysosomal accumulation and widespread tissue lesions. Many symptoms of MPS I are amenable to treatment with recombinant human α-L-iduronidase (rhIDU), however, peripherally administered rhIDU does not cross the blood-brain barrier and has no beneficial effects in the central nervous system (CNS). A feline model of MPS I was used to evaluate the CNS effects of rhIDU following repeated intrathecal (IT) administration. Twelve animals were randomized into four groups based on the time of euthanasia and tissue evaluation following three repeat IT administrations of 0.1 mg/kg rhIDU or placebo on Study Days 1, 4 or 5, and 9. Two days after the final IT injection, the mean tissue α-L-iduronidase (IDU) activity in the brains of the two treated animals were approximately 3-times higher (50.1 and 54.9 U/mg protein) than the activity found in normal cat brains (mean of 18.3 U/mg), and remained higher than untreated MPS1 brain at 1 month (2.4 and 4.1 U/mg protein) before returning to near-baseline levels after 2 months. This activity corresponded with decreased brain GAG concentrations after 2 days (1.4 and 2.0 mcg/mg) and 1 month (0.9 and 1.1 mcg/mg) which approached levels observed in normal animals (0.7 mcg/mg). Attenuation of GAG, gangliosides GM2 and GM3, and cholesterol reaccumulation was identified at both two days and one month following final IT injection. No adverse effects or rhIDU antibody response attributable to IT rhIDU administration were observed. IT rhIDU may be an effective means for providing enzyme replacement therapy for the central manifestations of MPS I. PMID:21482164

alpha-L-iduronidase, beta-D-glucuronidase, and 2-sulfo-L-iduronate 2-sulfatase: preparation and characterization of radioactive substrates from heparin.

PubMed

Hopwood, J J

1979-03-01

Radioactive disaccharide substrates for alpha-L-iduronidase, beta-D-glucuronidase, and 2-sulfo-L-iduronate 2-sulfatase have been prepared from heparin by deaminative cleavage followed by reduction with NaBT4. Six disaccharides were isolated from this reaction mixture and identified. Acid hydrolysis of the major disaccharide, O-(alpha-L-idopyranosyluronic acid 2-sulfate)-(1 linked to 4)-(2,5-anhydro-D-mannitol-l-t 6-sulfate (IdAs--Ms), produced 48% of O-(alpha-L-idopyranosyluronic acid)-(1 linked to 4)-(2,5-anhydro-D-mannitol-l-t 6-sulfate) (IdA--Ms) and 25% of O-(alpha-L-idopyranosyluronic acid)-(1 linked to 4)-2,5-anhydro-D-mannitol-l-t. The most-sensitive substrate for determining alpha-L-iduronidase activity was IdA--Ms which, when incubated with leucocyte and skin-fibroblast homogenates prepared from patients having a deficiency of alpha-L-iduronidase (Mucopolysaccharidosis Type I; MPS-I), was hydrolysed to yield 2,5-anhydro-D-mannitol-l-t 6-sulfate at a rate 50-times less than that found for normal control-preparations. Similarly, O-(beta-D-glucopyranosyluronic acid)-(1 linked to 4)-(2,5-anhydro-D-mannitol-l-t 6-sulfate) was degraded by whole-cell homogenates prepared from beta-D-glucuronidase-deficient (Mucopolysaccharidosis, Type VII) fibroblasts, to yield 2,5-anhydro-D-mannitol-l-t 5-sulfate at a rate 60-times less that that found for MPS-I and normal control-preparations. IdAs--Ms was degraded by 2-sulfo-L-iduronate 2-sulfatase at a rate more than 45-times greater than that found for O-(alpha-L-idopyranosyluronic acid 2-sulfate)-(1 linked to 4)-2,5-anhydro-D-mannitol-l-t. C-6 Sulfation of the anhydro-D-mannitol-l-t residue is an important structural determinant in the mechanism of action of both alpha-L-iduronidase and 2-sulfo-L-iduronate 2-sulfatase on disaccharide substrates.

Mutational analysis of a patient with mucopolysaccharidosis type VII, and identification of pseudogenes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Shipley, J.M.; Klinkenberg, M.; Wu, B.M.

1993-03-01

PCR of cDNA produced from patient fibroblasts allowed the authors to determine the paternal mutation in the first patient reported with [beta]-glucuronidase-deficiency mucopolysaccharidosis type VII (MPS VII). The G[r arrow]T transversion 1,881 bp downstream of the ATG translation initiation codon destroys an MboII restriction site and converts Trp627 to Cys (W627C). Digestion of genomic DNA PCR fragments with MboII indicated that the patient and the father were heterozygous for this missense mutation in exon 12. Failure to find cDNAs from patient RNA which did not contain this mutation suggested that the maternal mutation leads to greatly reduced synthesis or reducedmore » stability of mRNA from the mutant allele. In order to identify the maternal mutation, it was necessary to analyze genomic sequences. This approach was complicated by the finding of multiple unprocessed pseudogenes and/or closely related genes. Using PCR with a panel of human/rodent hybrid cell lines, the authors found that these pseudogenes were present over chromosomes 5-7, 20, and 22 and the Y chromosome. Conditions were defined which allowed them to amplify and characterize genomic sequences for the true [beta]-glucuronidase gene despite this background of related sequences. The patient proved to be heterozygous for a second mutation, in which a C[r arrow]T transition introduces a termination codon (R356STOP) in exon 7. The mother was also heterozygous for this mutation. Expression of a cDNA containing the maternal mutation produced no enzyme activity, as expected. Expression of the paternal mutation in COS-7 cells produced a surprisingly high (65% of control) level of activity. However, activity was 13% of control in transiently transfected murine MPS VII cells. The level of activity of this mutant allele appears to correlate with the level of overexpression. 39 refs., 5 figs., 1 tab.« less

Pentosan Polysulfate: Oral Versus Subcutaneous Injection in Mucopolysaccharidosis Type I Dogs

PubMed Central

Simonaro, Calogera M.; Tomatsu, Shunji; Sikora, Tracy; Kubaski, Francyne; Frohbergh, Michael; Guevara, Johana M.; Wang, Raymond Y.; Vera, Moin; Kang, Jennifer L.; Smith, Lachlan J.; Schuchman, Edward H.; Haskins, Mark E.

2016-01-01

Background We previously demonstrated the therapeutic benefits of pentosan polysulfate (PPS) in a rat model of mucopolysaccharidosis (MPS) type VI. Reduction of inflammation, reduction of glycosaminoglycan (GAG) storage, and improvement in the skeletal phenotype were shown. Herein, we evaluate the long-term safety and therapeutic effects of PPS in a large animal model of a different MPS type, MPS I dogs. We focused on the arterial phenotype since this is one of the most consistent and clinically significant features of the model. Methodology/Principal Findings MPS I dogs were treated with daily oral or biweekly subcutaneous (subQ) PPS at a human equivalent dose of 1.6 mg/kg for 17 and 12 months, respectively. Safety parameters were assessed at 6 months and at the end of the study. Following treatment, cytokine and GAG levels were determined in fluids and tissues. Assessments of the aorta and carotid arteries also were performed. No drug-related increases in liver enzymes, coagulation factors, or other adverse effects were observed. Significantly reduced IL-8 and TNF-alpha were found in urine and cerebrospinal fluid (CSF). GAG reduction was observed in urine and tissues. Increases in the luminal openings and reduction of the intimal media thickening occurred in the carotids and aortas of PPS-treated animals, along with a reduction of storage vacuoles. These results were correlated with a reduction of GAG storage, reduction of clusterin 1 staining, and improved elastin integrity. No significant changes in the spines of the treated animals were observed. Conclusions PPS treatment led to reductions of pro-inflammatory cytokines and GAG storage in urine and tissues of MPS I dogs, which were most evident after subQ administration. SubQ administration also led to significant cytokine reductions in the CSF. Both treatment groups exhibited markedly reduced carotid and aortic inflammation, increased vessel integrity, and improved histopathology. We conclude that PPS may be a safe and useful therapy for MPS I, either as an adjunct or as a stand-alone treatment that reduces inflammation and GAG storage. PMID:27064989

Effects of Neonatal Enzyme Replacement Therapy and Simvastatin Treatment on Cervical Spine Disease in Mucopolysaccharidosis I Dogs

PubMed Central

Chiaro, Joseph A; O’Donnell, Patricia; Shore, Eileen M; Malhotra, Neil R; Ponder, Katherine P; Haskins, Mark E; Smith, Lachlan J

2014-01-01

Mucopolysaccharidosis I (MPS I) is a lysosomal storage disease characterized by deficient α-L-iduronidase activity, leading to the accumulation of poorly degraded glycosaminoglycans (GAGs). Children with MPS I exhibit high incidence of spine disease, including accelerated disc degeneration and vertebral dysplasia, which in turn lead to spinal cord compression and kypho-scoliosis. In this study we investigated the efficacy of neonatal enzyme replacement therapy (ERT), alone or in combination with oral simvastatin (ERT+SIM) for attenuating cervical spine disease progression in MPS I, using a canine model. Four groups were studied: normal controls; MPS I untreated; MPS I ERT treated; and MPS I ERT+SIM treated. Animals were euthanized at one year-of-age. Intervertebral disc condition and spinal cord compression were evaluated from MRIs and plain radiographs, vertebral bone condition and odontoid hypoplasia were evaluated using microcomputed tomography, and epiphyseal cartilage to bone conversion was evaluated histologically. Untreated MPS I animals exhibited more advanced disc degeneration and more severe spinal cord compression than normal animals. Both treatment groups resulted in partial preservation of disc condition and cord compression, with ERT+SIM not significantly better than ERT alone. Untreated MPS I animals had significantly lower vertebral trabecular bone volume and mineral density, while ERT treatment resulted in partial preservation of these properties. ERT+SIM treatment demonstrated similar, but not greater, efficacy. Both treatment groups partially normalized endochondral ossification in the vertebral epiphyses (as indicated by absence of persistent growth plate cartilage), and odontoid process size and morphology. These results indicate that ERT begun from a very early age attenuates the severity of cervical spine disease in MPS I, particularly for the vertebral bone and odontoid process, and that additional treatment with simvastatin does not provide a significant additional benefit over ERT alone. PMID:24898323

Female Mucopolysaccharidosis IIIA Mice Exhibit Hyperactivity and a Reduced Sense of Danger in the Open Field Test

PubMed Central

Langford-Smith, Alex; Langford-Smith, Kia J.; Jones, Simon A.; Wynn, Robert F.; Wraith, J. E.; Wilkinson, Fiona L.; Bigger, Brian W.

2011-01-01

Reliable behavioural tests in animal models of neurodegenerative diseases allow us to study the natural history of disease and evaluate the efficacy of novel therapies. Mucopolysaccharidosis IIIA (MPS IIIA or Sanfilippo A), is a severe, neurodegenerative lysosomal storage disorder caused by a deficiency in the heparan sulphate catabolising enzyme, sulfamidase. Undegraded heparan sulphate accumulates, resulting in lysosomal enlargement and cellular dysfunction. Patients suffer a progressive loss of motor and cognitive function with severe behavioural manifestations and premature death. There is currently no treatment. A spontaneously occurring mouse model of the disease has been described, that has approximately 3% of normal enzyme activity levels. Behavioural phenotyping of the MPS IIIA mouse has been previously reported, but the results are conflicting and variable, even after full backcrossing to the C57BL/6 background. Therefore we have independently backcrossed the MPS IIIA model onto the C57BL/6J background and evaluated the behaviour of male and female MPS IIIA mice at 4, 6 and 8 months of age using the open field test, elevated plus maze, inverted screen and horizontal bar crossing at the same circadian time point. Using a 60 minute open field, we have demonstrated that female MPS IIIA mice are hyperactive, have a longer path length, display rapid exploratory behaviour and spend less time immobile than WT mice. Female MPS IIIA mice also display a reduced sense of danger and spend more time in the centre of the open field. There were no significant differences found between male WT and MPS IIIA mice and no differences in neuromuscular strength were seen with either sex. The altered natural history of behaviour that we observe in the MPS IIIA mouse will allow more accurate evaluation of novel therapeutics for MPS IIIA and potentially other neurodegenerative disorders. PMID:22028789

Female mucopolysaccharidosis IIIA mice exhibit hyperactivity and a reduced sense of danger in the open field test.

PubMed

Langford-Smith, Alex; Langford-Smith, Kia J; Jones, Simon A; Wynn, Robert F; Wraith, J E; Wilkinson, Fiona L; Bigger, Brian W

2011-01-01

Reliable behavioural tests in animal models of neurodegenerative diseases allow us to study the natural history of disease and evaluate the efficacy of novel therapies. Mucopolysaccharidosis IIIA (MPS IIIA or Sanfilippo A), is a severe, neurodegenerative lysosomal storage disorder caused by a deficiency in the heparan sulphate catabolising enzyme, sulfamidase. Undegraded heparan sulphate accumulates, resulting in lysosomal enlargement and cellular dysfunction. Patients suffer a progressive loss of motor and cognitive function with severe behavioural manifestations and premature death. There is currently no treatment. A spontaneously occurring mouse model of the disease has been described, that has approximately 3% of normal enzyme activity levels. Behavioural phenotyping of the MPS IIIA mouse has been previously reported, but the results are conflicting and variable, even after full backcrossing to the C57BL/6 background. Therefore we have independently backcrossed the MPS IIIA model onto the C57BL/6J background and evaluated the behaviour of male and female MPS IIIA mice at 4, 6 and 8 months of age using the open field test, elevated plus maze, inverted screen and horizontal bar crossing at the same circadian time point. Using a 60 minute open field, we have demonstrated that female MPS IIIA mice are hyperactive, have a longer path length, display rapid exploratory behaviour and spend less time immobile than WT mice. Female MPS IIIA mice also display a reduced sense of danger and spend more time in the centre of the open field. There were no significant differences found between male WT and MPS IIIA mice and no differences in neuromuscular strength were seen with either sex. The altered natural history of behaviour that we observe in the MPS IIIA mouse will allow more accurate evaluation of novel therapeutics for MPS IIIA and potentially other neurodegenerative disorders.

Human β-glucuronidase: structure, function, and application in enzyme replacement therapy.

PubMed

Naz, Huma; Islam, Asimul; Waheed, Abdul; Sly, William S; Ahmad, Faizan; Hassan, Imtaiyaz

2013-10-01

Lysosomal storage diseases occur due to incomplete metabolic degradation of macromolecules by various hydrolytic enzymes in the lysosome. Despite structural differences, most of the lysosomal enzymes share many common features including a lysosomal targeting motif and phosphotransferase recognition sites. β-Glucuronidase (GUSB) is an important lysosomal enzyme involved in the degradation of glucuronate-containing glycosaminoglycan. The deficiency of GUSB causes mucopolysaccharidosis type VII (MPSVII), leading to lysosomal storage in the brain. GUSB is a well-studied protein for its expression, sequence, structure, and function. The purpose of this review is to summarize our current understanding of sequence, structure, function, and evolution of GUSB and its lysosomal enzyme targeting. Enzyme replacement therapy reported for this protein is also discussed.

[Consequences of the judicialization of health policies: the cost of medicines for mucopolysaccharidosis].

PubMed

Diniz, Debora; Medeiros, Marcelo; Schwartz, Ida Vanessa D

2012-03-01

This study analyzes expenditures backed by court rulings to ensure the public provision of medicines for treatment of mucopolysaccharidosis (MPS), a rare disease that requires high-cost drugs not covered by the Brazilian government's policy for pharmaceutical care and which have disputed clinical efficacy. The methodology included a review of files from 196 court rulings ordering the Brazilian Ministry of Health to provide the medicines, in addition to Ministry of Health administrative records. According to the analysis, the "judicialization" of the health system subjected the Brazilian government to a monopoly in the distribution of medicines and consequently the loss of its capacity to manage drug purchases. The study also indicates that the imposition of immediate, individualized purchases prevents obtaining economies of scale with planned procurement of larger amounts of the medication, besides causing logistic difficulties in controlling the amounts consumed and stored. In conclusion, litigation results from the lack of a clear policy in the health system for rare diseases in general, thereby leading to excessive expenditures for MPS treatment.

Molecular Testing of 163 Patients with Morquio A (Mucopolysaccharidosis IVA) Identifies 39 Novel GALNS Mutations

PubMed Central

Morrone, A; Tylee, K.L.; Al-Sayed, M; Brusius-Facchin, A.C.; Caciotti, A.; Church, H.J.; Coll, M.J.; Davidson, K.; Fietz, M.J.; Gort, L.; Hegde, M.; Kubaski, F.; Lacerda, L.; Laranjeira, F.; Leistner-Segal, S.; Mooney, S.; Pajares, S.; Pollard, L.; Riberio, I.; Wang, R.Y.; Miller, N.

2014-01-01

Morquio A (Mucopolysaccharidosis IVA; MPS IVA) is an autosomal recessive lysosomal storage disorder caused by partial or total deficiency of the enzyme galactosamine-6-sulfate sulfatase (GALNS; also known as N-acetylgalactosamine-6-sulfate sulfatase) encoded by the GALNS gene. Patients who inherit two mutated GALNS gene alleles produce protein with decreased ability to degrade the glycosaminoglycans (GAGs) keratan sulfate and chondroitin 6-sulfate, thereby causing GAG accumulation within lysosomes and consequently pleiotropic disease. GALNS mutations occur throughout the gene and many mutations are identified only in single patients or families, causing difficulties both in mutation detection and interpretation. In this study, molecular analysis of 163 patients with Morquio A identified 99 unique mutations in the GALNS gene believed to negatively impact GALNS protein function, of which 39 are previously unpublished, together with 26 single-nucleotide polymorphisms. Recommendations for the molecular testing of patients, clear reporting of sequence findings, and interpretation of sequencing data are provided. PMID:24726177

Audiological findings in children with mucopolysaccharidoses type i-iv.

PubMed

Vargas-Gamarra, María F; de Paula-Vernetta, Carlos; Vitoria Miñana, Isidro; Ibañez-Alcañiz, Isabel; Cavallé-Garrido, Laura; Alamar-Velazquez, Agustín

The aim of our study is to reflect hearing impairment of 23children diagnosed with mucopolysaccharidosis (MPS) typeI, II, III and IV. Retrospective study of the clinical, audiological and treatment (medical vs surgical) findings of 23children diagnosed with MPS typeI, II, III or IV followed at a Tertiary Referral Hospital between 1997 and 2015. Six cases of MPSI, 8 of MPSII, 4 of MPSIII and 5 of MPSIV were reviewed. 71.2% of patients had secretory otitis media (SOM) and 54% of patients had some type of hearing loss (HL). The behaviour of hearing loss was variable in each of the subgroups of MPS, finding greater involvement and variability in typesI and II. Children with MPS have a high risk of hearing loss. A significant percentage of transmissive HL progressing to mixed or sensorineural HL was observed. This was more common in typesI and II. Periodic follow up of these patients is mandatory because of hearing impairment and consequences for their development and quality of life. Copyright © 2016 Elsevier España, S.L.U. and Sociedad Española de Otorrinolaringología y Cirugía de Cabeza y Cuello. All rights reserved.

Pathogenesis of lumbar spine disease in mucopolysaccharidosis VII

PubMed Central

Smith, Lachlan J; Baldo, Guilherme; Wu, Susan; Liu, Yuli; Whyte, Michael P; Giugliani, Roberto; Elliott, Dawn M; Haskins, Mark E; Ponder, Katherine P

2012-01-01

Mucopolysaccharidosis type VII (MPS VII) is characterized by deficient β-glucuronidase (GUSB) activity, which leads to accumulation of chondroitin, heparan and dermatan sulfate glycosaminoglycans (GAGs), and multisystemic disease. MPS VII patients can develop kypho-scoliotic deformity and spinal cord compression due to disease of intervertebral discs, vertebral bodies, and associated tissues. We have previously demonstrated in MPS VII dogs that intervertebral discs degenerate, vertebral bodies have irregular surfaces, and vertebral body epiphyses have reduced calcification, but the pathophysiological mechanisms underlying these changes are unclear. We hypothesized that some of these manifestations could be due to upregulation of destructive proteases, possibly via the binding of GAGs to Toll-like receptor 4 (TLR4), as has been proposed for other tissues in MPS models. In this study, the annulus fibrosus of the intervertebral disc of 6 month-old MPS VII dogs had cathepsin B and K activities that were 117- and 2-fold normal, respectively, which were associated with elevations in mRNA levels for cathepsins as well as TLR4. The epiphyses of MPS VII dogs had a marked elevation in mRNA for the cartilage-associated gene collagen II, consistent with a developmental delay in the conversion of the cartilage to bone in this region. A spine from a human patient with MPS VII exhibited similar increased cartilage in the vertebral bodies adjacent to the end plates, disorganization of the intervertebral discs, and irregular vertebral end plate morphology. These data suggest that the pathogenesis of destructive changes in the spine in MPS VII may involve upregulation of cathepsins. Inhibition of destructive proteases, such as cathepsins, might reduce spine disease in patients with MPS VII or related disorders. PMID:22513347

Restoration of central nervous system alpha-N-acetylglucosaminidase activity and therapeutic benefits in mucopolysaccharidosis IIIB mice by a single intracisternal recombinant adeno-associated viral type 2 vector delivery.

PubMed

Fu, Haiyan; DiRosario, Julianne; Kang, Lu; Muenzer, Joseph; McCarty, Douglas M

2010-07-01

Finding efficient central nervous system (CNS) delivery approaches has been the major challenge facing therapeutic development for treating diseases with global neurological manifestation, such as mucopolysaccharidosis (MPS) IIIB, a lysosomal storage disease, caused by autosomal recessive defect of alpha-N-acetylglucosaminidase (NaGlu). Previously, we developed an approach, intracisternal (i.c.) injection, to deliver recombinant adeno-associated viral (rAAV) vector to the CNS of mice, leading to a widespread periventricular distribution of transduction. In the present study, we delivered rAAV2 vector expressing human NaGlu into the CNS of MPS IIIB mice by an i.c. injection approach, to test its therapeutic efficacy and feasibility for treating the neurological manifestation of the disease. We demonstrated significant functional neurological benefits of a single i.c. vector infusion in adult MPS IIIB mice. The treatment slowed the disease progression by mediating widespread recombinant NaGlu expression in the CNS, resulting in the reduction of brain lysosomal storage pathology, significantly improved cognitive function and prolonged survival. However, persisting motor function deficits suggested that pathology in areas outside the CNS contributes to the MPS IIIB behavioral phenotype. The therapeutic benefit of i.c. rAAV2 delivery was dose-dependent and could be attribute solely to the CNS transduction because the procedure did not lead to detectable transduction in somatic tissues. A single IC rAAV2 gene delivery is functionally beneficial for treating the CNS disease of MPS IIIB in mice. It is immediately clinically translatable, with the potential of improving the quality of life for patients with MPS IIIB.

Illness Perception and Clinical Treatment Experiences in Patients with M. Maroteaux-Lamy (Mucopolysaccharidosis Type VI) and a Turkish Migration Background in Germany

PubMed Central

Dilger, Hansjörg; Leissner, Linn; Bosanska, Lenka; Lampe, Christina; Plöckinger, Ursula

2013-01-01

Introduction Mucopolysaccharidosis VI (MPS VI) is an inherited lysosomal storage disease caused by a mutation of the gene for arylsulfatase B (ASB). Of the thirty-one patients registered in Germany, almost fifty percent have a Turkish migration background. MPS VI is treated by enzyme replacement therapy (ERT), which is time-consuming and expensive. Methods This interdisciplinary study explored the illness perceptions and clinical treatment experiences among ten MPS VI patients with a Turkish migration background in two centers for metabolic diseases (Berlin and Mainz, Germany). The clinical treatment situation was observed and semi-structured interviews were conducted with patients and health care personnel, in addition to participatory observation in four patients' everyday environments in Berlin. The data from the interviews, patient records, and personal field notes were encoded, cross-related, and analyzed. Results Patients' acknowledgement of the disease and coping strategies are influenced predominantly by the perception of their individual health status and the handling of the disease within their family. Patients' willingness to cooperate with treatment strategies is further modified by their knowledge of the disease and the relationships with their health care providers. In this analysis, cultural factors turned out to be marginally relevant. Conclusion As with other chronic and debilitating diseases, effective treatment strategies have to reach beyond delivering medication. Health care providers need to strengthen the support for patients with a migration background. In this regard, they should respect the patients' cultural and social background and their personal perception of the disease and the therapy. Yet structural and social aspects (clinical setting, family and educational background) may be more crucial here than “cultural barriers.” PMID:23826140

A multinational, multidisciplinary consensus for the diagnosis and management of spinal cord compression among patients with mucopolysaccharidosis VI.

PubMed

Solanki, Guirish A; Alden, Tord D; Burton, Barbara K; Giugliani, Roberto; Horovitz, Dafne D G; Jones, Simon A; Lampe, Christina; Martin, Kenneth W; Ryan, Maura E; Schaefer, Matthias K; Siddiqui, Aisha; White, Klane K; Harmatz, Paul

2012-09-01

Cervical cord compression is a sequela of mucopolysaccharidosis VI, a rare lysosomal storage disorder, and has devastating consequences. An international panel of orthopedic surgeons, neurosurgeons, anesthesiologists, neuroradiologists, metabolic pediatricians, and geneticists pooled their clinical expertise to codify recommendations for diagnosing, monitoring, and managing cervical cord compression; for surgical intervention criteria; and for best airway management practices during imaging or anesthesia. The recommendations offer ideal best practices but also attempt to recognize the worldwide spectrum of resource availability. Functional assessments and clinical neurological examinations remain the cornerstone for identification of early signs of myelopathy, but magnetic resonance imaging is the gold standard for identification of cervical cord compression. Difficult airways of MPS VI patients complicate the anesthetic and, thus, the surgical management of cervical cord compression. All patients with MPS VI require expert airway management during any surgical procedure. Neurophysiological monitoring of the MPS VI patient during complex spine or head and neck surgery is considered standard practice but should also be considered for other procedures performed with the patient under general anesthesia, depending on the length and type of the procedure. Surgical interventions may include cervical decompression, stabilization, or both. Specific techniques vary widely among surgeons. The onset, presentation, and rate of progression of cervical cord compression vary among patients with MPS VI. The availability of medical resources, the expertise and experience of members of the treatment team, and the standard treatment practices vary among centers of expertise. Referral to specialized, experienced MPS treatment centers should be considered for high-risk patients and those requiring complex procedures. Therefore, the key to optimal patient care is to implement best practices through meaningful communication among treatment team members at each center and among MPS VI specialists worldwide. Copyright © 2012 Elsevier Inc. All rights reserved.

Systems biology study of mucopolysaccharidosis using a human metabolic reconstruction network.

PubMed

Salazar, Diego A; Rodríguez-López, Alexander; Herreño, Angélica; Barbosa, Hector; Herrera, Juliana; Ardila, Andrea; Barreto, George E; González, Janneth; Alméciga-Díaz, Carlos J

2016-02-01

Mucopolysaccharidosis (MPS) is a group of lysosomal storage diseases (LSD), characterized by the deficiency of a lysosomal enzyme responsible for the degradation of glycosaminoglycans (GAG). This deficiency leads to the lysosomal accumulation of partially degraded GAG. Nevertheless, deficiency of a single lysosomal enzyme has been associated with impairment in other cell mechanism, such as apoptosis and redox balance. Although GAG analysis represents the main biomarker for MPS diagnosis, it has several limitations that can lead to a misdiagnosis, whereby the identification of new biomarkers represents an important issue for MPS. In this study, we used a system biology approach, through the use of a genome-scale human metabolic reconstruction to understand the effect of metabolism alterations in cell homeostasis and to identify potential new biomarkers in MPS. In-silico MPS models were generated by silencing of MPS-related enzymes, and were analyzed through a flux balance and variability analysis. We found that MPS models used approximately 2286 reactions to satisfy the objective function. Impaired reactions were mainly involved in cellular respiration, mitochondrial process, amino acid and lipid metabolism, and ion exchange. Metabolic changes were similar for MPS I and II, and MPS III A to C; while the remaining MPS showed unique metabolic profiles. Eight and thirteen potential high-confidence biomarkers were identified for MPS IVB and VII, respectively, which were associated with the secondary pathologic process of LSD. In vivo evaluation of predicted intermediate confidence biomarkers (β-hexosaminidase and β-glucoronidase) for MPS IVA and VI correlated with the in-silico prediction. These results show the potential of a computational human metabolic reconstruction to understand the molecular mechanisms this group of diseases, which can be used to identify new biomarkers for MPS. Copyright © 2015. Published by Elsevier Inc.

Design, baseline characteristics, and early findings of the MPS VI (mucopolysaccharidosis VI) Clinical Surveillance Program (CSP).

PubMed

Hendriksz, Christian J; Giugliani, Roberto; Harmatz, Paul; Lampe, Christina; Martins, Ana Maria; Pastores, Gregory M; Steiner, Robert D; Leão Teles, Elisa; Valayannopoulos, Vassili

2013-03-01

To outline the design, baseline data, and 5-year follow-up data of patients with mucopolysaccharidosis (MPS) VI enrolled in the Clinical Surveillance Program (CSP), a voluntary, multinational, observational program. The MPS VI CSP was opened in 2005 to collect, for at least 15 years, observational data from standard clinical and laboratory assessments of patients with MPS VI. Baseline and follow-up data are documented by participating physicians in electronic case report forms. Between September 2005 and March 2010 the CSP enrolled 132 patients, including 123 who received enzyme replacement therapy (ERT) with galsulfase. Median age at enrolment was 13 years (range 1-59). Mean baseline data showed impaired growth, hepatosplenomegaly, and reduced endurance and pulmonary function. The most common findings were heart valve disease (90%), reduced visual acuity (79%), impaired hearing (59%), and hepatosplenomegaly (54%). Follow-up data up to 5 years in patients with pre- and post-ERT measurements showed a decrease in urinary glycosaminoglycans and increases in height and weight in patients <16 years and suggested reductions in liver and spleen size and improvements in endurance and pulmonary function after ERT was started. Vision, hearing, and cardiac function were unchanged. Safety data were in line with previous reports. The CSP represents the largest cross-sectional study of MPS VI to date. This first report provides information on the design and implementation of the program and population statistics for several clinical variables in patients with MPS VI. Data collected over 5 years suggest that ERT provides clinical benefit and is well-tolerated with no new safety concerns.

The Effect of Neonatal Gene Therapy with a Gamma Retroviral Vector on Cardiac Valve Disease in Mucopolysaccharidosis VII Dogs after a Decade

PubMed Central

Bigg, Paul W.; Sleeper, Meg M.; O’Donnell, Patricia A.; Liu, Yuli; Wu, Susan; Casal, Margret L.; Haskins, Mark E.; Ponder, Katherine P.

2013-01-01

Mucopolysaccharidosis VII (MPS VII) is due to deficient activity of the lysosomal enzyme β-glucuronidase (GUSB) and results in the accumulation of glycosaminoglycans (GAGs). This study determined the long-term effect of neonatal intravenous injection of a gamma retroviral vector (RV) on cardiac valve disease in MPS VII dogs. Transduced hepatocytes secreted GUSB into blood for up to 11 years at levels similar to or greater than those achieved with enzyme replacement therapy (ERT). Valve regurgitation and thickening were scored from 0 (normal) to +4 (severely abnormal). At 1 year, untreated MPS VII dogs had mitral regurgitation, mitral valve thickening, aortic regurgitation, and aortic valve thickening scores of 2.3±0.7, 2.3±0.6, 1.8±0.5, and 1.6±0.7, respectively, which were higher than the values of 0.6±0.1, 0.1±0.4, 0.3±0.8, and 0.1±0.4, respectively, in treated MPS VII dogs. Treated MPS VII dogs maintained low aortic regurgitation and aortic valve thickening scores for their lifetime. Although mitral regurgitation and mitral valve thickening scores increased to 2.0 at ≥8 years of age in the treated MPS VII dogs, older normal dogs from the colony had similar scores, making it difficult to assess mitral valve disease. Older treated dogs had calcification within the mitral and aortic valve annulus, while GUSB staining demonstrated enzyme activity within the mitral valve. We conclude that neonatal RV-mediated gene therapy reduced cardiac valve disease in MPS VII dogs for up to 11 years, and propose that neonatal initiation of ERT should have a similar effect. PMID:23860311

The effect of neonatal gene therapy with a gamma retroviral vector on cardiac valve disease in mucopolysaccharidosis VII dogs after a decade.

PubMed

Bigg, Paul W; Sleeper, Meg M; O'Donnell, Patricia A; Liu, Yuli; Wu, Susan; Casal, Margret L; Haskins, Mark E; Ponder, Katherine P

2013-11-01

Mucopolysaccharidosis VII (MPS VII) is due to deficient activity of the lysosomal enzyme β-glucuronidase (GUSB) and results in the accumulation of glycosaminoglycans (GAGs). This study determined the long-term effect of neonatal intravenous injection of a gamma retroviral vector (RV) on cardiac valve disease in MPS VII dogs. Transduced hepatocytes secreted GUSB into the blood for up to 11 years at levels similar to or greater than those achieved with enzyme replacement therapy (ERT). Valve regurgitation and thickening were scored from 0 (normal) to +4 (severely abnormal). At 1 year, untreated MPS VII dogs had mitral regurgitation, mitral valve thickening, aortic regurgitation, and aortic valve thickening scores of 2.3 ± 0.7, 2.3 ± 0.6, 1.8 ± 0.5, and 1.6 ± 0.7, respectively, which were higher than the values of 0.6 ± 0.1, 0.1 ± 0.4, 0.3 ± 0.8, and 0.1 ± 0.4, respectively, in treated MPS VII dogs. Treated MPS VII dogs maintained low aortic regurgitation and aortic valve thickening scores in their lifetime. Although mitral regurgitation and mitral valve thickening scores increased to 2.0 at ≥ 8 years of age in the treated MPS VII dogs, older normal dogs from the colony had similar scores, making it difficult to assess mitral valve disease. Older treated dogs had calcification within the mitral and the aortic valve annulus, while GUSB staining demonstrated enzyme activity within the mitral valve. We conclude that neonatal RV-mediated gene therapy reduced cardiac valve disease in MPS VII dogs for up to 11 years, and propose that neonatal initiation of ERT should have a similar effect. © 2013.

High Resolution Crystal Structure of Human β-Glucuronidase Reveals Structural Basis of Lysosome Targeting

PubMed Central

Hassan, Md. Imtaiyaz; Waheed, Abdul; Grubb, Jeffery H.; Klei, Herbert E.; Korolev, Sergey; Sly, William S.

2013-01-01

Human β-glucuronidase (GUS) cleaves β-D-glucuronic acid residues from the non-reducing termini of glycosaminoglycan and its deficiency leads to mucopolysaccharidosis type VII (MPSVII). Here we report a high resolution crystal structure of human GUS at 1.7 Å resolution and present an extensive analysis of the structural features, unifying recent findings in the field of lysosome targeting and glycosyl hydrolases. The structure revealed several new details including a new glycan chain at Asn272, in addition to that previously observed at Asn173, and coordination of the glycan chain at Asn173 with Lys197 of the lysosomal targeting motif which is essential for phosphotransferase recognition. Analysis of the high resolution structure not only provided new insights into the structural basis for lysosomal targeting but showed significant differences between human GUS, which is medically important in its own right, and E. coli GUS, which can be selectively inhibited in the human gut to prevent prodrug activation and is also widely used as a reporter gene by plant biologists. Despite these differences, both human and E. coli GUS share a high structure homology in all three domains with most of the glycosyl hydrolases, suggesting that they all evolved from a common ancestral gene. PMID:24260279

[Mucopolysaccharidosis: clinical features, diagnosis and management].

PubMed

Suarez-Guerrero, Jorge Luis; Gómez Higuera, Pedro José Iván; Arias Flórez, Juan Sebastian; Contreras-García, Gustavo Adolfo

2016-01-01

The mucopolysaccharidoses (MPS) are a group of rare (orphan) diseases, characterised by a deficiency of enzymes involved in the metabolism of glycosaminoglycans (GAGs) at lysosomal level. When there is a deficiency of a particular enzyme there is an accumulation of GAGs in the cells resulting in progressive cellular damage, which can affect multiple organ systems and lead to organ failure. Diagnosis is based on knowledge of the clinical manifestations, performing biochemical analyses to identify the type of GAG that is accumulating, and confirm the type of disorder with the corresponding enzymatic determination. Their identification is essential to initiate early treatment, taking into account that multidisciplinary management and enzyme replacement therapy is available for MPS I (Hurler syndrome), MPS II (Hunter syndrome), MPS IV (Morquio syndrome), and MPS VI (Maroteaux-Lamy syndrome. In this review, an analysis is made of each of these syndromes, as well as their diagnosis and treatment. Copyright © 2015 Sociedad Chilena de Pediatría. Publicado por Elsevier España, S.L.U. All rights reserved.

Intracisternal A-Particle Element Transposition into the Murine β-Glucuronidase Gene Correlates with Loss of Enzyme Activity: a New Model for β-Glucuronidase Deficiency in the C3H Mouse†

PubMed Central

Gwynn, Babette; Lueders, Kira; Sands, Mark S.; Birkenmeier, Edward H.

1998-01-01

The severity of human mucopolysaccharidosis type VII (MPS VII), or Sly syndrome, depends on the relative activity of the enzyme β-glucuronidase. Loss of β-glucuronidase activity can cause hydrops fetalis, with in utero or postnatal death of the patient. In this report, we show that β-glucuronidase activity is not detectable by a standard fluorometric assay in C3H/HeOuJ (C3H) mice homozygous for a new mutation, gusmps2J. These gusmps2J/gusmps2J mice are born and survive much longer than the previously characterized β-glucuronidase-null B6.C-H-2bm1/ByBir-gusmps (gusmps/gusmps) mice. Northern blot analysis of liver from gusmps2J/gusmps2J mice demonstrates a 750-bp reduction in size of β-glucuronidase mRNA. A 5.4-kb insertion in the Gus-sh nucleotide sequence from these mice was localized by Southern blot analysis to intron 8. The ends of the inserted sequences were cloned by inverse PCR and revealed an intracisternal A-particle (IAP) element inserted near the 3′ end of the intron. The sequence of the long terminal repeat (LTR) regions of the IAP most closely matches that of a composite LTR found in transposed IAPs previously identified in the C3H strain. The inserted IAP may contribute to diminished β-glucuronidase activity either by interfering with transcription or by destabilizing the message. The resulting phenotype is much less severe than that previously described in the gusmps/gusmps mouse and provides an opportunity to study MPS VII on a genetic background that clearly modulates disease severity. PMID:9774663

Early treatment with laronidase improves clinical outcomes in patients with attenuated MPS I: a retrospective case series analysis of nine sibships.

PubMed

Al-Sannaa, Nouriya A; Bay, Luisa; Barbouth, Deborah S; Benhayoun, Youssef; Goizet, Cyril; Guelbert, Norberto; Jones, Simon A; Kyosen, Sandra Obikawa; Martins, Ana Maria; Phornphutkul, Chanika; Reig, Celia; Pleat, Rebecca; Fallet, Shari; Ivanovska Holder, Iva

2015-10-07

Enzyme replacement therapy (ERT) with laronidase, (recombinant human α-L-iduronidase; Aldurazyme) is the primary treatment option for patients with attenuated mucopolysaccharidosis type I (MPS I). This study examined the effect of early ERT on clinical manifestations. This multinational, retrospective case series abstracted data from records of 20 patients with Hurler-Scheie syndrome within nine sibships that included older siblings treated with laronidase after the development of significant clinical symptoms, and younger siblings treated before significant symptomatology. Median age at diagnosis was 5.6 and 0.5 years for older and younger siblings, respectively. Median age at ERT initiation was 7.9 and 1.9 years for older and younger siblings, respectively. Improvement or stabilization of somatic signs and symptoms was more notable in younger siblings. Organomegaly present at onset of ERT improved in the majority of both older and younger siblings. Analysis of physician-rated symptom severity demonstrated that cardiac, musculoskeletal, and cognitive symptoms, when absent or mild in younger siblings at ERT initiation, generally did not develop or progress. The majority of older siblings had height/length Z-scores greater than two standard deviations below the mean (less than -2) at both time points. In general, Z-scores for younger siblings were closer to the sex- and age-matched means at follow-up. These findings suggest early initiation of laronidase, prior to the onset of symptoms in patients with attenuated MPS I, can slow or prevent the development of severe clinical manifestations.

δ-Tocopherol Reduces Lipid Accumulation in Niemann-Pick Type C1 and Wolman Cholesterol Storage Disorders*

PubMed Central

Xu, Miao; Liu, Ke; Swaroop, Manju; Porter, Forbes D.; Sidhu, Rohini; Finkes, Sally; Ory, Daniel S.; Marugan, Juan J.; Xiao, Jingbo; Southall, Noel; Pavan, William J.; Davidson, Cristin; Walkley, Steven U.; Remaley, Alan T.; Baxa, Ulrich; Sun, Wei; McKew, John C.; Austin, Christopher P.; Zheng, Wei

2012-01-01

Niemann-Pick disease type C (NPC) and Wolman disease are two members of a family of storage disorders caused by mutations of genes encoding lysosomal proteins. Deficiency in function of either the NPC1 or NPC2 protein in NPC disease or lysosomal acid lipase in Wolman disease results in defective cellular cholesterol trafficking. Lysosomal accumulation of cholesterol and enlarged lysosomes are shared phenotypic characteristics of both NPC and Wolman cells. Utilizing a phenotypic screen of an approved drug collection, we found that δ-tocopherol effectively reduced lysosomal cholesterol accumulation, decreased lysosomal volume, increased cholesterol efflux, and alleviated pathological phenotypes in both NPC1 and Wolman fibroblasts. Reduction of these abnormalities may be mediated by a δ-tocopherol-induced intracellular Ca2+ response and subsequent enhancement of lysosomal exocytosis. Consistent with a general mechanism for reduction of lysosomal lipid accumulation, we also found that δ-tocopherol reduces pathological phenotypes in patient fibroblasts from other lysosomal storage diseases, including NPC2, Batten (ceroid lipofuscinosis, neuronal 2, CLN2), Fabry, Farber, Niemann-Pick disease type A, Sanfilippo type B (mucopolysaccharidosis type IIIB, MPSIIIB), and Tay-Sachs. Our data suggest that regulated exocytosis may represent a potential therapeutic target for reduction of lysosomal storage in this class of diseases. PMID:23035117

Enzyme replacement therapy for mucopolysaccharidosis VI: Growth and pubertal development in patients treated with recombinant human N-acetylgalactosamine 4-sulfatase

PubMed Central

Decker, Celeste; Yu, Zi-Fan; Giugliani, Roberto; Schwartz, Ida Vanessa D.; Guffon, Nathalie; Teles, Elisa Leão; Miranda, M. Clara Sá; Wraith, J. Edmond; Beck, Michael; Arash, Laila; Scarpa, Maurizio; Ketteridge, David; Hopwood, John J.; Plecko, Barbara; Steiner, Robert; Whitley, Chester B.; Kaplan, Paige; Swiedler, Stuart J.; Conrad, Susan; Harmatz, Paul

2010-01-01

Background and Methods Growth failure is characteristic of untreated mucopolysaccharidosis type VI (MPS VI: Maroteaux-Lamy syndrome). Growth was studied in fifty-six MPS VI patients (5 to 29 years old) prior to and for up to 240 weeks of weekly infusions of recombinant human arylsulfatase B (rhASB) at 1 mg/kg during Phase 1/2, Phase 2, Phase 3 or Phase 3 Extension clinical trials. Height, weight, and Tanner stage data were collected. Pooled data were analyzed to determine mean height increase by treatment week, growth impacts of pubertal status, baseline urinary GAG, and age at treatment initiation. Growth rate for approximately 2 years prior to and following treatment initiation was analyzed using longitudinal modeling. Results Mean height increased by 2.9 cm after 48 weeks and 4.3 cm after 96 weeks on enzyme replacement therapy (ERT). Growth on ERT was not correlated with baseline urinary GAG. Patients under 16 years of age showed greatest increases in height on treatment. Model results based on pooled data showed significant improvement in growth rate during 96 weeks of ERT when compared to the equivalent pretreatment time period. Delayed pubertal onset or progression was noted in 10 patients entering the clinical trials; all of whom showed progression of at least one Tanner stage during 2 years on ERT, and 6 of whom (60%) completed puberty. Conclusion Analysis of mean height by treatment week and longitudinal modeling demonstrate significant increase in height and growth rate in MPS VI patients receiving long-term ERT. This impact was greatest in patients aged below 16 years. Height increase may result from bone growth and/or reduction in joint contractures. Bone growth and resolution of delayed puberty may be related to improvements in general health, bone cell health, nutrition, endocrine gland function and reduced inflammation. PMID:20634905

[Ocular Manifestation of Mucopolysaccharidosis I-S (Scheie's Syndrome)].

PubMed

Viestenz, Arne; Shin, Yoon S; Viestenz, Anja; Naumann, Gottfried O H

2002-10-01

Bilateral stromal corneal opacifications are a differential diagnostical challenge to identify associated systemic diseases. A 47-year old civil engineer (height 167 cm) with bilateral stromal corneal clouding presented with visual loss for the last 27 years: VA 20/100 OD and 20/50 OS (following penetrating keratoplasty OS). The cornea showed milky-whitish, cloudy, diffuse stromal deposits without a separate lipoid arc. The posterior segment showed tapetoretinal degeneration. Scotopic ERG was decreased. A suspicious stiffness of interphalangeal joints on both hands was observed. There was an aortic and mitral insufficiency grade I. Serum levels of LDL, HDL and triglycerides were normal. The biomicroscopical diagnosis of Scheie's syndrome (mucopolysaccharidosis I-S) was confirmed by a deficiency of alpha-L-iduronidase in leukocytes (0.02 nmol/min/mg protein, normal range: 0.3 - 1.5). The differential diagnosis of bilateral corneal stromal opacification includes in addition to the mucopolysaccharidoses HDL-deficiency diseases (LCAT deficiency, Tangier disease, Fish eye disease), Schnyder's crystalline stromal dystrophy, cystinosis, gout and mucolipidoses. MPS I-S may easily be detected by alpha-L-iduronidase deficiency in leukocytes and increased mucopolysaccharides in the urine. Furthermore, patients with MPS I-S need general medical care because of cardiovascular abnormalities, joint stiffness and myopathies.

Diffusion tensor imaging and myelin composition analysis reveal abnormal myelination in corpus callosum of canine mucopolysaccharidosis I

PubMed Central

Provenzale, James M.; Nestrasil, Igor; Chen, Steven; Kan, Shih-hsin; Le, Steven Q.; Jens, Jacqueline K.; Snella, Elizabeth M.; Vondrak, Kristen N.; Yee, Jennifer K.; Vite, Charles H.; Elashoff, David; Duan, Lewei; Wang, Raymond Y.; Ellinwood, N. Matthew; Guzman, Miguel A.; Shapiro, Elsa G.; Dickson, Patricia I.

2015-01-01

Children with mucopolysaccharidosis I (MPS I) develop hyperintense white matter foci on T2-weighted brain magnetic resonance (MR) imaging that are associated clinically with cognitive impairment. We report here a diffusion tensor imaging (DTI) and tissue evaluation of white matter in a canine model of MPS I. We found that two DTI parameters, fractional anisotropy (a measure of white matter integrity) and radial diffusivity (which reflects degree of myelination) were abnormal in the corpus callosum of MPS I dogs compared to carrier controls. Tissue studies of the corpus callosum showed reduced expression of myelin-related genes and an abnormal composition of myelin in MPS I dogs. We treated MPS I dogs with recombinant alpha-l-iduronidase, which is the enzyme that is deficient in MPS I disease. The recombinant alpha-l-iduronidase was administered by intrathecal injection into the cisterna magna. Treated dogs showed partial correction of corpus callosum myelination. Our findings suggest that abnormal myelination occurs in the canine MPS I brain, that it may underlie clinically-relevant brain imaging findings in human MPS I patients, and that it may respond to treatment. PMID:26222335

Delayed hypertrophic differentiation of epiphyseal chondrocytes contributes to failed secondary ossification in mucopolysaccharidosis VII dogs

PubMed Central

Peck, Sun H.; O'Donnell, Philip J.M.; Kang, Jennifer L.; Malhotra, Neil R.; Dodge, George R.; Pacifici, Maurizio; Shore, Eileen M.; Haskins, Mark E.; Smith, Lachlan J.

2015-01-01

Mucopolysaccharidosis (MPS) VII is a lysosomal storage disorder characterized by deficient β-glucuronidase activity, which leads to the accumulation of incompletely degraded glycosaminoglycans (GAGs). MPS VII patients present with severe skeletal abnormalities, which are particularly prevalent in the spine. Incomplete cartilage-to-bone conversion in MPS VII vertebrae during postnatal development is associated with progressive spinal deformity and spinal cord compression. The objectives of this study were to determine the earliest postnatal developmental stage at which vertebral bone disease manifests in MPS VII and to identify the underlying cellular basis of impaired cartilage-to-bone conversion, using the naturally-occurring canine model. Control and MPS VII dogs were euthanized at 9 and 14 days-of-age, and vertebral secondary ossification centers analyzed using micro-computed tomography, histology, qPCR, and protein immunoblotting. Imaging studies and mRNA analysis of bone formation markers established that secondary ossification commences between 9 and 14 days in control animals, but not in MPS VII animals. mRNA analysis of differentiation markers revealed that MPS VII epiphyseal chondrocytes are unable to successfully transition from proliferation to hypertrophy during this critical developmental window. Immunoblotting demonstrated abnormal persistence of Sox9 protein in MPS VII cells between 9 and 14 days-of-age, and biochemical assays revealed abnormally high intra and extracellular GAG content in MPS VII epiphyseal cartilage at as early as 9 days-of-age. In contrast, assessment of vertebral growth plates and primary ossification centers revealed no significant abnormalities at either age. The results of this study establish that failed vertebral bone formation in MPS VII can be traced to the failure of epiphyseal chondrocytes to undergo hypertrophic differentiation at the appropriate developmental stage, and suggest that aberrant processing of Sox9 protein may contribute to this cellular dysfunction. These results also highlight the importance of early diagnosis and therapeutic intervention to prevent the progression of debilitating skeletal disease in MPS patients. PMID:26422116

Incidence of the mucopolysaccharidoses in Northern Ireland.

PubMed

Nelson, J

1997-12-01

An epidemiological study of the mucopolysaccharidoses (MPS) in Northern Ireland using multiple ascertainment sources was carried out and the incidence rate for the period 1958-1985 was estimated. An incidence of approximately 1 in 76,000 live births was obtained for MPS 1H (Hurler phenotype); 1 in 280,000 for MPS 1 H/S (Hurler/Scheie phenotype); 1 in 140,000 live births (1 in 72,000 male live births) for MPS II (Hunter syndrome); 1 in 280,000 for MPS III (Sanfilippo syndrome) and 1 in 76,000 for MPS IV A (Morquio syndrome type A). No cases of MPS IS (Scheie phenotype), MPS IV B (Morquio syndrome type B) or MPS VI (Maroteaux-Lamy syndrome) were ascertained during the study period. Three cases of non-immune hydrops fetalis born to consanguineous parents were thought to be due to beta-glucuronidase deficiency (MPS VII) on the basis of placental histology and enzyme studies on both parents but no living cases of MPS VII were ascertained. The overall incidence for all types of mucopolysaccharidosis was approximately 1 in 25,000 live births. A comparison is made with incidence estimates obtained from other published studies.

International Guidelines for the Management and Treatment of Morquio A Syndrome

PubMed Central

Hendriksz, Christian J; Berger, Kenneth I; Giugliani, Roberto; Harmatz, Paul; Kampmann, Christoph; Mackenzie, William G; Raiman, Julian; Villarreal, Martha Solano; Savarirayan, Ravi

2015-01-01

Morquio A syndrome (mucopolysaccharidosis IVA) is a lysosomal storage disorder associated with skeletal and joint abnormalities and significant non-skeletal manifestations including respiratory disease, spinal cord compression, cardiac disease, impaired vision, hearing loss, and dental problems. The clinical presentation, onset, severity and progression rate of clinical manifestations of Morquio A syndrome vary widely between patients. Because of the heterogeneous and progressive nature of the disease, the management of patients with Morquio A syndrome is challenging and requires a multidisciplinary approach, involving an array of specialists. The current paper presents international guidelines for the evaluation, treatment and symptom-based management of Morquio A syndrome. These guidelines were developed during two expert meetings by an international panel of specialists in pediatrics, genetics, orthopedics, pulmonology, cardiology, and anesthesia with extensive experience in managing Morquio A syndrome. © 2014 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals, Inc. PMID:25346323

Intra-articular Enzyme Replacement Therapy with rhIDUA is Safe, Well-Tolerated, and Reduces Articular GAG Storage in the Canine Model of Mucopolysaccharidosis Type I

PubMed Central

Wang, Raymond Y; Aminian, Afshin; McEntee, Michael F; Kan, Shih-Hsin; Simonaro, Calogera M; Lamanna, William; Lawrence, Roger; Ellinwood, N. Matthew; Guerra, Catalina; Le, Steven Q; Dickson, Patricia I; Esko, Jeffrey D

2014-01-01

Background Treatment with intravenous enzyme replacement therapy and hematopoietic stem cell transplantation for mucopolysaccharidosis (MPS) type I does not address joint disease, resulting in persistent orthopedic complications and impaired quality of life. A proof-of-concept study was conducted to determine the safety, tolerability, and efficacy of intra-articular recombinant human iduronidase (IA-rhIDUA) enzyme replacement therapy in the canine MPS I model. Methods Four MPS I dogs underwent monthly rhIDUA injections (0.58 mg/joint) into the right elbow and knee for six months. Contralateral elbows and knees concurrently received normal saline. No intravenous rhIDUA therapy was administered. Monthly blood counts, chemistries, anti-rhIDUA antibody titers, and synovial fluid cell counts were measured. Lysosomal storage of synoviocytes and chondrocytes, synovial macrophages and plasma cells were scored at baseline and one month following the final injection. Results All injections were well-tolerated without adverse reactions. One animal required prednisone for spinal cord compression. There were no clinically significant abnormalities in blood counts or chemistries. Circulating anti-rhIDUA antibody titers gradually increased in all dogs except the prednisone-treated dog; plasma cells, which were absent in all baseline synovial specimens, were predominantly found in synovium of rhIDUA-treated joints at study-end. Lysosomal storage in synoviocytes and chondrocytes following 6 months of IA-rhIDUA demonstrated significant reduction compared to tissues at baseline, and saline-treated tissues at study-end. Mean joint synovial GAG levels in IA-rhIDUA joints was 8.62±5.86 μg/mg dry weight and 21.6±10.4 μg/mg dry weight in control joints (60% reduction). Cartilage heparan sulfate was also reduced in the IA-rhIDUA joints (113±39.5 ng/g wet weight) compared to saline-treated joints (142±56.4 ng/g wet weight). Synovial macrophage infiltration, which was present in all joints at baseline, was abolished in rhIDUA-treated joints only. Conclusions Intra-articular rhIDUA is well-tolerated and safe in the canine MPS I animal model. Qualitative and quantitative assessments indicate that IA-rhIDUA successfully reduces tissue and cellular GAG storage in synovium and articular cartilage, including cartilage deep to the articular surface, and eliminates inflammatory macrophages from synovial tissue. PMID:24951454

Reduction in Brain Heparan Sulfate with Systemic Administration of an IgG Trojan Horse-Sulfamidase Fusion Protein in the Mucopolysaccharidosis Type IIIA Mouse.

PubMed

Boado, Ruben J; Lu, Jeff Zhiqiang; Hui, Eric Ka-Wai; Pardridge, William M

2018-02-05

Mucopolysaccharidosis Type IIIA (MPSIIIA), also known as Sanfilippo A syndrome, is an inherited neurodegenerative disease caused by mutations in the lysosomal enzyme, N-sulfoglucosamine sulfohydrolase (SGSH), also known as sulfamidase. Mutations in the SGSH enzyme, the only mammalian heparan N-sulfatase, cause accumulation of lysosomal inclusion bodies in brain cells comprising heparan sulfate (HS) glycosaminoglycans (GAGs). Treatment of MPSIIIA with intravenous recombinant SGSH is not possible because this large molecule does not cross the blood-brain barrier (BBB). BBB penetration by SGSH was enabled in the present study by re-engineering this enzyme as an IgG-SGSH fusion protein, where the IgG domain is a chimeric monoclonal antibody (mAb) against the mouse transferrin receptor (TfR), designated the cTfRMAb. The IgG domain of the fusion protein acts as a molecular Trojan horse to deliver the enzyme into brain via transport on the endogenous BBB TfR. The cTfRMAb-SGSH fusion protein bound to the mouse TfR with high affinity, ED 50 = 0.74 ± 0.07 nM, and retained high SGSH enzyme activity, 10 043 ± 1003 units/mg protein, which is comparable to recombinant human SGSH. Male and female MPSIIIA mice, null for the SGSH enzyme, were treated for 6 weeks with thrice-weekly intraperitoneal injections of vehicle, 5 mg/kg of the cTfRMAb alone, or 5 mg/kg of the cTfRMAb-SGSH fusion protein, starting at the age of 2 weeks, and were euthanized 1 week after the last injection. Brain and liver HS, as determined by liquid chromatography-mass spectrometry, were elevated 30-fold and 36-fold, respectively, in the MPSIIIA mouse. Treatment of the mice with the cTfRMAb-SGSH fusion protein caused a 70% and 85% reduction in brain and liver HS, respectively. The reduction in brain HS was associated with a 28% increase in latency on the rotarod test of motor activity in male mice. The mice exhibited no injection related reactions, and only a low titer end of study antidrug antibody response was observed. In conclusion, substantial reductions in brain pathologic GAGs in a murine model of MPSIIIA are produced by chronic systemic administration of an IgG-SGSH fusion protein engineered to penetrate the BBB via receptor-mediated transport.

Mean Platelet Volume as an Indicator of Platelet Rejuvenation Following Bone Marrow Transplantation.

DTIC Science & Technology

1986-07-01

al., 1972 Family R ACD volume D D Murphy et al., 1972 Connective Tissue Disorders Ehlers - Danlos Syndrome diameter N I Estes, 1968 Marlan Syndrome ...autosomal dominant), Maran syndrome (autosomal dominant), Mucopolysaccharidosis syndrome (sex-linked), Ehlers - Danlos syndrome (autosomal dominant...individuals with hyperdestructive syndromes (Paulus, 1975). If macrothrombocytosis in hyperdestruction is due only to the young age of the circulating

Coenzyme Q10 and Pyridoxal Phosphate Deficiency Is a Common Feature in Mucopolysaccharidosis Type III.

PubMed

Yubero, Dèlia; Montero, Raquel; O'Callaghan, Mar; Pineda, Mercè; Meavilla, Silvia; Delgadillo, Veronica; Sierra, Cristina; Altimira, Laura; Navas, Plácido; Pope, Simon; Oppenheim, Marcus; Neergheen, Viruna; Ghosh, Arunabha; Mills, Phillipa; Clayton, Peter; Footitt, Emma; Cleary, Maureen; Hargreaves, Iain; Jones, Simon A; Heales, Simon; Artuch, Rafael

2016-01-01

Mucopolysaccharidoses (MPS) are a group of lysosomal storage disorders caused by deficiencies of lysosomal enzymes catalyzing degradation of glycosaminoglycans (GAGs). Previously, we reported a secondary plasma coenzyme Q 10 (CoQ) deficiency in MPS patients. For this study, nine MPS patients were recruited in the Hospital Sant Joan de Déu (HSJD, Barcelona) and two patients in the Neurometabolic Unit, National Hospital (NMU, London), to explore the nutritional status of MPS type III patients by analyzing several vitamins and micronutrients in blood and in cerebrospinal fluid. Plasma CoQ and plasma and cerebrospinal fluid pyridoxal phosphate (PLP) content were analyzed by high-pressure liquid chromatography (HPLC) with electrochemical and fluorescence detection, respectively. We found that most MPS-III patients disclosed low plasma pyridoxal phosphate (PLP) values (seven out of nine) and also low plasma CoQ concentrations (eight out of nine). We observed significantly lower median values of PLP, tocopherol, and CoQ (Mann-Whitney U test, p = 0.006, p = 0.004, and p = 0.001, respectively) in MPS patients when compared with age-matched controls. Chi-square test showed a significant association between the fact of having low plasma PLP and CoQ values in the whole cohort of patients. Cerebrospinal fluid PLP values were clearly deficient in the two patients studied. In conclusion, we report a combined CoQ and PLP deficiency in MPS-III patients. These observations could be related to the complexity of the physiopathology of the disease. If our results are confirmed in larger series of patients, CoQ and PLP therapy could be trialed as coadjuvant therapy with the current MPS treatments.

Beneath the floor: re-analysis of neurodevelopmental outcomes in untreated Hurler syndrome.

PubMed

Shapiro, Elsa G; Whitley, Chester B; Eisengart, Julie B

2018-05-11

Hurler syndrome (MPS IH), the severe, neurodegenerative form of type one mucopolysaccharidosis, is associated with rapid neurocognitive decline during toddlerhood and multi-system dysfunction. It is now standardly treated with hematopoietic cell transplantation (HCT), which halts accumulating disease pathology and prevents early death. While norm-based data on developmental functioning in untreated children have previously demonstrated neurocognitive decline, advances in methodology for understanding the cognitive functioning of children with neurodegenerative diseases have highlighted that the previous choice of scores to report results was not ideal. Specifically, the lowest possible norm-based score is 50, which obscures the complete range of cognitive functioning at more advanced stages of neurodeterioration. To a set of cognitive data collected on a sample of untreated children, we applied a modern method of score analysis, calculating a developmental quotient based on age equivalent scores, to reveal the full range of cognitive functioning beneath this cutoff of 50, uncovering new information about the rapidity of decline and the profound impairment in these children. Among 39 observations for 32 patients with untreated Hurler syndrome, the full array of cognitive functioning below 50 includes many children in the severely to profoundly impaired range. The loss of skills per time unit was 14 points between age 1 and 2. There was a very large range of developmental quotients corresponding to the norm-based cutoff of 50. This report enables clarification of functioning at levels that extend beneath the floor of 50 in previous work. At the dawn of newborn screening and amidst a proliferation of new therapies for MPS I, these data can provide crucial benchmark information for developing treatments, particularly for areas of the world where transplant may not be available.

Evaluation of AAV-mediated Gene Therapy for Central Nervous System Disease in Canine Mucopolysaccharidosis VII

PubMed Central

Gurda, Brittney L; De Guilhem De Lataillade, Adrien; Bell, Peter; Zhu, Yanqing; Yu, Hongwei; Wang, Ping; Bagel, Jessica; Vite, Charles H; Sikora, Tracey; Hinderer, Christian; Calcedo, Roberto; Yox, Alexander D; Steet, Richard A; Ruane, Therese; O'Donnell, Patricia; Gao, Guangping; Wilson, James M; Casal, Margret; Ponder, Katherine P; Haskins, Mark E

2016-01-01

Mucopolysaccharidosis VII (MPS VII) is a lysosomal storage disease arising from mutations in β-d-glucuronidase (GUSB), which results in glycosaminoglycan (GAG) accumulation and a variety of clinical manifestations including neurological disease. Herein, MPS VII dogs were injected intravenously (i.v.) and/or intrathecally (i.t.) via the cisterna magna with AAV9 or AAVrh10 vectors carrying the canine GUSB cDNA. Although i.v. injection alone at 3 days of age resulted in normal cerebrospinal fluid (CSF) GUSB activity, brain tissue homogenates had only ~1 to 6% normal GUSB activity and continued to have elevated GAG storage. In contrast, i.t. injection at 3 weeks of age resulted in CSF GUSB activity 44-fold normal while brain tissue homogenates had >100% normal GUSB activity and reduced GAGs compared with untreated dogs. Markers for secondary storage and inflammation were eliminated in i.t.-treated dogs and reduced in i.v.-treated dogs compared with untreated dogs. Given that i.t.-treated dogs expressed higher levels of GUSB in the CNS tissues compared to those treated i.v., we conclude that i.t. injection of AAV9 or AAVrh10 vectors is more effective than i.v. injection alone in the large animal model of MPS VII. PMID:26447927

Evaluation of AAV-mediated Gene Therapy for Central Nervous System Disease in Canine Mucopolysaccharidosis VII.

PubMed

Gurda, Brittney L; De Guilhem De Lataillade, Adrien; Bell, Peter; Zhu, Yanqing; Yu, Hongwei; Wang, Ping; Bagel, Jessica; Vite, Charles H; Sikora, Tracey; Hinderer, Christian; Calcedo, Roberto; Yox, Alexander D; Steet, Richard A; Ruane, Therese; O'Donnell, Patricia; Gao, Guangping; Wilson, James M; Casal, Margret; Ponder, Katherine P; Haskins, Mark E

2016-02-01

Mucopolysaccharidosis VII (MPS VII) is a lysosomal storage disease arising from mutations in β-d-glucuronidase (GUSB), which results in glycosaminoglycan (GAG) accumulation and a variety of clinical manifestations including neurological disease. Herein, MPS VII dogs were injected intravenously (i.v.) and/or intrathecally (i.t.) via the cisterna magna with AAV9 or AAVrh10 vectors carrying the canine GUSB cDNA. Although i.v. injection alone at 3 days of age resulted in normal cerebrospinal fluid (CSF) GUSB activity, brain tissue homogenates had only ~1 to 6% normal GUSB activity and continued to have elevated GAG storage. In contrast, i.t. injection at 3 weeks of age resulted in CSF GUSB activity 44-fold normal while brain tissue homogenates had >100% normal GUSB activity and reduced GAGs compared with untreated dogs. Markers for secondary storage and inflammation were eliminated in i.t.-treated dogs and reduced in i.v.-treated dogs compared with untreated dogs. Given that i.t.-treated dogs expressed higher levels of GUSB in the CNS tissues compared to those treated i.v., we conclude that i.t. injection of AAV9 or AAVrh10 vectors is more effective than i.v. injection alone in the large animal model of MPS VII.

Mucopolysaccharidosis IVA and glycosaminoglycans

PubMed Central

Khan, Shaukat; Alméciga-Díaz, Carlos J.; Sawamoto, Kazuki; Mackenzie, William G.; Theroux, Mary C; Pizarro, Christian; Mason, Robert W.; Orii, Tadao; Tomatsu, Shunji

2016-01-01

Mucopolysaccharidosis IVA (MPS IVA; Morquio A: OMIM 253000) is a lysosomal storage disease with an autosomal recessive trait caused by the deficiency of N-acetylgalactosamine-6-sulfate sulfatase. Deficiency of this enzyme leads to accumulation of specific glycosaminoglycans (GAGs): chondroitin-6-sulfate (C6S) and keratan sulfate (KS). C6S and KS are mainly produced in the cartilage. Therefore, the undegraded substrates are stored primarily in cartilage and in its extracellular matrix (ECM), leading to a direct impact on cartilage and bone development, and successive systemic skeletal dysplasia. Chondrogenesis, the earliest phase of skeletal formation, is maintained by cellular interactions with the ECM, growth and differentiation factors, signaling pathways, and transcription factors in a temporal-spatial manner. In patients with MPS IVA, the cartilage is disrupted at birth as a consequence of abnormal chondrogenesis and/or endochondral ossification. The unique skeletal features are distinguished by a disproportional short stature, odontoid hypoplasia, spinal cord compression, tracheal obstruction, pectus carinatum, kyphoscoliosis, platyspondyly, coxa valga, genu valgum, waddling gait, and laxity of joints. In spite of many descriptions of these unique clinical features, delay of diagnosis still happens. The pathogenesis and treatment of systemic skeletal dysplasia in MPS IVA remains an unmet challenge. In this review article, we comprehensively describe historical aspect, property of GAGs, diagnosis, screening, pathogenesis, and current and future therapies of MPS IVA. PMID:27979613

Characterization of an MPS I-H Knock-In Mouse that Carries a Nonsense Mutation Analogous to the Human IDUA-W402X Mutation

PubMed Central

Wang, Dan; Shukla, Charu; Liu, Xiaoli; Schoeb, Trenton R.; Clarke, Lorne A.; Bedwell, David M.; Keeling, Kim M.

2009-01-01

Here we report the characterization of a knock-in mouse model for the autosomal recessive disorder mucopolysaccharidosis type I-Hurler (MPS I-H), also known as Hurler syndrome. MPS I-H is the most severe form of α-L-iduronidase deficiency. α-L-iduronidase (encoded by the IDUA gene) is a lysosomal enzyme that participates in the degradation of dermatan sulfate and heparan sulfate. Using gene replacement methodology, a nucleotide change was introduced into the mouse Idua locus that resulted in a nonsense mutation at codon W392. The Idua-W392X mutation is analogous to the human IDUA-W402X mutation commonly found in MPS I-H patients. We found that the phenotype in homozygous Idua-W392X mice closely correlated with the human MPS I-H disease. Homozygous W392X mice showed no detectable α-L-iduronidase activity. We observed a defect in GAG degradation as evidenced by an increase in sulfated GAGs excreted in the urine and stored in multiple tissues. Histology and electron microscopy also revealed evidence of GAG storage in all tissues examined. Additional assessment revealed bone abnormalities and altered metabolism within the Idua-W392X mouse. This new mouse will provide an important tool to investigate therapeutic approaches for MPS I-H that cannot be addressed using current MPS I-H animal models. PMID:19751987

LCR-initiated rearrangements at the IDS locus, completed with Alu-mediated recombination or non-homologous end joining.

PubMed

Oshima, Junko; Lee, Jennifer A; Breman, Amy M; Fernandes, Priscilla H; Babovic-Vuksanovic, Dusica; Ward, Patricia A; Wolfe, Lynne A; Eng, Christine M; Del Gaudio, Daniela

2011-07-01

Mucopolysaccharidosis type II (MPS II) is caused by mutations in the IDS gene, which encodes the lysosomal enzyme iduronate-2-sulfatase. In ∼20% of MPS II patients the disorder is caused by gross IDS structural rearrangements. We identified two male cases harboring complex rearrangements involving the IDS gene and the nearby pseudogene, IDSP1, which has been annotated as a low-copy repeat (LCR). In both cases the rearrangement included a partial deletion of IDS and an inverted insertion of the neighboring region. In silico analyses revealed the presence of repetitive elements as well as LCRs at the junctions of rearrangements. Our models illustrate two alternative consequences of rearrangements initiated by non-allelic homologous recombination of LCRs: resolution by a second recombination event (that is, Alu-mediated recombination), or resolution by non-homologous end joining repair. These complex rearrangements have the potential to be recurrent and may be present among those MSP II cases with previously uncharacterized aberrations involving IDS.

Mucopolysaccharidosis VI in cats - clarification regarding genetic testing.

PubMed

Lyons, Leslie A; Grahn, Robert A; Genova, Francesca; Beccaglia, Michela; Hopwood, John J; Longeri, Maria

2016-07-02

The release of new DNA-based diagnostic tools has increased tremendously in companion animals. Over 70 different DNA variants are now known for the cat, including DNA variants in disease-associated genes and genes causing aesthetically interesting traits. The impact genetic tests have on animal breeding and health management is significant because of the ability to control the breeding of domestic cats, especially breed cats. If used properly, genetic testing can prevent the production of diseased animals, causing the reduction of the frequency of the causal variant in the population, and, potentially, the eventual eradication of the disease. However, testing of some identified DNA variants may be unwarranted and cause undo strife within the cat breeding community and unnecessary reduction of gene pools and availability of breeding animals. Testing for mucopolysaccharidosis Type VI (MPS VI) in cats, specifically the genetic testing of the L476P (c.1427T>C) and the D520N (c.1558G>A) variants in arylsulfatase B (ARSB), has come under scrutiny. No health problems are associated with the D520N (c.1558G>A) variant, however, breeders that obtain positive results for this variant are speculating as to possible correlation with health concerns. Birman cats already have a markedly reduced gene pool and have a high frequency of the MPS VI D520N variant. Further reduction of the gene pool by eliminating cats that are heterozygous or homozygous for only the MPS VI D520N variant could lead to more inbreeding depression effects on the breed population. Herein is debated the genetic testing of the MPS VI D520N variant in cats. Surveys from different laboratories suggest the L476P (c.1427T>C) disease-associated variant should be monitored in the cat breed populations, particularly breeds with Siamese derivations and outcrosses. However, the D520N has no evidence of association with disease in cats and testing is not recommended in the absence of L476P genotyping. Selection against the D520N is not warranted in cat populations. More rigorous guidelines may be required to support the genetic testing of DNA variants in all animal species.

Extracellular matrix disruption is an early event in the pathogenesis of skeletal disease in mucopolysaccharidosis I.

PubMed

Heppner, Jonathan M; Zaucke, Frank; Clarke, Lorne A

2015-02-01

Progressive skeletal and connective tissue disease represents a significant clinical burden in all of the mucopolysaccharidoses. Despite the introduction of enzyme replacement strategies for many of the mucopolysaccharidoses, symptomatology related to bone and joint disease appears to be recalcitrant to current therapies. In order to address these unmet medical needs a clearer understanding of skeletal and connective tissue disease pathogenesis is required. Historically the pathogenesis of the mucopolysaccharidoses has been assumed to directly relate to progressive storage of glycosaminoglycans. It is now apparent for many lysosomal storage disorders that more complex pathogenic mechanisms underlie patients' clinical symptoms. We have used proteomic and genome wide expression studies in the murine mucopolysaccharidosis I model to identify early pathogenic events occurring in micro-dissected growth plate tissue. Studies were conducted using 3 and 5-week-old mice thus representing a time at which no obvious morphological changes of bone or joints have taken place. An unbiased iTRAQ differential proteomic approach was used to identify candidates followed by validation with multiple reaction monitoring mass spectrometry and immunohistochemistry. These studies reveal significant decreases in six key structural and signaling extracellular matrix proteins; biglycan, fibromodulin, PRELP, type I collagen, lactotransferrin, and SERPINF1. Genome-wide expression studies in embryonic day 13.5 limb cartilage and 5 week growth plate cartilage followed by specific gene candidate qPCR studies in the 5week growth plate identified fourteen significantly deregulated mRNAs (Adamts12, Aspn, Chad, Col2a1, Col9a1, Hapln4, Lum, Matn1, Mmp3, Ogn, Omd, P4ha2, Prelp, and Rab32). The involvement of biglycan, PRELP and fibromodulin; all members of the small leucine repeat proteoglycan family is intriguing, as this protein family is implicated in the pathogenesis of late onset osteoarthritis. Taken as a whole, our data indicates that alteration of the extracellular matrix represents a very early event in the pathogenesis of the mucopolysaccharidoses and implies that biomechanical failure of chondro-osseous tissue may underlie progressive bone and joint disease symptoms. These findings have important therapeutic implications. Copyright © 2014 Elsevier Inc. All rights reserved.

Mucopolysaccharidosis IVA and glycosaminoglycans.

PubMed

Khan, Shaukat; Alméciga-Díaz, Carlos J; Sawamoto, Kazuki; Mackenzie, William G; Theroux, Mary C; Pizarro, Christian; Mason, Robert W; Orii, Tadao; Tomatsu, Shunji

Mucopolysaccharidosis IVA (MPS IVA; Morquio A: OMIM 253000) is a lysosomal storage disease with an autosomal recessive trait caused by the deficiency of N-acetylgalactosamine-6-sulfate sulfatase. Deficiency of this enzyme leads to accumulation of specific glycosaminoglycans (GAGs): chondroitin-6-sulfate (C6S) and keratan sulfate (KS). C6S and KS are mainly produced in the cartilage. Therefore, the undegraded substrates are stored primarily in cartilage and in its extracellular matrix (ECM), leading to a direct impact on cartilage and bone development, and successive systemic skeletal dysplasia. Chondrogenesis, the earliest phase of skeletal formation, is maintained by cellular interactions with the ECM, growth and differentiation factors, signaling pathways, and transcription factors in a temporal-spatial manner. In patients with MPS IVA, the cartilage is disrupted at birth as a consequence of abnormal chondrogenesis and/or endochondral ossification. The unique skeletal features are distinguished by a disproportional short stature, odontoid hypoplasia, spinal cord compression, tracheal obstruction, pectus carinatum, kyphoscoliosis, platyspondyly, coxa valga, genu valgum, waddling gait, and laxity of joints. In spite of many descriptions of these unique clinical features, delay of diagnosis still happens. The pathogenesis and treatment of systemic skeletal dysplasia in MPS IVA remains an unmet challenge. In this review article, we comprehensively describe historical aspect, property of GAGs, diagnosis, screening, pathogenesis, and current and future therapies of MPS IVA. Copyright © 2016 Elsevier Inc. All rights reserved.

Gene therapy ameliorates cardiovascular disease in dogs with mucopolysaccharidosis VII.

PubMed

Sleeper, M M; Fornasari, B; Ellinwood, N M; Weil, M A; Melniczek, J; O'Malley, T M; Sammarco, C D; Xu, L; Ponder, K P; Haskins, M E

2004-08-17

Mucopolysaccharidosis VII (MPS VII) is a lysosomal storage disease caused by deficient beta-glucuronidase (GUSB) activity resulting in defective catabolism of glycosaminoglycans (GAGs). Cardiac disease is a major cause of death in MPS VII because of accumulation of GAGs in cardiovascular cells. Manifestations include cardiomyopathy, mitral and aortic valve thickening, and aortic root dilation and may cause death in the early months of life or may be compatible with a fairly normal lifespan. We previously reported that neonatal administration of a retroviral vector (RV) resulted in transduction of hepatocytes, which secreted GUSB into the blood and could be taken up by cells throughout the body. The goal of this study was to evaluate the effect on cardiac disease. Six MPS VII dogs were treated intravenously with an RV-expressing canine GUSB. Echocardiographic parameters, cardiovascular lesions, and biochemical parameters of these dogs were compared with those of normal and untreated MPS VII dogs. RV-treated dogs were markedly improved compared with untreated MPS VII dogs. Most RV-treated MPS VII dogs had mild or moderate mitral regurgitation at 4 to 5 months after birth, which improved or disappeared when evaluated at 9 to 11 and at 24 months. Similarly, mitral valve thickening present early in some animals disappeared over time, whereas aortic dilation and aortic valve thickening were absent at all times. Both myocardium and aorta had significant levels of GUSB and reduction in GAGs.

Intra-articular enzyme replacement therapy with rhIDUA is safe, well-tolerated, and reduces articular GAG storage in the canine model of mucopolysaccharidosis type I.

PubMed

Wang, Raymond Y; Aminian, Afshin; McEntee, Michael F; Kan, Shih-Hsin; Simonaro, Calogera M; Lamanna, William C; Lawrence, Roger; Ellinwood, N Matthew; Guerra, Catalina; Le, Steven Q; Dickson, Patricia I; Esko, Jeffrey D

2014-08-01

Treatment with intravenous enzyme replacement therapy and hematopoietic stem cell transplantation for mucopolysaccharidosis (MPS) type I does not address joint disease, resulting in persistent orthopedic complications and impaired quality of life. A proof-of-concept study was conducted to determine the safety, tolerability, and efficacy of intra-articular recombinant human iduronidase (IA-rhIDUA) enzyme replacement therapy in the canine MPS I model. Four MPS I dogs underwent monthly rhIDUA injections (0.58 mg/joint) into the right elbow and knee for 6 months. Contralateral elbows and knees concurrently received normal saline. No intravenous rhIDUA therapy was administered. Monthly blood counts, chemistries, anti-rhIDUA antibody titers, and synovial fluid cell counts were measured. Lysosomal storage of synoviocytes and chondrocytes, synovial macrophages and plasma cells were scored at baseline and 1 month following the final injection. All injections were well-tolerated without adverse reactions. One animal required prednisone for spinal cord compression. There were no clinically significant abnormalities in blood counts or chemistries. Circulating anti-rhIDUA antibody titers gradually increased in all dogs except the prednisone-treated dog; plasma cells, which were absent in all baseline synovial specimens, were predominantly found in synovium of rhIDUA-treated joints at study-end. Lysosomal storage in synoviocytes and chondrocytes following 6 months of IA-rhIDUA demonstrated significant reduction compared to tissues at baseline, and saline-treated tissues at study-end. Mean joint synovial GAG levels in IA-rhIDUA joints were 8.62 ± 5.86 μg/mg dry weight and 21.6 ± 10.4 μg/mg dry weight in control joints (60% reduction). Cartilage heparan sulfate was also reduced in the IA-rhIDUA joints (113 ± 39.5 ng/g wet weight) compared to saline-treated joints (142 ± 56.4 ng/g wet weight). Synovial macrophage infiltration, which was present in all joints at baseline, was abolished in rhIDUA-treated joints only. Intra-articular rhIDUA is well-tolerated and safe in the canine MPS I animal model. Qualitative and quantitative assessments indicate that IA-rhIDUA successfully reduces tissue and cellular GAG storage in synovium and articular cartilage, including cartilage deep to the articular surface, and eliminates inflammatory macrophages from synovial tissue. The MPS I canine IA-rhIDUA results suggest that clinical studies should be performed to determine if IA-rhIDUA is a viable approach to ameliorating refractory orthopedic disease in human MPS I. Copyright © 2014 Elsevier Inc. All rights reserved.

Agreement between the results of meta-analyses from case reports and from clinical studies regarding the efficacy of laronidase therapy in patients with mucopolysaccharidosis type I who initiated enzyme replacement therapy in adult age: An example of case reports meta-analyses as an useful tool for evidence-based medicine in rare diseases.

PubMed

Sampayo-Cordero, Miguel; Miguel-Huguet, Bernat; Pardo-Mateos, Almudena; Moltó-Abad, Marc; Muñoz-Delgado, Cecilia; Pérez-López, Jordi

2018-02-01

Case reports might have a prominent role in the rare diseases field, due to the small number of patients affected by one such disease. A previous systematic review regarding the efficacy of laronidase therapy in patients with mucopolysaccharidosis type I (MPS-I) who initiated enzyme replacement therapy (ERT) in adult age has been published. The review included a meta-analysis of 19 clinical studies and the description of eleven case reports. It was of interest to perform a meta-analysis of those case reports to explore the role of such meta-analyses as a tool for evidence-based medicine in rare diseases. The study included all case reports with standard treatment regimen. Primary analysis was the percentage of case reports showing an improvement in a specific outcome. Only when that percentage was statistically higher than 5%, the improvement was confirmed as such. The outcomes that accomplished this criterion were ranked and compared to the GRADE criteria obtained by those same outcomes in the previous meta-analysis of clinical studies. There were three outcomes that had a significant improvement: Urine glycosaminoglycans, liver volume and 6-minute walking test. Positive and negative predictive values, sensitivity and specificity for the results of the meta-analysis of case reports as compared to that of clinical studies were 100%, 88.9%, 75% and 100%, respectively. Accordingly, absolute (Rho=0.82, 95%CI: 0.47 to 0.95) and relative agreement (Kappa=0.79, 95%CI: 0.593 to 0.99) between the number of case reports with improvement in a specific outcome and the GRADE evidence score for that outcome were good. Sensitivity analysis showed that agreement between the meta-analysis of case reports and that of the clinical studies were good only when using a strong confirmatory strategy for outcome improvement in case reports. We found an agreement between the results of meta-analyses from case reports and from clinical studies in the efficacy of laronidase therapy in patients with MPS-I who initiated ERT in adult age. This agreement suggests that combining case reports quantitatively, rather than analyzing them separately or qualitatively, may improve conclusions in the field of rare diseases. Copyright © 2018 Elsevier Inc. All rights reserved.

Newborn screening for six lysosomal storage disorders in a cohort of Mexican patients: Three-year findings from a screening program in a closed Mexican health system.

PubMed

Navarrete-Martínez, Juana Inés; Limón-Rojas, Ana Elena; Gaytán-García, Maria de Jesús; Reyna-Figueroa, Jesús; Wakida-Kusunoki, Guillermo; Delgado-Calvillo, Ma Del Rocío; Cantú-Reyna, Consuelo; Cruz-Camino, Héctor; Cervantes-Barragán, David Eduardo

2017-05-01

To evaluate the results of a lysosomal newborn screening (NBS) program in a cohort of 20,018 Mexican patients over the course of 3years in a closed Mexican Health System (Petróleos Mexicanos [PEMEX] Health Services). Using dried blood spots (DBS), we performed a multiplex tandem mass spectrometry enzymatic assay for six lysosomal storage disorders (LSDs) including Pompe disease, Fabry disease, Gaucher disease, mucopolysaccharidosis type I (MPS-I), Niemann-Pick type A/B, and Krabbe disease. Screen-positive cases were confirmed using leukocyte enzymatic activity and DNA molecular analysis. From July 2012 to April 2016, 20,018 patients were screened; 20 patients were confirmed to have an LSD phenotype (99.9 in 100,000 newborns). Final distributions include 11 Pompe disease, five Fabry disease, two MPS-I, and two Niemann-Pick type A/B patients. We did not find any Gaucher or Krabbe patients. A final frequency of 1 in 1001 LSD newborn phenotypes was established. NBS is a major public health achievement that has decreased the morbidity and mortality of inborn errors of metabolism. The introduction of NBS for LSD presents new challenges. This is the first multiplex Latin-American study of six LSDs detected through NBS. Copyright © 2017 Elsevier Inc. All rights reserved.

Disease correction by AAV-mediated gene therapy in a new mouse model of mucopolysaccharidosis type IIID.

PubMed

Roca, Carles; Motas, Sandra; Marcó, Sara; Ribera, Albert; Sánchez, Víctor; Sánchez, Xavier; Bertolin, Joan; León, Xavier; Pérez, Jennifer; Garcia, Miguel; Villacampa, Pilar; Ruberte, Jesús; Pujol, Anna; Haurigot, Virginia; Bosch, Fatima

2017-04-15

Gene therapy is a promising therapeutic alternative for Lysosomal Storage Disorders (LSD), as it is not necessary to correct the genetic defect in all cells of an organ to achieve therapeutically significant levels of enzyme in body fluids, from which non-transduced cells can uptake the protein correcting their enzymatic deficiency. Animal models are instrumental in the development of new treatments for LSD. Here we report the generation of the first mouse model of the LSD Muccopolysaccharidosis Type IIID (MPSIIID), also known as Sanfilippo syndrome type D. This autosomic recessive, heparan sulphate storage disease is caused by deficiency in N-acetylglucosamine 6-sulfatase (GNS). Mice deficient in GNS showed lysosomal storage pathology and loss of lysosomal homeostasis in the CNS and peripheral tissues, chronic widespread neuroinflammation, reduced locomotor and exploratory activity and shortened lifespan, a phenotype that closely resembled human MPSIIID. Moreover, treatment of the GNS-deficient animals with GNS-encoding adeno-associated viral (AAV) vectors of serotype 9 delivered to the cerebrospinal fluid completely corrected pathological storage, improved lysosomal functionality in the CNS and somatic tissues, resolved neuroinflammation, restored normal behaviour and extended lifespan of treated mice. Hence, this work represents the first step towards the development of a treatment for MPSIIID. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Mannose 6-Phosphate Receptor–mediated Transport of Sulfamidase Across the Blood–brain Barrier in the Newborn Mouse

PubMed Central

Urayama, Akihiko; Grubb, Jeffrey H; Sly, William S; Banks, William A

2010-01-01

Mucopolysaccharidosis type IIIA (MPS IIIA), which is a lysosomal storage disorder (LSD) caused by inherited deficiency of sulfamidase, is characterized by severe, progressive central nervous system (CNS) dysfunction. Enzyme replacement therapy (ERT) to treat CNS storage is challenging, because the access of enzymes to the brain is restricted by the blood–brain barrier (BBB). In a prior study, we found that phosphorylated β-glucuronidase (P-GUS) could be transcytosed across the BBB in newborn mice by the mannose 6-phosphate (M6P) receptor. In order to determine whether sulfamidase can utilize this pathway, we examined brain influx and the specificity of uptake of sulfamidase after intravenous (IV) injection in 2-day-old and 8-week-old mice. [131I]Sulfamidase was transported across the BBB in neonates at rates higher than that of simultaneously injected [125I]albumin. In contrast, the transport of [131I]sulfamidase was negligible in 8-week-old mice, thereby showing that the BBB transport mechanism is developmentally downregulated. Capillary depletion revealed that 83.7% of the [131I]sulfamidase taken up by the brain was in the parenchyma, demonstrating transfer across the capillary wall. The uptake of [131I]sulfamidase into the brain was significantly reduced by co-injections of M6P and P-GUS. That is, the transport of sulfamidase into the brain parenchyma in early postnatal life is mediated by the M6P receptor, which is shared with P-GUS and is likely accessible to other M6P-containing lysosomal enzymes. PMID:18443601

Mucopolysaccharidosis IVA: Four new exonic mutations in patients with N-acetylgalactosamine-6-sulfate sulfatase deficiency

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tomatsu, Shunji; Fukuda, Seiji; Yamagishi, Atsushi

1996-05-01

We report four new mutations in Japanese patients with mucopolysaccharidosis IVA (MPSIVA) who were heterozygous for a common double gene deletion. A nonsense mutation of CAG to TAG at codon 148 in exon 4 was identified, resulting in a change of Q to a stop codon and three missense mutations: V (GTC) to A (GCC) at codon 138 in exon 4, P (CCC) to S (TCC) at codon 151 in exon 5, and P (CCC) to L (CTC) at codon 151 in exon 5. Introduction of these mutations into the normal GALNS cDNA and transient expression in cultured fibroblasts resultedmore » in a significant decrease in the enzyme activity. V138A and Q148X mutations result in changes of restriction site, which were analyzed by restriction-enzyme assay. P151S and P151L mutations that did not alter the restriction site were detected by direct sequencing or allele specific oligohybridization. Detection of the double gene deletion was initially done using Southern blots and was confirmed by PCR. Haplotypes were determined using seven polymorphisms to the GALNS locus in families with the double gene deletion. Haplotype analysis showed that the common double gene deletion occurred on a single haplotype, except for some variation in a VNTR-like polymorphism. This finding is consistent with a common founder for all individuals with this mutation. 48 refs., 5 figs., 1 tab.« less

The Effect of Neonatal Gene Therapy on Skeletal Manifestations in Mucopolysaccharidosis VII Dogs after a Decade

PubMed Central

Xing, Elizabeth M.; Knox, Van W.; O'Donnell, Patricia A.; Sikura, Tracey; Liu, Yuli; Wu, Susan; Casal, Margret L.; Haskins, Mark E.; Ponder, Katherine P.

2013-01-01

Mucopolysaccharidosis (MPS) VII is a lysosomal storage disease due to deficient activity of β-glucuronidase (GUSB), and results in glycosaminoglycan accumulation. Skeletal manifestations include bone dysplasia, degenerative joint disease, and growth retardation. One gene therapy approach for MPS VII involves neonatal intravenous injection of a gamma retroviral vector expressing GUSB, which results in stable expression in liver and secretion of enzyme into blood at levels predicted to be similar or higher to enzyme replacement therapy. The goal of this study was to evaluate the long-term effect of neonatal gene therapy on skeletal manifestations in MPS VII dogs. Treated MPS VII dogs could walk throughout their lives, while untreated MPS VII dogs could not stand beyond 6 months and were dead by 2 years. Luxation of the coxofemoral joint and the patella, dysplasia of the acetabulum and supracondylar ridge, deep erosions of the distal femur, and synovial hyperplasia were reduced, and the quality of articular bone was improved in treated dogs at 6 to 11 years of age compared with untreated MPS VII dogs at 2 years or less. However, treated dogs continued to have osteophyte formation, cartilage abnormalities, and an abnormal gait. Enzyme activity was found near synovial blood vessels, and there was 2% as much GUSB activity in synovial fluid as in serum. We conclude that neonatal gene therapy reduces skeletal abnormalities in MPS VII dogs, but clinically-relevant abnormalities remain. Enzyme replacement therapy will probably have similar limitations long-term. PMID:23628461

Effects of cryopreservation and hypothermic storage on cell viability and enzyme activity in recombinant encapsulated cells overexpressing alpha-L-iduronidase.

PubMed

Mayer, Fabiana Quoos; Baldo, Guilherme; de Carvalho, Talita Giacomet; Lagranha, Valeska Lizzi; Giugliani, Roberto; Matte, Ursula

2010-05-01

Here, we show the effects of cryopreservation and hypothermic storage upon cell viability and enzyme release in alginate beads containing baby hamster kidney cells overexpressing alpha-L-iduronidase (IDUA), the enzyme deficient in mucopolysaccharidosis type I. In addition, we compared two different concentrations of alginate gel (1% and 1.5%) in respect to enzyme release from the beads and their shape and integrity. Our results indicate that in both alginate concentrations, the enzyme is released in lower amounts compared with nonencapsulated cells. Alginate 1% beads presented increased levels of IDUA release, although this group presented more deformities when compared with alginate 1.5% beads. Importantly, both encapsulated groups presented higher cell viability after long cryopreservation period and hypothermic storage. In addition, alginate 1.5% beads presented higher enzyme release after freezing protocols. Taken together, our findings suggest a benefic effect of alginate upon cell viability and functionality. These results may have important application for treatment of both genetic and nongenetic diseases using microencapsulation-based artificial organs.

Bioinformatic Analysis of the Human Recombinant Iduronate 2-Sulfate Sulfatase

PubMed Central

Morales-Álvarez, Edwin D.; Rivera-Hoyos, Claudia M.; Landázuri, Patricia; Poutou-Piñales, Raúl A.; Pedroza-Rodríguez, Aura M.

2016-01-01

Mucopolysaccharidosis type II is a human recessive disease linked to the X chromosome caused by deficiency of lysosomal enzyme Iduronate 2-Sulfate Sulfatase (IDS), which leads to accumulation of glycosaminoglycans in tissues and organs. The human enzyme has been expressed in Escherichia coli and Pichia pastoris in attempt to develop more successful expression systems that allow the production of recombinant IDS for Enzyme Replacement Therapy (ERT). However, the preservation of native signal peptide in the sequence has caused conflicts in processing and recognition in the past, which led to problems in expression and enzyme activity. With the main object being the improvement of the expression system, we eliminate the native signal peptide of human recombinant IDS. The resulting sequence showed two modified codons, thus, our study aimed to analyze computationally the nucleotide sequence of the IDSnh without signal peptide in order to determine the 3D structure and other biochemical properties to compare them with the native human IDS (IDSnh). Results showed that there are no significant differences between both molecules in spite of the two-codon modifications detected in the recombinant DNA sequence. PMID:27335624

Aspartylglucosaminuria: psychomotor retardation masquerading as a mucopolysaccharidosis.

PubMed

Isenberg, J N; Sharp, H L

1975-05-01

A 5-year-old girl with coarse facies, visceromegaly, and vacuolated lymphocytes is presented as the first case of aspartylglucosaminuria diagnosed in this country. This metabolic defect in glycoprotein catabolism can be clinically confused with other storage diseases such as the mucopolysaccharidoses and mucolipidoses. It is not diagnosed by routine laboratory screening methods. Special studies are required to confirm the diagnosis, but a thin-layer chromatography method for screening urine is presented for use when the diagnosis is suspected. The developmental potential in this inborn error of metabolism is documented.

Targeting Chondroitin Sulfate Glycosaminoglycans to Treat Cardiac Fibrosis in Pathological Remodeling.

PubMed

Zhao, Rong-Rong; Ackers-Johnson, Matthew; Stenzig, Justus; Chen, Chen; Ding, Tao; Zhou, Yue; Wang, Peipei; Ng, Shi Ling; Li, Peter Y; Teo, Gavin; Rudd, Pauline M; Fawcett, James W; Foo, Roger S Y

2018-06-05

Heart failure is a leading cause of mortality and morbidity, and the search for novel therapeutic approaches continues. In the monogenic disease mucopolysaccharidosis VI, loss-of-function mutations in arylsulfatase B lead to myocardial accumulation of chondroitin sulfate (CS) glycosaminoglycans, manifesting as myriad cardiac symptoms. Here, we studied changes in myocardial CS in nonmucopolysaccharidosis failing hearts and assessed its generic role in pathological cardiac remodeling. Healthy and diseased human and rat left ventricles were subjected to histological and immunostaining methods to analyze glycosaminoglycan distribution. Glycosaminoglycans were extracted and analyzed for quantitative and compositional changes with Alcian blue assay and liquid chromatography-mass spectrometry. Expression changes in 20 CS-related genes were studied in 3 primary human cardiac cell types and THP-1-derived macrophages under each of 9 in vitro stimulatory conditions. In 2 rat models of pathological remodeling induced by transverse aortic constriction or isoprenaline infusion, recombinant human arylsulfatase B (rhASB), clinically used as enzyme replacement therapy in mucopolysaccharidosis VI, was administered intravenously for 7 or 5 weeks, respectively. Cardiac function, myocardial fibrosis, and inflammation were assessed by echocardiography and histology. CS-interacting molecules were assessed with surface plasmon resonance, and a mechanism of action was verified in vitro. Failing human hearts displayed significant perivascular and interstitial CS accumulation, particularly in regions of intense fibrosis. Relative composition of CS disaccharides remained unchanged. Transforming growth factor-β induced CS upregulation in cardiac fibroblasts. CS accumulation was also observed in both the pressure-overload and the isoprenaline models of pathological remodeling in rats. Early treatment with rhASB in the transverse aortic constriction model and delayed treatment in the isoprenaline model proved rhASB to be effective at preventing cardiac deterioration and augmenting functional recovery. Functional improvement was accompanied by reduced myocardial inflammation and overall fibrosis. Tumor necrosis factor-α was identified as a direct binding partner of CS glycosaminoglycan chains, and rhASB reduced tumor necrosis factor-α-induced inflammatory gene activation in vitro in endothelial cells and macrophages. CS glycosaminoglycans accumulate during cardiac pathological remodeling and mediate myocardial inflammation and fibrosis. rhASB targets CS effectively as a novel therapeutic approach for the treatment of heart failure. © 2018 American Heart Association, Inc.

Laronidase.

PubMed

2002-01-01

BioMarin Pharmaceutical is developing laronidase, recombinant alpha-L-iduronidase enzyme replacement therapy for the treatment of mucopolysaccharidosis I (MPS-I) [the most severe form of this is called Hurler syndrome]. The company has received US and European orphan drug designation for the enzyme and has fast-track review status with the FDA. In 1998, BioMarin Pharmaceutical and Genzyme General formed a joint venture for development and marketing of laronidase. A Phase I trial in 10 patients with a range of disease severity of MPS-I required for US and European filing was completed at the Harbor-UCLA Medical Center in California. This open label trial involved weekly infusions with laronidase. The two-year follow-up data revealed sustained and, in certain parameters, improved clinical results recorded at the end of 1 year of therapy. BioMarin and Genzyme General have completed a pivotal, Phase III trial in the centres in the USA, Canada and Europe, including patients with Hurler-Scheie and Scheie syndromes. In a multicentre, double-blind, placebo-controlled study, all 45 patients with MPS-I have received at least their initial weekly infusion of laronidase. Patients are being evaluated over a 6-month period. BioMarin Pharmaceutical and Genzyme General have filed on 15 April 2002 the first portion of a 'rolling' BLA with the US FDA for use of laronidase in the treatment of MPS-I. The companies are planning to complete the BLA filing in Q3 2002. The application will include 6-month data from the ongoing open-label Phase III extension study and also the 6-month data from the placebo-controlled part of the Phase III study. In the open-label extension study, patients from both the treatment and placebo arms of the Phase III trial received weekly infusions of laronidase for at least 6 months. The response from the US FDA is anticipated during the H1 of 2003. Both companies plan to initiate two new clinical trials in patients with MPS-I. One study will enrol patients with MPS-I under 5 years old. Another study will investigate laronidase in patients with advanced clinical symptoms of MPS-I. Additionally, patients from the ongoing Phase III study will continue to receive treatment with laronidase. On 1 March 2002, BioMarin and Genzyme filed a marketing approval application with European regulatory authorities for AldurazymeOE for the treatment of MPS-I. Mucopolysaccharidosis I is a rare autosomal recessive lysosomal storage disorder caused by alpha-L-iduronidase deficiency. Its manifestations in children can include growth and developmental delay, enlargement of spleen and liver, skeletal deformity, cardiac and pulmonary impairment, vision or hearing loss and mental dysfunction. At present, bone marrow transplantation is the only available treatment.

Newborn screening for lysosomal storage disorders by tandem mass spectrometry in North East Italy.

PubMed

Burlina, Alberto B; Polo, Giulia; Salviati, Leonardo; Duro, Giovanni; Zizzo, Carmela; Dardis, Andrea; Bembi, Bruno; Cazzorla, Chiara; Rubert, Laura; Zordan, Roberta; Desnick, Robert J; Burlina, Alessandro P

2018-03-01

Lysosomal storage diseases (LSDs) are inborn errors of metabolism resulting from 50 different inherited disorders. The increasing availability of treatments and the importance of early intervention have stimulated newborn screening (NBS) to diagnose LSDs and permit early intervention to prevent irreversible impairment or severe disability. We present our experience screening newborns in North East Italy to identify neonates with Mucopolysaccharidosis type I (MPS I) and Pompe, Fabry, and Gaucher diseases. Activities of acid β-glucocerebrosidase (ABG; Gaucher), acid α-glucosidase (GAA; Pompe), acid α-galactosidase (GLA; Fabry), and acid α-L-iduronidase (IDUA; MPS-I) in dried blood spots (DBS) from all newborns during a 17-month period were determined by multiplexed tandem mass spectrometry (MS/MS) using the NeoLSD ® assay system. Enzymatic activity cutoff values were determined from 3500 anonymous newborn DBS. In the screening study, samples were retested if the value was below cutoff and a second spot was requested, with referral for confirmatory testing and medical evaluation if a low value was obtained. From September 2015 to January 2017, 44,411 newborns were screened for the four LSDs. We recalled 40 neonates (0.09%) for collection of a second DBS. Low activity was confirmed in 20, who had confirmatory testing. Ten of 20 had pathogenic mutations: two Pompe, two Gaucher, five Fabry, and one MPS-I. The incidences of Pompe and Gaucher diseases were similar (1/22,205), with Fabry disease the most frequent (1/8882) and MPS-I the rarest (1/44411). The combined incidence of the four disorders was 1/4411 births. Simultaneously determining multiple enzyme activities by MS/MS, with a focus on specific biochemical markers, successfully detected newborns with LSDs. The high incidence of these disorders supports this screening program.

Parental social support, coping strategies, resilience factors, stress, anxiety and depression levels in parents of children with MPS III (Sanfilippo syndrome) or children with intellectual disabilities (ID).

PubMed

Grant, Sheena; Cross, Elaine; Wraith, James Edmond; Jones, Simon; Mahon, Louise; Lomax, Michelle; Bigger, Brian; Hare, Dougal

2013-03-01

Mucopolysaccharidosis type III (MPS III, Sanfilippo syndrome) is a lysosomal storage disorder, caused by a deficiency in one of four enzymes involved in the catabolism of the glycosaminoglycan heparan sulphate. It is a degenerative disorder, with a progressive decline in children's intellectual and physical functioning. There is currently no cure for the disorder. To date there is a paucity of research on how this disorder impacts parents psychological functioning. Specifically, research in the area has failed to employ adequate control groups to assess if the impact of this disorder on parents psychological functioning differs from parenting a child with intellectual disability (ID). The current study examined child behaviour and parental psychological functioning in 23 parents of children with MPS III and 23 parents of children with ID. Parents completed postal questionnaires about their child's behaviour and abilities and their own psychological functioning. Parents of children with MPS III reported fewer behavioural difficulties as their child aged, more severe level of intellectual disability, and similar levels of perceived social support, coping techniques, stress, anxiety and depression levels as parents of children with ID. Both groups of parents scored above the clinical cut off for anxiety and depression. Parents of children with MPS III rated themselves as significantly less future-orientated and goal directed than parents of children with ID. Services should develop support packages for parents of children with MPS III that incorporate an understanding of the unique stressors and current-difficulty approach of this population. Future research should examine gender differences between parental psychological functioning, using mixed qualitative and quantitative approaches, and utilise matched developmental level and typically developing control groups.

Intrathecal enzyme replacement therapy reduces lysosomal storage in the brain and meninges of the canine model of MPS I.

PubMed

Kakkis, E; McEntee, M; Vogler, C; Le, S; Levy, B; Belichenko, P; Mobley, W; Dickson, P; Hanson, S; Passage, M

2004-01-01

Enzyme replacement therapy (ERT) has been developed for several lysosomal storage disorders, including mucopolysaccharidosis I (MPS I), and is effective at reducing lysosomal storage in many tissues and in ameliorating clinical disease. However, intravenous ERT does not adequately treat storage disease in the central nervous system (CNS), presumably due to effects of the blood-brain barrier on enzyme distribution. To circumvent this barrier, we studied whether intrathecal (IT) recombinant human alpha-L-iduronidase (rhIDU) could penetrate and treat the brain and meninges. An initial dose-response study showed that doses of 0.46-4.14 mg of IT rhIDU successfully penetrated the brain of normal dogs and reached tissue levels 5.6 to 18.9-fold normal overall and 2.7 to 5.9-fold normal in deep brain sections lacking CSF contact. To assess the efficacy and safety in treating lysosomal storage disease, four weekly doses of approximately 1 mg of IT rhIDU were administered to MPS I-affected dogs resulting in a mean 23- and 300-fold normal levels of iduronidase in total brain and meninges, respectively. Quantitative glycosaminoglycan (GAG) analysis showed that the IT treatment reduced mean total brain GAG to normal levels and achieved a 57% reduction in meningeal GAG levels accompanied by histologic improvement in lysosomal storage in all cell types. The dogs did develop a dose-dependent immune response against the recombinant human protein and a meningeal lymphocytic/plasmacytic infiltrate. The IT route of ERT administration may be an effective way to treat the CNS disease in MPS I and could be applicable to other lysosomal storage disorders.

Characterization of the Biosynthesis, Processing and Kinetic Mechanism of Action of the Enzyme Deficient in Mucopolysaccharidosis IIIC

PubMed Central

Fan, Xiaolian; Tkachyova, Ilona; Sinha, Ankit; Rigat, Brigitte; Mahuran, Don

2011-01-01

Heparin acetyl-CoA:alpha-glucosaminide N-acetyltransferase (N-acetyltransferase, EC 2.3.1.78) is an integral lysosomal membrane protein containing 11 transmembrane domains, encoded by the HGSNAT gene. Deficiencies of N-acetyltransferase lead to mucopolysaccharidosis IIIC. We demonstrate that contrary to a previous report, the N-acetyltransferase signal peptide is co-translationally cleaved and that this event is required for its intracellular transport to the lysosome. While we confirm that the N-acetyltransferase precursor polypeptide is processed in the lysosome into a small amino-terminal alpha- and a larger ß- chain, we further characterize this event by identifying the mature amino-terminus of each chain. We also demonstrate this processing step(s) is not, as previously reported, needed to produce a functional transferase, i.e., the precursor is active. We next optimize the biochemical assay procedure so that it remains linear as N-acetyltransferase is purified or protein-extracts containing N-acetyltransferase are diluted, by the inclusion of negatively charged lipids. We then use this assay to demonstrate that the purified single N-acetyltransferase protein is both necessary and sufficient to express transferase activity, and that N-acetyltransferase functions as a monomer. Finally, the kinetic mechanism of action of purified N-acetyltransferase was evaluated and found to be a random sequential mechanism involving the formation of a ternary complex with its two substrates; i.e., N-acetyltransferase does not operate through a ping-pong mechanism as previously reported. We confirm this conclusion by demonstrating experimentally that no acetylated enzyme intermediate is formed during the reaction. PMID:21957468

Enzyme replacement therapy in newborn mucopolysaccharidosis IVA mice: early treatment rescues bone lesions?

PubMed Central

Tomatsu, Shunji; Montaño, Adriana M.; Oikawa, Hirotaka; Dung, Vu Chi; Hashimoto, Amiko; Oguma, Toshihiro; Takahashi, Tatsuo; Shimada, Tsutomu; Orii, Tadao; Sly, William S.

2014-01-01

We treated mucopolysaccharidosis IVA (MPS IVA) mice to assess the effects of long-term enzyme replacement therapy (ERT) initiated at birth, since adult mice treated by ERT showed little improvement in bone pathology (1). To conduct ERT in newborn mice, we used recombinant human N-acetylgalactosamine-6-sulfate sulfatase (GALNS) produced in a CHO cell line. First, to observe the tissue distribution pattern, a dose of 250 units/g body weight was administered intravenously in MPS IVA mice at day 2 or 3. The infused enzyme was primarily recovered in liver and spleen, with detectable activity in bone and brain. Second, newborn ERT was conducted after tissue distribution study. The first injection of newborn ERT was performed intravenously, the second to fourth weekly injections were intraperitoneal, and the remaining injections from 5th to 14th week were intravenous into the tail vein. MPS IVA mice treated with GALNS showed clearance of lysosomal storage in liver, spleen, and sinus lining cells in bone marrow. The column structure of the growth plate was organized better than adult mice treated with ERT; however, hyaline and fibrous cartilage cells in femur, spine, ligaments, discs, synovium, and periosteum still had storage materials to some extent. Heart valves were refractory to the treatment. Levels of serum keratan sulfate were kept normal in newborn ERT mice. In conclusion, the enzyme, which enters the cartilage before the cartilage cell layer becomes mature, prevents disorganization of column structure. Early treatment from birth leads to partial remission of bone pathology in MPS IVA mouse. PMID:24953405

Effect of neonatal gene therapy on lumbar spine disease in mucopolysaccharidosis VII dogs

PubMed Central

Smith, Lachlan J; Martin, John T; O'Donnell, Patricia; Wang, Ping; Elliott, Dawn M; Haskins, Mark E; Ponder, Katherine P

2012-01-01

Mucopolysaccharidosis VII (MPS VII) is due to deficient β-glucuronidase (GUSB) activity, which leads to accumulation of chondroitin, heparan, and dermatan sulfate glycosaminoglycans in various tissues including those of the spine. Associated spine disease can be due to abnormalities in the vertebrae, the intervertebral discs, or other spine tissues. The goal of this study was to determine if neonatal gene therapy could prevent lumbar spine disease in MPS VII dogs. MPS VII dogs were injected intravenously with a retroviral vector (RV) expressing canine GUSB at 2 to 3 days after birth, which resulted in transduction of hepatocytes that secreted GUSB into blood. Expression was stable for up to 11 years, and mean survival was increased from 0.4 years in untreated dogs to 6.1 years in treated dogs. Despite a profound positive clinical effect, 6-month-old RV-treated MPS VII dogs still had hypoplastic ventral epiphyses with reduced calcification in the lumbar spine, which resulted in a reduced stiffness and increased range of motion that was not improved relative to untreated MPS VII dogs. At six to 11 years of age, ventral vertebrae remained hypoplastic in RV-treated MPS VII dogs, and there was desiccation of the nucleus pulposus in some discs. Histochemical staining demonstrated that discs did not have detectable GUSB activity despite high serum GUSB activity, which is likely due to poor diffusion into this relatively avascular structure. Thus, neonatal gene therapy cannot prevent lumbar spine disease in MPS VII dogs, which predicts that enzyme replacement therapy (ERT) will similarly be relatively ineffective even if started at birth. PMID:22510705

The effect of neonatal gene therapy on skeletal manifestations in mucopolysaccharidosis VII dogs after a decade.

PubMed

Xing, Elizabeth M; Knox, Van W; O'Donnell, Patricia A; Sikura, Tracey; Liu, Yuli; Wu, Susan; Casal, Margret L; Haskins, Mark E; Ponder, Katherine P

2013-06-01

Mucopolysaccharidosis (MPS) VII is a lysosomal storage disease due to deficient activity of β-glucuronidase (GUSB), and results in glycosaminoglycan accumulation. Skeletal manifestations include bone dysplasia, degenerative joint disease, and growth retardation. One gene therapy approach for MPS VII involves neonatal intravenous injection of a gamma retroviral vector expressing GUSB, which results in stable expression in liver and secretion of enzyme into blood at levels predicted to be similar or higher to enzyme replacement therapy. The goal of this study was to evaluate the long-term effect of neonatal gene therapy on skeletal manifestations in MPS VII dogs. Treated MPS VII dogs could walk throughout their lives, while untreated MPS VII dogs could not stand beyond 6 months and were dead by 2 years. Luxation of the coxofemoral joint and the patella, dysplasia of the acetabulum and supracondylar ridge, deep erosions of the distal femur, and synovial hyperplasia were reduced, and the quality of articular bone was improved in treated dogs at 6 to 11 years of age compared with untreated MPS VII dogs at 2 years or less. However, treated dogs continued to have osteophyte formation, cartilage abnormalities, and an abnormal gait. Enzyme activity was found near synovial blood vessels, and there was 2% as much GUSB activity in synovial fluid as in serum. We conclude that neonatal gene therapy reduces skeletal abnormalities in MPS VII dogs, but clinically-relevant abnormalities remain. Enzyme replacement therapy will probably have similar limitations long-term. Copyright © 2013 Elsevier Inc. All rights reserved.

Pathogenesis of mitral valve disease in mucopolysaccharidosis VII dogs.

PubMed

Bigg, Paul W; Baldo, Guilherme; Sleeper, Meg M; O'Donnell, Patricia A; Bai, Hanqing; Rokkam, Venkata R P; Liu, Yuli; Wu, Susan; Giugliani, Roberto; Casal, Margret L; Haskins, Mark E; Ponder, Katherine P

2013-11-01

Mucopolysaccharidosis VII (MPS VII) is due to the deficient activity of β-glucuronidase (GUSB) and results in the accumulation of glycosaminoglycans (GAGs) in lysosomes and multisystemic disease with cardiovascular manifestations. The goal here was to determine the pathogenesis of mitral valve (MV) disease in MPS VII dogs. Untreated MPS VII dogs had a marked reduction in the histochemical signal for structurally-intact collagen in the MV at 6 months of age, when mitral regurgitation had developed. Electron microscopy demonstrated that collagen fibrils were of normal diameter, but failed to align into large parallel arrays. mRNA analysis demonstrated a modest reduction in the expression of genes that encode collagen or collagen-associated proteins such as the proteoglycan decorin which helps collagen fibrils assemble, and a marked increase for genes that encode proteases such as cathepsins. Indeed, enzyme activity for cathepsin B (CtsB) was 19-fold normal. MPS VII dogs that received neonatal intravenous injection of a gamma retroviral vector had an improved signal for structurally-intact collagen, and reduced CtsB activity relative to that seen in untreated MPS VII dogs. We conclude that MR in untreated MPS VII dogs was likely due to abnormalities in MV collagen structure. This could be due to upregulation of enzymes that degrade collagen or collagen-associated proteins, to the accumulation of GAGs that compete with proteoglycans such as decorin for binding to collagen, or to other causes. Further delineation of the etiology of abnormal collagen structure may lead to treatments that improve biomechanical properties of the MV and other tissues. © 2013.

Pathogenesis of Mitral Valve Disease in Mucopolysaccharidosis VII Dogs

PubMed Central

Bigg, Paul W.; Baldo, Guilherme; Sleeper, Meg M.; O'Donnell, Patricia A.; Bai, Hanqing; Rokkam, Venkata R.P.; Liu, Yuli; Wu, Susan; Giugliani, Roberto; Casal, Margret L.; Haskins, Mark E.; Ponder, Katherine P.

2013-01-01

Mucopolysaccharidosis VII (MPS VII) is due to deficient activity of β-glucuronidase (GUSB) and results in the accumulation of glycosaminoglycans (GAGs) in lysosomes and multisystemic disease with cardiavascular manifestations. The goal here was to determine the pathogenesis of mitral valve (MV) disease in MPS VII dogs. Untreated MPS VII dogs had a marked reduction in the histochemical signal for structurally-intact collagen in the MV at 6 months of age, when mitral regurgitation had developed. Electron microscopy demonstrated that collagen fibrils were of normal diameter, but failed to align into large parallel arrays. mRNA analysis demonstrated a modest reduction in the expression of genes that encode collagen or collagen-associated proteins such as the proteoglycan decorin which helps collagen fibrils assemble, and a marked increase for genes that encode proteases such as cathepsins. Indeed, enzyme activity for cathepsin B (CtsB) was 19-fold normal. MPS VII dogs that received neonatal intravenous injection of a gamma retroviral vector had an improved signal for structurally-intact collagen, and reduced CtsB activity relative to that seen in untreated MPS VII dogs. We conclude that MR in untreated MPS VII dogs was likely due to abnormalities in MV collagen structure. This could be due to upregulation of enzymes that degrade collagen or collagen-associated proteins, to the accumulation of GAGs that compete with proteoglycans such as decorin for binding to collagen, or to other causes. Further delineation of the etiology of abnormal collagen structure may lead to treatments that improve biomechanical properties of the MV and other tissues. PMID:23856419

Mucopolysaccharidosis enzyme production by bone marrow and dental pulp derived human mesenchymal stem cells.

PubMed

Jackson, Matilda; Derrick Roberts, Ainslie; Martin, Ellenore; Rout-Pitt, Nathan; Gronthos, Stan; Byers, Sharon

2015-04-01

Mucopolysaccharidoses (MPS) are inherited metabolic disorders that arise from a complete loss or a reduction in one of eleven specific lysosomal enzymes. MPS children display pathology in multiple cell types leading to tissue and organ failure and early death. Mesenchymal stem cells (MSCs) give rise to many of the cell types affected in MPS, including those that are refractory to current treatment protocols such as hematopoietic stem cell (HSC) based therapy. In this study we compared multiple MPS enzyme production by bone marrow derived (hBM) and dental pulp derived (hDP) MSCs to enzyme production by HSCs. hBM MSCs produce significantly higher levels of MPS I, II, IIIA, IVA, VI and VII enzyme than HSCs, while hDP MSCs produce significantly higher levels of MPS I, IIIA, IVA, VI and VII enzymes. Higher transfection efficiency was observed in MSCs (89%) compared to HSCs (23%) using a lentiviral vector. Over-expression of four different lysosomal enzymes resulted in up to 9303-fold and up to 5559-fold greater levels in MSC cell layer and media respectively. Stable, persistent transduction of MSCs and sustained over-expression of MPS VII enzyme was observed in vitro. Transduction of MSCs did not affect the ability of the cells to differentiate down osteogenic, adipogenic or chondrogenic lineages, but did partially delay differentiation down the non-mesodermal neurogenic lineage. Copyright © 2015 Elsevier Inc. All rights reserved.

Clinical response to long term enzyme replacement treatment in children, adolescent and adult patients with Hunter syndrome.

PubMed

Dalmau Serra, Jaime; Vitoria Miñana, Isidro; Calderón Fernández, Rafael; Cortell Aznar, Isidoro

2015-11-06

Since enzyme replacement treatment (ERT) with idursulfase is available for Hunter syndrome (HS; mucopolysaccharidosis type II), for the first time, disease progression can be limited and organ damage reduced or prevented. We described retrospectively the clinical evolution of eight HS males, treated with ERT and followed in routine clinical practice in Hospital Infantil La Fe (Valencia, Spain). We studied three children, three adolescents and two adults. Time from diagnosis to ERT ranged from 13.7 to 0.2 years, and duration of ERT ranged from 24 to 77.1 months. From the start of ERT, weight and height increased in children and adolescents and remained stable in adults. Glycosaminoglycans (GAG) decreased in all patients; in patient 5 (aged 23 years), we observed the highest reduction (86%) with recovery of carpal tunnel syndrome, splenomegaly and a decrease in nocturnal oxygen dependence. Our results show that ERT improve respiratory impairment and organomegalies and decrease GAGs levels in all patients including children, adolescent and adults. While cardiac manifestations and facial features stabilized, responses in other parameters were heterogeneous. Copyright © 2015 Elsevier España, S.L.U. All rights reserved.

Enzyme replacement therapy started at birth improves outcome in difficult-to-treat organs in mucopolysaccharidosis I mice.

PubMed

Baldo, Guilherme; Mayer, Fabiana Q; Martinelli, Bárbara Z; de Carvalho, Talita G; Meyer, Fabiola S; de Oliveira, Patrícia G; Meurer, Luise; Tavares, Angela; Matte, Ursula; Giugliani, Roberto

2013-05-01

Since we previously observed that in patients with mucopolysaccharidosis (MPS) the storage of undegraded glycosaminoglycans (GAG) occurs from birth, in the present study we aimed to compare normal, untreated MPS I mice (knockout for alpha-l-iduronidase-IDUA), and MPS I mice treated with enzyme replacement therapy (ERT, Laronidase, 1.2mg/kg every 2 weeks) started from birth (ERT-neo) or from 2 months of age (ERT-ad). All mice were sacrificed at 6 months. Both treatments were equally effective in normalizing GAG levels in the viscera but had no detectable effect on the joint. Heart function was also improved with both treatments. On the other hand, mice treated from birth presented better outcomes in the difficult-to-treat aortas and heart valves. Surprisingly, both groups had improvements in behavior tests, and normalization of GAG levels in the brain and IDUA injection resulted in detectable levels of enzyme in the brain tissue 1h after administration. ERT-ad mice developed significantly more anti-IDUA-IgG antibodies, and mice that didn't develop antibodies had better performances in behavior tests, indicating that development of antibodies may reduce enzyme bioavailability. Our results suggest that ERT started from birth leads to better outcomes in the aorta and heart valves, as well as a reduction in antibody levels. Some poor vascularized organs, such as the joints, had partial or no benefit and ancillary therapies might be needed for patients. The results presented here support the idea that ERT started from birth leads to better treatment outcomes and should be considered whenever possible, a observation that gains relevance as newborn screening programs are being considered for MPS and other treatable lysosomal storage disorders. Copyright © 2013 Elsevier Inc. All rights reserved.

Pathogenesis of aortic dilatation in mucopolysaccharidosis VII mice may involve complement activation

PubMed Central

Baldo, Guilherme; Wu, Susan; Howe, Ruth A.; Ramamoothy, Meera; Knutsen, Russell H.; Fang, Jiali; Mecham, Robert P.; Liu, Yuli; Wu, Xiaobo; Atkinson, John P.; Ponder, Katherine P.

2012-01-01

Mucopolysaccharidosis VII (MPS VII) is due to mutations within the gene encoding the lysosomal enzyme β-glucuronidase, and results in the accumulation of glycosaminoglycans. MPS VII causes aortic dilatation and elastin fragmentation, which is associated with upregulation of the elastases cathepsin S (CtsS) and matrix metalloproteinase 12 (MMP12). To test the role of these enzymes, MPS VII mice were crossed with mice deficient in CtsS or MMP12, and the effect upon aortic dilatation was determined. CtsS deficiency did not protect against aortic dilatation in MPS VII mice, but also failed to prevent an upregulation of cathepsin enzyme activity. Further analysis with substrates and inhibitors specific for particular cathepsins suggests that this enzyme activity was due to CtsB, which could contribute to elastin fragmentation. Similarly, MMP12 deficiency and deficiency of both MMP12 and CtsS could not prevent aortic dilatation in MPS VII mice. Microarray and reverse-transcriptase real-time PCR were performed to look for upregulation of other elastases. This demonstrated that mRNA for complement component D was elevated in MPS VII mice, while immunostaining demonstrated high levels of complement component C3 on surfaces within the aortic media. Finally, we demonstrate that neonatal intravenous injection of a retroviral vector encoding β-glucuronidase reduced aortic dilatation. We conclude that neither CtsS nor MMP12 are necessary for elastin fragmentation in MPS VII mouse aorta, and propose that CtsB and/or complement component D may be involved. Complement may be activated by the GAGs that accumulate, and may play a role in signal transduction pathways that upregulate elastases. PMID:21944884

N-butyldeoxynojirimycin treatment restores the innate fear response and improves learning in mucopolysaccharidosis IIIA mice.

PubMed

Kaidonis, Xenia; Byers, Sharon; Ranieri, Enzo; Sharp, Peter; Fletcher, Janice; Derrick-Roberts, Ainslie

2016-06-01

Mucopolysaccharidosis IIIA is a heritable neurodegenerative disorder resulting from the dysfunction of the lysosomal hydrolase sulphamidase. This leads to the primary accumulation of the complex carbohydrate heparan sulphate in a wide range of tissues and the secondary neuronal storage of gangliosides GM2 and GM3 in the brain. GM2 storage is associated with CNS deterioration in the GM2 gangliosidosis group of lysosomal storage disorders and may also contribute to MPS CNS disease. N-butyldeoxynojirimycin, an inhibitor of ceramide glucosyltransferase activity and therefore of ganglioside synthesis, was administered to MPS IIIA mice both prior to maximal GM2 and GM3 accumulation (early treatment) and after the maximum level of ganglioside had accumulated in the brain (late treatment) to determine if behaviour was altered by ganglioside level. Ceramide glucosyltransferase activity was decreased in both treatment groups; however, brain ganglioside levels were only decreased in the late treatment group. Learning in the water cross maze was improved in both groups and the innate fear response was also restored in both groups. A reduction in the expression of inflammatory gene Ccl3 was observed in the early treatment group, while IL1β expression was reduced in both treatment groups. Thus, it appears that NB-DNJ elicits a transient decrease in brain ganglioside levels, some modulation of inflammatory cytokines and a functional improvement in behaviour that can be elicited both before and after overt neurological changes manifest. NB-DNJ improves learning and restores the innate fear response in MPS IIIA mice by decreasing ceramide glucosyltransferase activity and transiently reducing ganglioside storage and/or modulating inflammatory signals. Copyright © 2016 Elsevier Inc. All rights reserved.

Effect of neonatal gene therapy on lumbar spine disease in mucopolysaccharidosis VII dogs.

PubMed

Smith, Lachlan J; Martin, John T; O'Donnell, Patricia; Wang, Ping; Elliott, Dawn M; Haskins, Mark E; Ponder, Katherine P

2012-09-01

Mucopolysaccharidosis VII (MPS VII) is due to deficient β-glucuronidase (GUSB) activity, which leads to accumulation of chondroitin, heparan, and dermatan sulfate glycosaminoglycans in various tissues including those of the spine. Associated spine disease can be due to abnormalities in the vertebrae, the intervertebral disks, or other spine tissues. The goal of this study was to determine if neonatal gene therapy could prevent lumbar spine disease in MPS VII dogs. MPS VII dogs were injected intravenously with a retroviral vector (RV) expressing canine GUSB at 2 to 3 days after birth, which resulted in transduction of hepatocytes that secreted GUSB into blood. Expression was stable for up to 11 years, and mean survival was increased from 0.4 years in untreated dogs to 6.1 years in treated dogs. Despite a profound positive clinical effect, 6-month-old RV-treated MPS VII dogs still had hypoplastic ventral epiphyses with reduced calcification in the lumbar spine, which resulted in a reduced stiffness and increased range of motion that were not improved relative to untreated MPS VII dogs. At six to 11 years of age, ventral vertebrae remained hypoplastic in RV-treated MPS VII dogs, and there was desiccation of the nucleus pulposus in some disks. Histochemical staining demonstrated that disks did not have detectable GUSB activity despite high serum GUSB activity, which is likely due to poor diffusion into this relatively avascular structure. Thus, neonatal gene therapy cannot prevent lumbar spine disease in MPS VII dogs, which predicts that enzyme replacement therapy (ERT) will similarly be relatively ineffective even if started at birth. Copyright © 2012 Elsevier Inc. All rights reserved.

Social/economic costs and health-related quality of life of mucopolysaccharidosis patients and their caregivers in Europe.

PubMed

Péntek, Márta; Gulácsi, László; Brodszky, Valentin; Baji, Petra; Boncz, Imre; Pogány, Gábor; López-Bastida, Julio; Linertová, Renata; Oliva-Moreno, Juan; Serrano-Aguilar, Pedro; Posada-de-la-Paz, Manuel; Taruscio, Domenica; Iskrov, Georgi; Schieppati, Arrigo; von der Schulenburg, Johann Matthias Graf; Kanavos, Panos; Chevreul, Karine; Persson, Ulf; Fattore, Giovanni

2016-04-01

To assess the health-related quality of life (HRQOL) of patients with mucopolysaccharidosis (MPS) and their caregivers and to quantify the disease-related costs from a societal perspective. In the context of a multi-country study of rare diseases (BURQOL-RD project), a cross-sectional survey was performed among MPS patients in seven European countries. Data on demographic characteristics, health resource utilization, informal care, and loss of labor productivity were collected. The EQ-5D, Barthel index (BI), and Zarit burden interview (ZBI) questionnaires were used to assess patients' and their informal caregivers' quality of life, patients' functional ability, and caregivers' burden, respectively. Altogether, 120 patients (children 62 %, females 40 %) and 66 caregivers completed the questionnaire. Patients' mean age was 16.5 years and median age at diagnosis was 3 years. Adult patients' average EQ-5D and EQ VAS scores varied across countries from 0.13 to 0.43 and 30.0 to 62.2, respectively, mean BI was 46.7, and ZBI was 32.7. Mean informal care time was 51.3 h/week. The mean total annual cost per patient (reference year 2012) was €24,520 in Hungary, €25,993 in France, €84,921 in Italy, €94,384 in Spain, and €209,420 in Germany. Costs are also shown to differ between children and adults. Direct costs accounted for most of the costs in all five countries (80, 100, 99, 98, and 93 %, respectively). MPS patients experience substantial loss of HRQOL and their families take a remarkable part in their care. Although utilization of health and social care resources varies significantly across countries, MPS incurs considerable societal costs in all the countries studied.

PATIENT-REPORTED OUTCOMES IN RARE LYSOSOMAL STORAGE DISEASES: KEY INFORMANT INTERVIEWS AND A SYSTEMATIC REVIEW PROTOCOL.

PubMed

Miller, Patricia A; Mulla, Sohail M; Adams-Webber, Thomasin; Sivji, Yasmin; Guyatt, Gordon H; Johnston, Bradley C

2016-01-01

To investigate the use, challenges and opportunities associated with using patient-reported outcomes (PROs) in studies with patients with rare lysosomal storage diseases (LSDs), we conducted interviews with researchers and health technology assessment (HTA) experts, and developed the methods for a systematic review of the literature. The purpose of the review is to identify the psychometrically sound generic and disease-specific PROs used in studies with patients with five LSDs of interest: Fabry, Gaucher (Type I), Niemann-Pick (Type B) and Pompe diseases, and mucopolysaccharidosis (Types I and II). Researchers and HTA experts who responded to an email invitation participated in a telephone interview. We used qualitative content analysis to analyze the anonymized transcripts. We conducted a comprehensive literature search for studies that used PROs to investigate burden of disease or to assess the impact of interventions across the five LSDs of interest. Interviews with seven researchers and six HTA experts representing eight countries revealed five themes. These were: (i) the importance of using psychometrically sound PROs in studies with rare diseases, (ii) the paucity of disease-specific PROs, (iii) the importance of having PRO data for economic analyses, (iv) practical and psychometric limitations of existing PROs, and (v) suggestions for new PROs. The systematic review has been completed. The interviews highlight current challenges and opportunities experienced by researchers and HTA experts involved in work with rare LSDs. The ongoing systematic review will highlight the experience, opportunities, and limitations of PROs in LSDs and provide suggestions for future research.

Activity of daily living for Morquio A syndrome.

PubMed

Yasuda, Eriko; Suzuki, Yasuyuki; Shimada, Tsutomu; Sawamoto, Kazuki; Mackenzie, William G; Theroux, Mary C; Pizarro, Christian; Xie, Li; Miller, Freeman; Rahman, Tariq; Kecskemethy, Heidi H; Nagao, Kyoko; Morlet, Thierry; Shaffer, Thomas H; Chinen, Yasutsugu; Yabe, Hiromasa; Tanaka, Akemi; Shintaku, Haruo; Orii, Kenji E; Orii, Koji O; Mason, Robert W; Montaño, Adriana M; Fukao, Toshiyuki; Orii, Tadao; Tomatsu, Shunji

2016-06-01

The aim of this study was to evaluate the activity of daily living (ADL) and surgical interventions in patients with mucopolysaccharidosis IVA (MPS IVA). The factor(s) that affect ADL are age, clinical phenotypes, surgical interventions, therapeutic effect, and body mass index. The ADL questionnaire comprises three domains: "Movement," "Movement with cognition," and "Cognition." Each domain has four subcategories rated on a 5-point scale based on the level of assistance. The questionnaire was collected from 145 healthy controls and 82 patients with MPS IVA. The patient cohort consisted of 63 severe and 17 attenuated phenotypes (2 were undefined); 4 patients treated with hematopoietic stem cell transplantation (HSCT), 33 patients treated with enzyme replacement therapy (ERT) for more than a year, and 45 untreated patients. MPS IVA patients show a decline in ADL scores after 10years of age. Patients with a severe phenotype have a lower ADL score than healthy control subjects, and lower scores than patients with an attenuated phenotype in domains of "Movement" and "Movement with cognition." Patients, who underwent HSCT and were followed up for over 10years, had higher ADL scores and fewer surgical interventions than untreated patients. ADL scores for ERT patients (2.5years follow-up on average) were similar with the-age-matched controls below 10years of age, but declined in older patients. Surgical frequency was higher for severe phenotypic patients than attenuated ones. Surgical frequency for patients treated with ERT was not decreased compared to untreated patients. In conclusion, we have shown the utility of the proposed ADL questionnaire and frequency of surgical interventions in patients with MPS IVA to evaluate the clinical severity and therapeutic efficacy compared with age-matched controls. Copyright © 2016. Published by Elsevier Inc.

4th Rare Disease South Eastern Europe (See) Meeting Skopje, Macedonia (November 14th, 2015).

PubMed

Gucev, Zoran; Tasic, Velibor; Polenakovic, Momir

2015-01-01

The 4th meeting on rare diseases in South Eastern Europe (SEE) was held in Skopje, at the Macedonian Academy of Sciences and Arts (MASA) on the 14(th) of November 2015. The focuses were metabolic, rare brain diseases as well as the rare dysmorphic syndrome. The authors of the report are particularly keen on stating that one of the main goals of the meeting, namely to help the treatment of patients with rare disease has begun to bear fruits. The talk on an iminosugar-based pharmacological chaperone compound as a drug candidate for the treatment of GM1-gangliosidosis and mucopolysaccharidosis IVB (Morquio disease type B) was enlightening. To date, there is no treatment available to be offered to patients, but chaperones lead mutated proteins to adopt a native-like conformation and to successfully traffic to their normal cellular destination. DORPHAN is developing an iminosugar-based pharmacological chaperone compound for the treatment of GM1-gangliosidosis and mucopolysaccharidosis IVB. A talk on recent developments in the laboratory diagnosis of mucopolysaccharidoses (MPS) was particularly interesting, covering the laboratory diagnosis of the MPS diseases by a strategy of clinical examination, biochemical analysis of urine samples, enzyme tests and genetic characterization of underlying mutations. New techniques were developed, including analysis of urinary glycosaminoglycans with tandem mass spectrometry, miniaturized enzyme tests or novel synthetic substrates for enzyme assays using mass spectrometry detection of products using dried blood spots. Feasibility and cost-effectiveness of these methods in newborn screening programs have been demonstrated. Neuromuscular RDs, and especially familial amyloid polyneuropathy (FAP) were a topic of the Bulgarian colleagues. Diagnosis, screening and the role of microglia were also topics of particular interest. In summary, this year RD meeting was exciting and productive on a wide range of diseases and on a novel insights on diagnosis and treatment. New methods are expanding our capabilities for a fast and precise diagnosis. Novel knowledge offers better distinction on whom to treat with which medications (e.g. steroid dependent nephrotic syndrome). Novel diseases or variants are published (segmental overgrowth). The authors of the report are particularly keen on stating that one of the main goals of the meeting, namely to help the treatment of patients with rare disease has begun to bear fruits. Namely, the Health Fund of Macedonia for the first time treats the patients with Gaucher's disease. We are hopeful that the number of patients treated for Gaucher's disease and the number of treated patients with other treatable RDs diseases will continue to grow.

AGE-RELATED FUNCTIONAL AND HISTOPATHOLOGICAL CHANGES OF THE EAR IN THE MPS I MOUSE

PubMed Central

Schachern, Patricia A.; Cureoglu, Sebahattin; Tsuprun, Vladimir; Paparella, Michael M.; Whitley, Chester

2007-01-01

Objective Mucopolysaccharidosis type I (MPS I) is an autosomal recessive disorder caused by a mutation in the gene encoding the enzyme α-L-iduronidase. This enzyme is responsible for degradation of dermatan and heparan sulfates. Enzyme deficiency results in their accumulation in lysosomes of virtually all organs, resulting in severe somatic and neurological changes. Clinical findings of otitis media with mixed hearing loss are common. Cellular and molecular mechanisms of ear pathology and hearing loss are not understood. The purpose of this study is to describe the age-related audiologic and histopathologic changes of the ear in the mouse model of MPS I. Methods Auditory brainstemresponses (ABR) were obtained to clicks and tone bursts at 1-32 kHz, and pathological changes to middle and inner ears were studied with light and electron microscopy in fifty-three mice that included: 1) wild type (+/+) - five at 2 months, five at 4 to 6 months, and five at 13 to 19 months; 2) heterozygotes (+/−) - four at 2 months; five at 4 to 6 months; and eight at 13 to 19 months; and 3) homozygotes (−/−); five at 2 months; six at 4 to 6 months; and five at 13 to 19 months. Histopathology was also done on five newborn −/− mice. Results In newborns no lysosomal storage was observed and the ear appeared age appropriately normal. In all other −/− mice, cells with lysosomal storage vacuoles were observed in spiral ligament, spiral prominence, spiral limbus, basilar membrane, epithelial and mesothelial cells of Reissner’s membrane, endothelial cells of vessels, and some ganglion cells; their number increased with aging. Hair cell loss was not observed at 2 or 6 months, but there was total loss of the organ of Corti in year-old mice. Hearing of −/− mice was significantly decreased at all ages compared to +/+ and +/−. Hearing loss progressed from mild to moderate loss at 2 months to profound at 6 months and total deafness by one year of age. Conclusions Progressive age-related changes suggest early therapeutic intervention to prevent sensory cell damage and hearing loss. PMID:17101178

Toward reducing immunogenicity of enzyme replacement therapy: altering the specificity of human β-glucuronidase to compensate for α-iduronidase deficiency.

PubMed

Chuang, Huai-Yao; Suen, Ching-Shu; Hwang, Ming-Jing; Roffler, Steve R

2015-11-01

Enzyme replacement therapy (ERT) is an effective treatment for many patients with lysosomal storage disorders caused by deficiency in enzymes involved in cell metabolism. However, immune responses that develop against the administered enzyme in some patients can hinder therapeutic efficacy and cause serious side effects. Here we investigated the feasibility of a general approach to decrease ERT immunogenicity by altering the specificity of a normal endogenous enzyme to compensate for a defective enzyme. We sought to identify human β-glucuronidase variants that display α-iduronidase activity, which is defective in mucopolysaccharidosis (MPS) type I patients. A human β-glucuronidase library was screened by the Enzyme Cleavable Surface-Tethered All-purpose Screen sYstem to isolate variants that exhibited 100-290-fold greater activity against the α-iduronidase substrate 4-methylumbelliferyl α-l-iduronide and 7900-24 500-fold enzymatic specificity shift when compared with wild-type β-glucuronidase. In vitro treatment of MPS I cells with the β-glucuronidase variants significantly restored lysosome appearance similar to treatment with α-iduronidase. Our study suggests that β-glucuronidase variants can be isolated to display α-iduronidase activity and produce significant phenotype improvement of MPS I cells. This strategy may represent a possible approach to produce enzymes that display therapeutic benefits with potentially less immunogenicity. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

The effect of idursulfase on growth in patients with Hunter syndrome: data from the Hunter Outcome Survey (HOS).

PubMed

Jones, Simon A; Parini, Rossella; Harmatz, Paul; Giugliani, Roberto; Fang, Juanzhi; Mendelsohn, Nancy J

2013-05-01

Hunter syndrome (mucopolysaccharidosis type II) is a rare and life-limiting multisystemic disorder with an X-linked recessive pattern of inheritance. Short stature is a prominent feature of this condition. This analysis aimed to investigate the effects of enzyme replacement therapy with idursulfase on growth in patients enrolled in HOS - the Hunter Outcome Survey which is a multinational observational database. As of Jan 2012, height data before treatment were available for 567 of 740 males followed prospectively after HOS entry. Cross-sectional analysis showed that short stature became apparent after approximately 8 years of age; before this, height remained within the normal range. Age-corrected standardized height scores (z-scores) before and after treatment were assessed using piecewise regression model analysis in 133 patients (8-15 years of age at treatment start; data available on ≥ 1 occasion within +/-24 months of treatment start; growth hormone-treated patients excluded). Results showed that the slope after treatment (slope=-0.005) was significantly improved compared with before treatment (slope=-0.043) (difference=0.038, p=0.004). Analysis of covariates (age at treatment start, cognitive involvement, presence of puberty at the start of ERT, mutation type, functional classification), showed a significant influence on growth of mutation type (height deficit in terms of z-scores most pronounced in patients with deletions/large rearrangements/nonsense mutations, p<0.0001) and age (most pronounced in the 12-15-year group, p<0.0001). Cognitive involvement, pubertal status at the start of ERT and functional classification were not related to the growth deficit or response to treatment. In conclusion, the data showed an improvement in growth rate in patients with Hunter syndrome following idursulfase treatment. Copyright © 2013 Elsevier Inc. All rights reserved.

Elevation of glycosaminoglycans in the amniotic fluid of a fetus with mucopolysaccharidosis VII

PubMed Central

Kubaski, Francyne; Brusius-Facchin, Ana Carolina; Mason, Robert W.; Patel, Pravin; Burin, Maira G.; Michelin-Tirelli, Kristiane; Kessler, Rejane Gus; Bender, Fernanda; Leistner-Segal, Sandra; Moreno, Carolina A.; Cavalcanti, Denise P.; Giugliani, Roberto; Tomatsu, Shunji

2017-01-01

Objective The aim of this study was to quantify GAGs in amniotic fluid (AF) from an MPS VII fetus compared with age-matched fetuses obtained from normal pregnancies. Method Disaccharides were measured by liquid chromatography tandem mass spectrometry (LC/MS/MS), compared to age-matched controls. Enzyme assay was performed in AF supernatant or cultured amniocytes. GUSB was analyzed by next generation sequencing using Ion Torrent Personal Genome Machine with a customized panel. Results No activity of β-glucuronidase was detected in fetal cells. The pregnancy was spontaneously terminated in the third trimester. Genetic studies identified a homozygous mutation of p.N379D (c.1135A>G) in the GUSB gene. LC/MS/MS showed that chondroitin sulfate, dermatan sulfate, heparan sulfate, and keratan sulfate levels were markedly increased in the MPS VII AF, compared to those in age-matched control AF (DS, HS, and C6S more than 10 × than age-matched controls; C4S and KS more than 3 times higher). Conclusion This is the first report of specific GAG analysis in AF from an MPS VII fetus, indicating that GAG elevation in AF occurs by 21 weeks of gestation and could be an additional tool for prenatal diagnosis of MPS VII and potentially other MPS types. PMID:28207930

Glial degeneration with oxidative damage drives neuronal demise in MPSII disease

PubMed Central

Zalfa, Cristina; Verpelli, Chiara; D'Avanzo, Francesca; Tomanin, Rosella; Vicidomini, Cinzia; Cajola, Laura; Manara, Renzo; Sala, Carlo; Scarpa, Maurizio; Vescovi, Angelo Luigi; De Filippis, Lidia

2016-01-01

Mucopolysaccharidosis type II (MPSII) is a lysosomal storage disorder due to the deficit of the iduronate 2-sulfatase (IDS) enzyme, causing progressive neurodegeneration in patients. Neural stem cells (NSCs) derived from the IDS-ko mouse can recapitulate MPSII pathogenesis in vitro. In differentiating IDS-ko NSCs and in the aging IDS-ko mouse brain, glial degeneration precedes neuronal degeneration. Here we show that pure IDS-ko NSC-derived astrocytes are selectively able to drive neuronal degeneration when cocultured with healthy neurons. This phenotype suggests concurrent oxidative damage with metabolic dysfunction. Similar patterns were observed in murine IDS-ko animals and in human MPSII brains. Most importantly, the mutant phenotype of IDS-ko astrocytes was reversed by low oxygen conditions and treatment with vitamin E, which also reversed the toxic effect on cocultured neurons. Moreover, at very early stages of disease we detected in vivo the development of a neuroinflammatory background that precedes astroglial degeneration, thus suggesting a novel model of MPSII pathogenesis, with neuroinflammation preceding glial degeneration, which is finally followed by neuronal death. This hypothesis is also consistent with the progression of white matter abnormalities in MPSII patients. Our study represents a novel breakthrough in the elucidation of MPSII brain pathogenesis and suggests the antioxidant molecules as potential therapeutic tools to delay MPSII onset and progression. PMID:27512952

AAV Gene Therapy for MPS1-associated Corneal Blindness.

PubMed

Vance, Melisa; Llanga, Telmo; Bennett, Will; Woodard, Kenton; Murlidharan, Giridhar; Chungfat, Neil; Asokan, Aravind; Gilger, Brian; Kurtzberg, Joanne; Samulski, R Jude; Hirsch, Matthew L

2016-02-22

Although cord blood transplantation has significantly extended the lifespan of mucopolysaccharidosis type 1 (MPS1) patients, over 95% manifest cornea clouding with about 50% progressing to blindness. As corneal transplants are met with high rejection rates in MPS1 children, there remains no treatment to prevent blindness or restore vision in MPS1 children. Since MPS1 is caused by mutations in idua, which encodes alpha-L-iduronidase, a gene addition strategy to prevent, and potentially reverse, MPS1-associated corneal blindness was investigated. Initially, a codon optimized idua cDNA expression cassette (opt-IDUA) was validated for IDUA production and function following adeno-associated virus (AAV) vector transduction of MPS1 patient fibroblasts. Then, an AAV serotype evaluation in human cornea explants identified an AAV8 and 9 chimeric capsid (8G9) as most efficient for transduction. AAV8G9-opt-IDUA administered to human corneas via intrastromal injection demonstrated widespread transduction, which included cells that naturally produce IDUA, and resulted in a >10-fold supraphysiological increase in IDUA activity. No significant apoptosis related to AAV vectors or IDUA was observed under any conditions in both human corneas and MPS1 patient fibroblasts. The collective preclinical data demonstrate safe and efficient IDUA delivery to human corneas, which may prevent and potentially reverse MPS1-associated cornea blindness.

AAV Gene Therapy for MPS1-associated Corneal Blindness

PubMed Central

Vance, Melisa; Llanga, Telmo; Bennett, Will; Woodard, Kenton; Murlidharan, Giridhar; Chungfat, Neil; Asokan, Aravind; Gilger, Brian; Kurtzberg, Joanne; Samulski, R. Jude; Hirsch, Matthew L.

2016-01-01

Although cord blood transplantation has significantly extended the lifespan of mucopolysaccharidosis type 1 (MPS1) patients, over 95% manifest cornea clouding with about 50% progressing to blindness. As corneal transplants are met with high rejection rates in MPS1 children, there remains no treatment to prevent blindness or restore vision in MPS1 children. Since MPS1 is caused by mutations in idua, which encodes alpha-L-iduronidase, a gene addition strategy to prevent, and potentially reverse, MPS1-associated corneal blindness was investigated. Initially, a codon optimized idua cDNA expression cassette (opt-IDUA) was validated for IDUA production and function following adeno-associated virus (AAV) vector transduction of MPS1 patient fibroblasts. Then, an AAV serotype evaluation in human cornea explants identified an AAV8 and 9 chimeric capsid (8G9) as most efficient for transduction. AAV8G9-opt-IDUA administered to human corneas via intrastromal injection demonstrated widespread transduction, which included cells that naturally produce IDUA, and resulted in a >10-fold supraphysiological increase in IDUA activity. No significant apoptosis related to AAV vectors or IDUA was observed under any conditions in both human corneas and MPS1 patient fibroblasts. The collective preclinical data demonstrate safe and efficient IDUA delivery to human corneas, which may prevent and potentially reverse MPS1-associated cornea blindness. PMID:26899286

Neonatal Systemic AAV Induces Tolerance to CNS Gene Therapy in MPS I Dogs and Nonhuman Primates

PubMed Central

Hinderer, Christian; Bell, Peter; Louboutin, Jean-Pierre; Zhu, Yanqing; Yu, Hongwei; Lin, Gloria; Choa, Ruth; Gurda, Brittney L; Bagel, Jessica; O'Donnell, Patricia; Sikora, Tracey; Ruane, Therese; Wang, Ping; Tarantal, Alice F; Casal, Margret L; Haskins, Mark E; Wilson, James M

2015-01-01

The potential host immune response to a nonself protein poses a fundamental challenge for gene therapies targeting recessive diseases. We demonstrate in both dogs and nonhuman primates that liver-directed gene transfer using an adeno-associated virus (AAV) vector in neonates induces a persistent state of immunological tolerance to the transgene product, substantially improving the efficacy of subsequent vector administration targeting the central nervous system (CNS). We applied this approach to a canine model of mucopolysaccharidosis type I (MPS I), a progressive neuropathic lysosomal storage disease caused by deficient activity of the enzyme α-l-iduronidase (IDUA). MPS I dogs treated systemically in the first week of life with a vector expressing canine IDUA did not develop antibodies against the enzyme and exhibited robust expression in the CNS upon intrathecal AAV delivery at 1 month of age, resulting in complete correction of brain storage lesions. Newborn rhesus monkeys treated systemically with AAV vector expressing human IDUA developed tolerance to the transgene, resulting in high cerebrospinal fluid (CSF) IDUA expression and no antibody induction after subsequent CNS gene therapy. These findings suggest that inducing tolerance to the transgene product during a critical period in immunological development can improve the efficacy and safety of gene therapy. PMID:26022732

Neonatal Systemic AAV Induces Tolerance to CNS Gene Therapy in MPS I Dogs and Nonhuman Primates.

PubMed

Hinderer, Christian; Bell, Peter; Louboutin, Jean-Pierre; Zhu, Yanqing; Yu, Hongwei; Lin, Gloria; Choa, Ruth; Gurda, Brittney L; Bagel, Jessica; O'Donnell, Patricia; Sikora, Tracey; Ruane, Therese; Wang, Ping; Tarantal, Alice F; Casal, Margret L; Haskins, Mark E; Wilson, James M

2015-08-01

The potential host immune response to a nonself protein poses a fundamental challenge for gene therapies targeting recessive diseases. We demonstrate in both dogs and nonhuman primates that liver-directed gene transfer using an adeno-associated virus (AAV) vector in neonates induces a persistent state of immunological tolerance to the transgene product, substantially improving the efficacy of subsequent vector administration targeting the central nervous system (CNS). We applied this approach to a canine model of mucopolysaccharidosis type I (MPS I), a progressive neuropathic lysosomal storage disease caused by deficient activity of the enzyme α-l-iduronidase (IDUA). MPS I dogs treated systemically in the first week of life with a vector expressing canine IDUA did not develop antibodies against the enzyme and exhibited robust expression in the CNS upon intrathecal AAV delivery at 1 month of age, resulting in complete correction of brain storage lesions. Newborn rhesus monkeys treated systemically with AAV vector expressing human IDUA developed tolerance to the transgene, resulting in high cerebrospinal fluid (CSF) IDUA expression and no antibody induction after subsequent CNS gene therapy. These findings suggest that inducing tolerance to the transgene product during a critical period in immunological development can improve the efficacy and safety of gene therapy.

Glial degeneration with oxidative damage drives neuronal demise in MPSII disease.

PubMed

Zalfa, Cristina; Verpelli, Chiara; D'Avanzo, Francesca; Tomanin, Rosella; Vicidomini, Cinzia; Cajola, Laura; Manara, Renzo; Sala, Carlo; Scarpa, Maurizio; Vescovi, Angelo Luigi; De Filippis, Lidia

2016-08-11

Mucopolysaccharidosis type II (MPSII) is a lysosomal storage disorder due to the deficit of the iduronate 2-sulfatase (IDS) enzyme, causing progressive neurodegeneration in patients. Neural stem cells (NSCs) derived from the IDS-ko mouse can recapitulate MPSII pathogenesis in vitro. In differentiating IDS-ko NSCs and in the aging IDS-ko mouse brain, glial degeneration precedes neuronal degeneration. Here we show that pure IDS-ko NSC-derived astrocytes are selectively able to drive neuronal degeneration when cocultured with healthy neurons. This phenotype suggests concurrent oxidative damage with metabolic dysfunction. Similar patterns were observed in murine IDS-ko animals and in human MPSII brains. Most importantly, the mutant phenotype of IDS-ko astrocytes was reversed by low oxygen conditions and treatment with vitamin E, which also reversed the toxic effect on cocultured neurons. Moreover, at very early stages of disease we detected in vivo the development of a neuroinflammatory background that precedes astroglial degeneration, thus suggesting a novel model of MPSII pathogenesis, with neuroinflammation preceding glial degeneration, which is finally followed by neuronal death. This hypothesis is also consistent with the progression of white matter abnormalities in MPSII patients. Our study represents a novel breakthrough in the elucidation of MPSII brain pathogenesis and suggests the antioxidant molecules as potential therapeutic tools to delay MPSII onset and progression.

Brain and Organ Uptake in the Rhesus Monkey in Vivo of Recombinant Iduronidase Compared to an Insulin Receptor Antibody-Iduronidase Fusion Protein.

PubMed

Boado, Ruben J; Pardridge, William M

2017-04-03

Mucopolysaccharidosis type I (MPSI) is caused by mutations in the gene encoding the lysosomal enzyme, α-l-iduronidase (IDUA), and patients with MPSI are currently treated with IDUA enzyme replacement therapy (ERT). However, the majority of MPSI patients have severe CNS involvement, and conventional ERT does not treat the brain. The failure of ERT to treat the brain is believed to be due to the lack of IDUA transport through the blood-brain barrier (BBB). However, BBB transport of IDUA has not been directly measured, to date. BBB transport of IDUA may be enhanced by fusion of the enzyme to a monoclonal antibody (mAb) against the human insulin receptor (HIR). The HIRMAb binds the insulin receptor on the BBB to trigger transport into the brain and acts as a molecular Trojan horse to deliver IDUA to brain cells. Therefore, the purpose of the present investigation was to compare, side-by-side, the BBB transport of IDUA alone and the HIRMAb-IDUA fusion protein in the Rhesus monkey in vivo. Each protein was radio-iodinated by conjugation with the [ 125 I]-Bolton-Hunter reagent and injected intravenously (IV) in the primate. The uptake by brain, and peripheral organs, was measured by whole body autoradiography. The results show there is no transport of IDUA alone into the brain, but that the brain uptake of the HIRMAb-IDUA fusion protein is high, 1.2% injected dose/brain. There is comparable uptake of the IDUA and the HIRMAb-IDUA fusion protein by peripheral organs, where uptake is primarily controlled by the mannose 6-phosphate receptor. The work suggests that treatment of MPSI with the HIRMAb-IDUA fusion protein will be as effective as IDUA in peripheral organs, but offer the benefit of treatment of the central nervous system in MPSI.

Natural history and galsulfase treatment in mucopolysaccharidosis VI (MPS VI, Maroteaux-Lamy syndrome)--10-year follow-up of patients who previously participated in an MPS VI Survey Study.

PubMed

Giugliani, Roberto; Lampe, Christina; Guffon, Nathalie; Ketteridge, David; Leão-Teles, Elisa; Wraith, James E; Jones, Simon A; Piscia-Nichols, Cheri; Lin, Ping; Quartel, Adrian; Harmatz, Paul

2014-08-01

Mucopolysaccharidosis VI (MPS VI) is a clinically heterogeneous and progressive disorder with multiorgan manifestations caused by deficient N-acetylgalactosamine-4-sulfatase activity. A cross-sectional Survey Study in individuals (n = 121) affected with MPS VI was conducted between 2001 and 2002 to establish demographics, urinary glycosaminoglycan (GAG) levels, and clinical progression of disease. We conducted a Resurvey Study (ClinicalTrials.gov: NCT01387854) to obtain 10-year follow-up data, including medical histories and clinical assessments (n = 59), and survival status over 12 years (n = 117). Patients received a mean (SD) of 6.8 (2.2) years of galsulfase ERT between baseline (Survey Study) and follow-up. ERT patients increased in height by 20.4 cm in the 4-7-year-old baseline age group and by 16.8 cm in the 8-12-year-old baseline age group. ERT patients <13 years-old demonstrated improvement in forced vital capacity (FVC) by 68% and forced expiratory volume in 1 sec (FEV1) by 55%, and those ≥13 years-old increased FVC by 12.8% and maintained FEV1. Patients with >200 µg/mg baseline uGAG levels increased FVC by 48% in the <13-year-old baseline age group and by 15% in the ≥13-year-old baseline age group. ERT patients who completed the 6-min walk test demonstrated a mean (SD) increase of 65.7 (100.6) m. Cardiac outcomes did not significantly improve or worsen. Observed mortality rate among naïve patients was 50% (7/14) and 16.5% (17/103) in the ERT group (unadjusted hazard ratio, 0.24; 95% CI, 0.10-0.59). Long-term galsulfase ERT was associated with improvements in pulmonary function and endurance, stabilized cardiac function and increased survival. © 2014 Wiley Periodicals, Inc.

Activities of Daily Living in patients with Hunter syndrome: Impact of enzyme replacement therapy and hematopoietic stem cell transplantation

PubMed Central

Tanjuakio, Julian; Suzuki, Yasuyuki; Patel, Pravin; Yasuda, Eriko; Kubaski, Francyne; Tanaka, Akemi; Yabe, Hiromasa; Mason, Robert W.; Montaño, Adriana M.; Orii, Kenji E.; Orii, Koji O.; Fukao, Toshiyuki; Orii, Tadao; Tomatsu, Shunji

2014-01-01

The aim of this study was to assess the Activities of Daily Living (ADL) in patients with Hunter syndrome (mucopolysaccharidosis II; MPS II) using a newly designed ADL questionnaire. We applied the questionnaire to evaluate clinical phenotypes and therapeutic efficacies of enzyme replacement therapy (ERT) and hematopoietic stem cell transplantation (HSCT). We also explored early signs and symptoms to make early diagnosis feasible. We devised a new ADL questionnaire with three domains: “Movement,” “Movement with Cognition,” and “Cognition.” Each domain has four subcategories rated on a 5-point scale based on level of assistance. We also scored signs and symptoms unique to MPS by 12 subcategories (five points per category), providing 60 points in total. The questionnaire was first administered to 138 healthy Japanese controls (0.33 – 50 years), and successively, to 74 Japanese patients with Hunter syndrome (4 – 49 years). The patient cohort consisted of 51 severe and 23 attenuated phenotypes; 20 patients treated with HSCT, 23 patients treated early with ERT (≤ 8 years), and 25 patients treated late with ERT (> 8 years), and 4 untreated patients. Among 18 severe phenotypic patients treated by HSCT, 10 were designated as early HSCT (≤ 5 years), while 8 were designated as late HSCT (> 5 years). Scores from patients with severe phenotypes were lower than controls and attenuated phenotypes in all categories. Among patients with severe phenotypes, there was a trend that HSCT provides a higher ADL score than early ERT, and there was a significant difference in ADL scores between late ERT and HSCT groups. Early ERT and early HSCT provided a higher score than late ERT and late HSCT, respectively. In conclusion, we have evaluated the feasibility of a new questionnaire in control population and patients with Hunter syndrome, leading to a novel evaluation method for clinical phenotypes and therapeutic efficacy. Early treatment with HSCT provides a better consequence in ADL of patients. PMID:25468646

Respiratory and sleep disorders in mucopolysaccharidosis.

PubMed

Berger, Kenneth I; Fagondes, Simone C; Giugliani, Roberto; Hardy, Karen A; Lee, Kuo Sheng; McArdle, Ciarán; Scarpa, Maurizio; Tobin, Martin J; Ward, Susan A; Rapoport, David M

2013-03-01

MPS encompasses a group of rare lysosomal storage disorders that are associated with the accumulation of glycosaminoglycans (GAG) in organs and tissues. This accumulation can lead to the progressive development of a variety of clinical manifestations. Ear, nose, throat (ENT) and respiratory problems are very common in patients with MPS and are often among the first symptoms to appear. Typical features of MPS include upper and lower airway obstruction and restrictive pulmonary disease, which can lead to chronic rhinosinusitis or chronic ear infections, recurrent upper and lower respiratory tract infections, obstructive sleep apnoea, impaired exercise tolerance, and respiratory failure. This review provides a detailed overview of the ENT and respiratory manifestations that can occur in patients with MPS and discusses the issues related to their evaluation and management.

Polar body biopsy in the diagnosis of monogenic diseases: the birth of three healthy children.

PubMed

Griesinger, Georg; Bündgen, Nana; Salmen, Diana; Schwinger, Eberhard; Gillessen-Kaesbach, Gabriele; Diedrich, Klaus

2009-08-01

For prospective parents at risk of transmitting a monogenic disease, polar body analysis is an option for pre-conception genetic diagnosis. In Germany, polar body analysis is currently performed in only two centers (Lübeck and Regensburg). The authors present a clinical series of 9 couples at risk for the transmission of a monogenic disease who underwent in vitro fertilization with polar body analysis. Nine couples have undergone in vitro fertilization with polar body analysis at the center in Lübeck since 2004. Three healthy children were born after polar body analysis for mucopolysaccharidosis type I, incontinentia pigmenti, and cystic fibrosis. The decision to undergo in vitro fertilization with polar body analysis is not easy for prospective parents to take, even though it often follows years of emotional suffering. Treatment with the methods of reproductive medicine in general, and with polar body analysis in particular, can cause considerable physical and emotional stress. For prospective parents in Germany at risk of transmitting a monogenic disease, polar body-based preimplantation diagnosis is an alternative to prenatal diagnosis and possible termination of pregnancy. The live birth rate per treatment cycle in this clinical series was 30%, which can be considered satisfactory. Nonetheless, most of the couples who did not achieve pregnancy after a first treatment cycle dropped out of treatment prematurely and did not go on to a second cycle.

Active site mutant transgene confers tolerance to human β-glucuronidase without affecting the phenotype of MPS VII mice

PubMed Central

Sly, William S.; Vogler, Carole; Grubb, Jeffrey H.; Zhou, Mi; Jiang, Jinxing; Zhou, Xiao Yan; Tomatsu, Shunji; Bi, Yanhua; Snella, Elizabeth M.

2001-01-01

Mucopolysaccharidosis type VII (MPS VII; Sly syndrome) is an autosomal recessive lysosomal storage disorder due to an inherited deficiency of β-glucuronidase. A naturally occurring mouse model for this disease was discovered at The Jackson Laboratory and shown to be due to homozygosity for a 1-bp deletion in exon 10 of the gus gene. The murine model MPS VII (gusmps/mps) has been very well characterized and used extensively to evaluate experimental strategies for lysosomal storage diseases, including bone marrow transplantation, enzyme replacement therapy, and gene therapy. To enhance the value of this model for enzyme and gene therapy, we produced a transgenic mouse expressing the human β-glucuronidase cDNA with an amino acid substitution at the active site nucleophile (E540A) and bred it onto the MPS VII (gusmps/mps) background. We demonstrate here that the mutant mice bearing the active site mutant human transgene retain the clinical, morphological, biochemical, and histopathological characteristics of the original MPS VII (gusmps/mps) mouse. However, they are now tolerant to immune challenge with human β-glucuronidase. This “tolerant MPS VII mouse model” should be useful for preclinical trials evaluating the effectiveness of enzyme and/or gene therapy with the human gene products likely to be administered to human patients with MPS VII. PMID:11226217

High proportion of mannosidosis and fucosidosis among lysosomal storage diseases in Cuba.

PubMed

Menéndez-Sainz, C; González-Quevedo, A; González-García, S; Peña-Sánchez, M; Giugliani, R

2012-08-13

Although lysosomal storage disorders (LSDs) are considered individually rare, as a group they present a non-negligible frequency. Few studies have been made of populational occurrence of LSDs; they have been conducted predominantly on Caucasian populations. We studied the occurrence of LSDs in Cuba. Data from individuals who had been referred to the Institute of Neurology and Neurosurgery in Havana from hospitals all over the country between January 1990 and December 2005 were analyzed. This institute was the only laboratory to provide enzyme-based diagnostic testing for 19 LSDs in Cuba during this period. Occurrence rates were calculated by dividing the number of postnatal diagnoses by the number of births during the study period. The combined occurrence of LSDs in Cuba was 5.6 per 100,000, lower than that reported in other studies conducted on Caucasian populations. The most frequent individual LSDs were: mucopolysaccharidosis type I (1.01 per 100,000) and, surprisingly, alpha-mannosidosis (0.72 per 100,000) and fucosidosis (0.62 per 100,000). These findings may be related to specific genetic characteristics and admixture of the Cuban population. This is the first comprehensive study of the occurrence of LSDs in Cuba. We conclude that the epidemiology of these diseases can vary regionally, and we stress the need for similar surveys in other Latin American countries.

Unique medical issues in adult patients with mucopolysaccharidoses.

PubMed

Mitchell, John; Berger, Kenneth I; Borgo, Andrea; Braunlin, Elizabeth A; Burton, Barbara K; Ghotme, Kemel A; Kircher, Susanne G; Molter, David; Orchard, Paul J; Palmer, James; Pastores, Gregory M; Rapoport, David M; Wang, Raymond Y; White, Klane

2016-10-01

The mucopolysaccharidoses are a group of inherited metabolic diseases caused by deficiencies in enzymes involved in the sequential degradation of glycosaminoglycans (GAGs) leading to substrate accumulation in various tissues and organs. GAG accumulation can cause growth retardation and progressive damage to respiratory, cardiovascular, musculoskeletal, nervous, gastrointestinal, auditory, and visual systems. In the past, few people with severe phenotypic mucopolysaccharidosis (MPS) reached adulthood. However, better methods for diagnosis, multi-disciplinary care, and new therapies have extended lifespan, leading to an increasing number of patients surviving beyond childhood. The growing number of adult MPS patients poses significant challenges for clinicians who may not be familiar with the clinical manifestations of MPS. In addition, as new interventions have changed the natural history of these disorders, it is difficult to anticipate both the impact on life expectancy and other complications that may occur as these patients age. Because the MPS disorders are multi-organ diseases, their management requires a coordinated multi-disciplinary approach. Here we discuss the unique pattern of medical issues and multi-organ involvement in adult patients with MPS and identify the challenges that are associated with management of MPS. This review is based on information from an expert investigator meeting with MPS specialists held October 2-4, 2014 in Dublin, Ireland, as well as on current literature searches focusing on MPS and adults. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

Aversive and non-aversive memory impairment in the mucopolysaccharidosis II mouse model.

PubMed

Azambuja, Amanda Stapenhorst; Correa, Lilian; Gabiatti, Bernardo Pappi; Martins, Giselle Renata; de Oliveira Franco, Álvaro; Ribeiro, Maria Flávia Marques; Baldo, Guilherme

2018-02-01

Hunter syndrome (MPS II, OMIM 309900) is a lysosomal storage disorder due to deficient iduronate sulphatase activity. Patients present multiple cognitive alterations, and the aim of this work was to verify if MPS II mice also present some progressive cognitive alterations. For that, MPS II mice from 2 to 6 months of age were submitted to repeated open field and inhibitory avoidance tests to evaluate memory parameters. MPS II mice presented impaired memory at 6 months evaluated by open field test. They also performed poorly in the inhibitory avoidance test from 4 months. We conclude that MPS II mice develop cognitive alterations as the disease progresses. These tests can be used in the future to study the efficacy of therapeutic approaches in the central nervous system.

Postnatal progression of bone disease in the cervical spines of mucopolysaccharidosis I dogs

PubMed Central

Chiaro, Joseph A; Baron, Matthew D; del Alcazar, Chelsea; O’Donnell, Patricia; Shore, Eileen M; Elliott, Dawn M; Ponder, Katherine P; Haskins, Mark E; Smith, Lachlan J

2013-01-01

Introduction Mucopolysaccharidosis I (MPS I) is a lysosomal storage disorder characterized by deficient α-L-iduronidase activity leading to accumulation of poorly degraded dermatan and heparan sulfate glycosaminoglycans (GAGs). MPS I is associated with significant cervical spine disease, including vertebral dysplasia, odontoid hypoplasia, and accelerated disc degeneration, leading to spinal cord compression and kypho-scoliosis. The objective of this study was to establish the nature and rate of progression of cervical vertebral bone disease in MPS I using a canine model. Methods C2 vertebrae were obtained post-mortem from normal and MPS I dogs at 3, 6 and 12 months-of-age. Morphometric parameters and mineral density for the vertebral trabecular bone and odontoid process were determined using micro-computed tomography. Vertebrae were then processed for paraffin histology, and cartilage area in both the vertebral epiphyses and odontoid process were quantified. Results Vertebral bodies of MPS I dogs had lower trabecular bone volume/total volume (BV/TV), trabecular thickness (Tb.Th), trabecular number (Tb.N) and bone mineral density (BMD) than normals at all ages. For MPS I dogs, BV/TV, Tb.Th and BMD plateaued after 6 months-of-age. The odontoid process appeared morphologically abnormal for MPS I dogs at 6 and 12 months-of-age, although BV/TV and TMD were not significantly different from normals. MPS I dogs had significantly more cartilage in the vertebral epiphyses at both 3 and 6 months-of-age. At 12 months-of-age, epiphyseal growth plates in normal dogs were absent, but in MPS I dogs they persisted. Conclusions In this study we report reduced trabecular bone content and mineralization, and delayed cartilage to bone conversion in MPS I dogs from 3 months-of-age, which may increase vertebral fracture risk and contribute to progressive deformity. The abnormalities of the odontoid process we describe likely contribute to increased incidence of atlanto-axial subluxation observed clinically. Therapeutic strategies that enhance bone formation may decrease incidence of spine disease in MPS I patients. PMID:23563357

Expensive drugs for rare disorders: to treat or not to treat? The case of enzyme replacement therapy for mucopolysaccharidosis VI.

PubMed

Schlander, M; Beck, M

2009-05-01

Mucopolysaccharidosis VI (MPS VI) is a very rare, chronically debilitating lysosomal storage disorder that develops in people with an enzyme deficiency. Clinical characteristics and progression rates vary widely between patients. The recent introduction of enzyme replacement therapy (ERT) has improved considerably the lives of patients with MPS VI, at an annual cost of treatment between euro 150,000 and euro 450,000 per patient. This Commentary article addresses the controversial topic of granting reimbursement for expensive treatment options for orphan diseases, such as MPS VI. The discussion reflects clinical, economic and ethical aspects and incorporates insights from the relevant literature (based on a Medline search to September 2008) on MPS VI, efficacy of ERT, orphan drugs, and the economics and ethics of health-care prioritisation. Although ERT for MPS VI received marketing authorisation in the European Union in January 2006, patients' access to this therapy varies geographically due to differences between national reimbursement schemes for orphan drugs. Some inclusion and exclusion criteria for treatment of MPS VI patients with ERT appear arbitrary and may contribute to the exclusion from treatment of patients who could benefit in the long term. Reimbursement schemes which rely on proof of short-term treatment effectiveness may discriminate against slowly progressive patients, as health gain can often not be confirmed over a short period of time in these patients. Conventional cost-effectiveness analysis remains silent on crucial issues related to budgetary impact, i.e. opportunity cost from a system perspective, and fair access to treatment. To prevent patients from being deprived of effective treatment, it is suggested that inclusion and exclusion criteria for treatment should be primarily based on a careful individual assessment of expected long-term clinical benefits. Once treatment has been agreed to as the correct option on clinical grounds, it is further argued that the conventional cost-effectiveness criterion currently in widespread use does not offer a sufficient basis for rejecting reimbursement of expensive treatments for exceptionally rare disorders, providing that decisions on reimbursement are intended to reflect public preferences.

The effectiveness and cost-effectiveness of enzyme and substrate replacement therapies: a longitudinal cohort study of people with lysosomal storage disorders.

PubMed

Wyatt, K; Henley, W; Anderson, L; Anderson, R; Nikolaou, V; Stein, K; Klinger, L; Hughes, D; Waldek, S; Lachmann, R; Mehta, A; Vellodi, A; Logan, S

2012-01-01

To determine natural history and estimate effectiveness and cost of enzyme replacement therapy (ERT) and substrate replacement therapy (SRT) for patients with Gaucher disease, Fabry disease, mucopolysaccharidosis type I (MPS I), mucopolysaccharidosis type II (MPS II), Pompe disease and Niemann-Pick type C (NPC) disease. Cohort study including prospective and retrospective clinical- and patient-reported data. Age- and gender-adjusted treatment effects were estimated using generalised linear mixed models. Treated patients contributed data before and during treatment. Untreated patients contributed natural history data. National Specialised Commissioning Group-designated lysosomal storage disorder (LSD) treatment centres in England. Consenting adults and children with a diagnosis of Gaucher disease (n = 272), Fabry disease (n = 499), MPS I (n = 126), MPS II (n = 58), NPC (n = 58) or Pompe disease (n = 93) who had attended a treatment centre in England. ERT and SRT. Clinical outcomes chosen by clinicians to reflect disease progression for each disorder; patient-reported quality-of-life (QoL) data; cost of treatment and patient-reported service-use data; numbers of hospitalisations, outpatient and general practitioner appointments; medication use; data pertaining to associated family/carer costs and QoL impacts. Seven hundred and eleven adults and children were recruited. In those with Gaucher disease (n = 175) ERT was associated with improved platelet count, haemoglobin, liver function and reduced risk of enlarged liver or spleen. No association was found between ERT and QoL. In patients with Fabry disease (n = 311) increased time on ERT was associated with small decreases in left ventricular mass and improved glomerular filtration rate, but not with changes in risk of stroke/transient ischaemic attacks or the need for a hearing aid. There was a statistically significant association between duration of ERT use and worsening QoL and fatigue scores. We found no statistical difference in estimates of treatment effectiveness between the two preparations, agalsidase beta (Fabrazyme(®), Genzyme) (n = 127) and agalsidase alpha (Replagal(®), Shire HGT) (n = 91), licensed for this condition. In Pompe disease (n = 77) our data provide some evidence of a beneficial effect on muscle strength and mobility as measured by a 6-minute walk test in adult-onset patients; there were insufficient data from infantile-onset Pompe patients to estimate associations between ERT and outcome. Among subjects with MPS I (n = 68), 42 of the 43 patients with MPS I subtype Hurler's disease had undergone a bone marrow transplant. No significant associations were found between ERT and any outcome measure for the MPS I subtype Scheie disease and heparan sulphate patients. An association between duration of ERT and growth in children was the only statistically significant finding among patients with MPS II (n = 39). There were insufficient data for patients with NPC disease to draw any conclusions regarding the effectiveness of SRT. The current annual cost to the NHS of the different ERTs means that between 3.6 and 17.9 discounted quality-adjusted life-years (QALYs) for adult patients and between 2.6 and 10.5 discounted QALYs for child patients would need to be generated for each year of being on treatment for ERTs to be considered cost-effective by conventional criteria. These data provide further evidence on the effectiveness of ERT in people with LSDs. However, the results need to be interpreted in light of the fact that the data are observational and the relative lack of power due to the small numbers of patients with MPS I, MPS II, Pompe disease and NPC disease. Future work should aim to effectively address the unanswered questions and this will require agreement on a common set of outcome measures and their consistent collection across all treatment centres. This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 16, No. 39. See the HTA programme website for further project information.

Lower Extremity Deformity Management in MPS IVA, Morquio-Brailsford Syndrome: Preliminary Report of Hemiepiphysiodesis Correction of Genu Valgum.

PubMed

Cooper, George A; Southorn, Thomas; Eastwood, Deborah M; Bache, C Edward

2016-06-01

Morquio-Brailsford syndrome or mucopolysaccharidosis type IV-A (MPS IV-A) is an inherited metabolic disease in which skeletal deformities can be extreme. An international registry has shown that 46% of patients are unable to walk 200 m and 30% use a wheelchair. Lower limb surgery is performed to restore alignment with the expectation of maintaining mobility. We are, however, not aware of reports correlating function with alignment. This study assesses the role of orthopaedic intervention with reference to anatomic and functional outcome in MPS IV-A: specifically hemiepiphysiodesis correction of genu valgum. Interrogation of the MPS patient database identified 63 patients. Patient demographic and radiographic data were collected along with information on deformity, correction, mobility, and genotype. Genu valgum was assessed by intermalleolar distance and mobility by a standardized 6-minute walk test. Sequential hip anatomy was assessed radiographically. Twenty-six surgical hemiepiphysiodesis episodes were performed on 23 patients. There were no cases of implant failure, loosening, or infection. The average intermalleolar distance reduction was 6.12 cm (paired t test, P=0.0001) (95% confidence interval, 7.6-4.7 cm) and the mean change in 6-minute walk test was +69.5 m (P=0.0339). There was no correlation between hip subluxation/dislocation and mobility (Fisher exact test, P=1.000), although hip parameters deteriorated over time. Three patients required repeat 8-plate insertion and 1 a femoral osteotomy. Eight-plate hemiepiphysiodesis correction of genu valgum in MPS IV-A is an effective treatment with low complication rates. The insult of surgery is minimal compared with that of osteotomy which can reduce mobility further. Our outcomes suggest that mobility is maintained or improved even in severe genotypes where mobility typically worsens. We have found hip pathology to be less debilitating, but further studies are needed to assess the effect of genu valgum correction upon femoral head subluxation and collapse.We suggest hemiepiphysiodesis should be considered as part of the treatment strategy for limb alignment in MPS IV-A patients, depending on remaining growth, mobility status, and genotype. Level IV-therapeutic case series.

Sanfilippo syndrome: causes, consequences, and treatments

PubMed Central

Fedele, Anthony O

2015-01-01

Sanfilippo syndrome, or mucopolysaccharidosis (MPS) type III, refers to one of five autosomal recessive, neurodegenerative lysosomal storage disorders (MPS IIIA to MPS IIIE) whose symptoms are caused by the deficiency of enzymes involved exclusively in heparan sulfate degradation. The primary characteristic of MPS III is the degeneration of the central nervous system, resulting in mental retardation and hyperactivity, typically commencing during childhood. The significance of the order of events leading from heparan sulfate accumulation through to downstream changes in the levels of biomolecules within the cell and ultimately the (predominantly neuropathological) clinical symptoms is not well understood. The genes whose deficiencies cause the MPS III subtypes have been identified, and their gene products, as well as a selection of disease-causing mutations, have been characterized to varying degrees with respect to both frequency and direct biochemical consequences. A number of genetic and biochemical diagnostic methods have been developed and adopted by diagnostic laboratories. However, there is no effective therapy available for any form of MPS III, with treatment currently limited to clinical management of neurological symptoms. The availability of animal models for all forms of MPS III, whether spontaneous or generated via gene targeting, has contributed to improved understanding of the MPS III subtypes, and has provided and will deliver invaluable tools to appraise emerging therapies. Indeed, clinical trials to evaluate intrathecally-delivered enzyme replacement therapy in MPS IIIA patients, and gene therapy for MPS IIIA and MPS IIIB patients are planned or underway. PMID:26648750

Kissing molars: report of three cases and new prospective on aetiopathogenetic theories

PubMed Central

Menditti, Dardo; Laino, Luigi; Cicciù, Marco; Mezzogiorno, Antonio; Perillo, Letizia; Menditti, Marco; Cervino, Gabriele; Muzio, Lorenzo Lo; Baldi, Alfonso

2015-01-01

Kissing molars (KMs) is an extremely rare condition of impacted third molars, pointed in the opposite direction in a single follicular space; it consists exactly in a full impacted of permanent molars which occurs only in the lower jaw. Actually, about less than thirty cases have been reported in scientific literatures. The aetiology and pathogenesis of this pathological double dental inclusion remain unknown; above all events that lead two molars to appear, as KMs remain mysterious. The association to metabolic connective diseases such as mucopolysaccharidosis was emphasized. KMs considered as an isolated event, may be associated to an abnormal position of the tooth-bud from lower permanent molars, or fourth supernumerary tooth (distomolar). Recently, hyperplastic dental follicle (HDF), with a down regulation of matrix metal-proteinases and up regulation of several genes of collagens, has been mentioned in association with KMs. In this paper, after having analyzed three new cases of KMs that have been treated, we report a new hypothesis. This last is based on the failure in the dental follicle’s ability to initiate or continue properly resorption of the overlying alveolar bone, by many exogenous factors which may act on eruptive phase that would lead to its rotation with its contents coming out a pathological situation of KMs. The therapy of choice is related to the surgical removal of KMs through a double odontectomy with transalveolar method. Other treatments can be, eventually, orthodontic therapy of the impacted teeth and a radiological follow-up without surgery. PMID:26884840

Multigene panel next generation sequencing in a patient with cherry red macular spot: Identification of two novel mutations in NEU1 gene causing sialidosis type I associated with mild to unspecific biochemical and enzymatic findings.

PubMed

Mütze, Ulrike; Bürger, Friederike; Hoffmann, Jessica; Tegetmeyer, Helmut; Heichel, Jens; Nickel, Petra; Lemke, Johannes R; Syrbe, Steffen; Beblo, Skadi

2017-03-01

Lysosomal storage diseases (LSD) often manifest with cherry red macular spots. Diagnosis is based on clinical features and specific biochemical and enzymatic patterns. In uncertain cases, genetic testing with next generation sequencing can establish a diagnosis, especially in milder or atypical phenotypes. We report on the diagnostic work-up in a boy with sialidosis type I, presenting initially with marked cherry red macular spots but non-specific urinary oligosaccharide patterns and unusually mild excretion of bound sialic acid. Biochemical, enzymatic and genetic tests were performed in the patient. The clinical and electrophysiological data was reviewed and a genotype-phenotype analysis was performed. In addition a systematic literature review was carried out. Cherry red macular spots were first noted at 6 years of age after routine screening myopia. Physical examination, psychometric testing, laboratory investigations as well as cerebral MRI were unremarkable at 9 years of age. So far no clinical myoclonic seizures occurred, but EEG displays generalized epileptic discharges and visual evoked potentials are prolonged bilaterally. Urine thin layer chromatography showed an oligosaccharide pattern compatible with different LSD including sialidosis, galactosialidosis, GM1 gangliosidosis or mucopolysaccharidosis type IV B. Urinary bound sialic acid excretion was mildly elevated in spontaneous and 24 h urine samples. In cultured fibroblasts, α-sialidase activity was markedly decreased to < 1%; however, bound and free sialic acid were within normal range. Diagnosis was eventually established by multigene panel next generation sequencing of genes associated to LSD, identifying two novel, compound heterozygous variants in NEU1 gene (c.699C > A, p.S233R in exon 4 and c.803A > G; p.Y268C in Exon 5 in NEU1 transcript NM_000434.3), leading to amino acid changes predicted to impair protein function. Sialidosis should be suspected in patients with cherry red macular spots, even with non-significant urinary sialic acid excretion. Multigene panel next generation sequencing can establish a definite diagnosis, allowing for counseling of the patient and family.

Large proteoglycan complexes and disturbed collagen architecture in the corneal extracellular matrix of mucopolysaccharidosis type VII (Sly syndrome).

PubMed

Young, Robert D; Liskova, Petra; Pinali, Christian; Palka, Barbara P; Palos, Michalis; Jirsova, Katerina; Hrdlickova, Enkela; Tesarova, Marketa; Elleder, Milan; Zeman, Jiri; Meek, Keith M; Knupp, Carlo; Quantock, Andrew J

2011-08-24

Deficiencies in enzymes involved in proteoglycan (PG) turnover underlie a number of rare mucopolysaccharidoses (MPS), investigations of which can considerably aid understanding of the roles of PGs in corneal matrix biology. Here, the authors analyze novel pathologic changes in MPS VII (Sly syndrome) to determine the nature of PG-collagen associations in stromal ultrastructure. Transmission electron microscopy and electron tomography were used to investigate PG-collagen architectures and interactions in a cornea obtained at keratoplasty from a 22-year-old man with MPS VII, which was caused by a compound heterozygous mutation in the GUSB gene. Transmission electron microscopy showed atypical morphology of the epithelial basement membrane and Bowman's layer in MPS VII. Keratocytes were packed with cytoplasmic vacuoles containing abnormal glycosaminoglycan (GAG) material, and collagen fibrils were thinner than in normal cornea and varied considerably throughout anterior (14-32 nm), mid (13-42 nm), and posterior (17-39 nm) regions of the MPS VII stroma. PGs viewed in three dimensions were striking in appearance in that they were significantly larger than PGs in normal cornea and formed highly extended linkages with multiple collagen fibrils. Cellular changes in the MPS VII cornea resemble those in other MPS. However, the wide range of collagen fibril diameters throughout the stroma and the extensive matrix presence of supranormal-sized PG structures appear to be unique features of this disorder. The findings suggest that the accumulation of stromal chondroitin-, dermatan-, and heparan-sulfate glycosaminoglycans in the absence of β-glucuronidase-mediated degradation can modulate collagen fibrillogenesis.

Wide allelic heterogeneity with predominance of large IDS gene complex rearrangements in a sample of Mexican patients with Hunter syndrome.

PubMed

Alcántara-Ortigoza, M A; García-de Teresa, B; González-Del Angel, A; Berumen, J; Guardado-Estrada, M; Fernández-Hernández, L; Navarrete-Martínez, J I; Maza-Morales, M; Rius-Domínguez, R

2016-05-01

Hunter syndrome or mucopolysaccharidosis type II (MPSII) is caused by pathogenic variants in the IDS gene. This is the first study that examines the mutational spectrum in 25 unrelated Mexican MPSII families. The responsible genotype was identified in 96% of the families (24/25) with 10 novel pathogenic variants: c.133G>C, c.1003C>T, c.1025A>C, c.463_464delinsCCGTATAGCTGG, c.754_767del, c.1132_1133del, c.1463del, c.508-1G>C, c.1006+1G>T and c.(-217_103del). Extensive IDS gene deletions were identified in four patients; using DNA microarray analysis two patients showed the loss of the entire AFF2 gene, and epilepsy developed in only one of them. Wide allelic heterogeneity was noted, with large gene alterations (e.g. IDS/IDSP1 gene inversions, partial to extensive IDS deletions, and one chimeric IDS-IDSP1 allele) that occurred at higher frequencies than previously reported (36% vs 18.9-29%). The frequency of carrier mothers (80%) is consistent with previous descriptions (>70%). Carrier assignment allowed molecular prenatal diagnoses. Notably, somatic and germline mosaicism was identified in one family, and two patients presented thrombocytopenic purpura and pancytopenia after idursulfase enzyme replacement treatment. Our findings suggest a wide allelic heterogeneity in Mexican MPSII patients; DNA microarray analysis contributes to further delineation of the resulting phenotype for IDS and neighboring loci deletions. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Lysosomal Accumulation of SCMAS (Subunit c of Mitochondrial ATP Synthase) in Neurons of the Mouse Model of Mucopolysaccharidosis III B

PubMed Central

Ryazantsev, Sergey; Yu, Wei-Hong; Zhao, Hui-Zhi; Neufeld, Elizabeth F.; Ohmi, Kazuhiro

2007-01-01

The neurodegenerative disease MPS III B (Sanfilippo syndrome type B) is caused by mutations in the gene encoding the lysosomal enzyme α-N-acetylglucosaminidase, with a resulting block in heparan sulfate degradation. A mouse model with disruption of the Naglu gene allows detailed study of brain pathology. In contrast to somatic cells, which accumulate primarily heparan sulfate, neurons accumulate a number of apparently unrelated metabolites, including subunit c of mitochondrial ATP synthase (SCMAS). SCMAS accumulated from 1 month of age, primarily in the medial entorhinal cortex and layer V of the somatosensory cortex. Its accumulation was not due to the absence of specific proteases. Light microscopy of brain sections of 6 months-old mice showed SCMAS to accumulate in the same areas as glycosaminoglycan and unesterified cholesterol, in the same cells as ubiquitin and GM3 ganglioside, and in the same organelles as Lamp 1 and Lamp 2. Cryo-immuno electron microscopy showed SCMAS to be present in Lamp positive vesicles bounded by a single membrane (lysosomes), in fingerprint-like layered arrays. GM3 ganglioside was found in the same lysosomes, but was not associated with the SCMAS arrays. GM3 ganglioside was also seen in lysosomes of microglia, suggesting phagocytosis of neuronal membranes. Samples used for cryo-EM and further processed by standard EM procedures (osmium tetroxide fixation and plastic embedding) showed the disappearance of the SCMAS fingerprint arrays and appearance in the same location of “zebra bodies”, well known but little understood inclusions in the brain of patients with mucopolysaccharidoses. PMID:17185018

Safety, immunogenicity, and clinical outcomes in patients with Morquio A syndrome participating in 2 sequential open-label studies of elosulfase alfa enzyme replacement therapy (MOR-002/MOR-100), representing 5 years of treatment.

PubMed

Hendriksz, Christian; Santra, Saikat; Jones, Simon A; Geberhiwot, Tarekegn; Jesaitis, Lynne; Long, Brian; Qi, Yulan; Hawley, Sara M; Decker, Celeste

2018-04-01

Elosulfase alfa is an enzyme replacement therapy for Morquio A syndrome (mucopolysaccharidosis IVA), a multisystemic progressive lysosomal storage disorder. This report includes the primary treatment outcomes and immunogenicity profile of elosulfase alfa in patients with Morquio A syndrome from 2 sequential studies, MOR-002 (ClinicalTrials.govNCT00884949) and MOR-100 (NCT01242111), representing >5 years of clinical study data. MOR-002 was an open-label, single-arm phase 1/2 study that evaluated the pharmacokinetics, safety, immunogenicity, and preliminary efficacy of 3 sequential doses of elosulfase alfa (0.1, 1.0, and 2.0 mg/kg/week) in patients with Morquio A syndrome (n = 20) over 36 weeks, followed by an optional 36- to 48-week treatment period using elosulfase alfa 1.0 mg/kg once weekly (qw). During the 0.1 mg/kg dosing phase, 1 patient discontinued due to a type I hypersensitivity adverse event (AE), and that patient's sibling voluntarily discontinued in the absence of AEs. An additional patient discontinued due to recurrent infusion reactions during the 1.0 mg/kg continuation phase. The remaining 17 patients completed MOR-002 and enrolled in MOR-100, an open-label, long-term extension study that further evaluated safety and clinical outcomes with elosulfase alfa administered at 2.0 mg/kg qw. During the course of MOR-100, patients were given the option of receiving elosulfase alfa infusions at home with nursing assistance. Over the course of both studies, all patients experienced ≥1 AE and most patients experienced a drug-related AE, generally of mild or moderate severity. Hypersensitivity reactions reported as related to study drug occurred in 25% of patients. Thirteen patients who chose to receive infusions at home had the same tolerability and safety profile, as well as comparable compliance rates, as patients who chose to receive on-site infusions. All patients developed antibodies to elosulfase alfa. Positivity for neutralizing antibodies was associated with increased drug half-life and decreased drug clearance. Despite formation of antidrug-binding (total antidrug antibodies, TAb) and in vitro neutralizing antibodies (NAb) in all patients, these types of immunogenicity to elosulfase alfa were not correlated with safety or clinical outcomes. In contrast with the reported natural history of Morquio A, no trends toward decreasing endurance, respiratory function, or ability to perform activities of daily living were observed in this cohort over the 5-year period. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Gene editing of MPS I human fibroblasts by co-delivery of a CRISPR/Cas9 plasmid and a donor oligonucleotide using nanoemulsions as nonviral carriers.

PubMed

Schuh, Roselena Silvestri; de Carvalho, Talita Giacomet; Giugliani, Roberto; Matte, Ursula; Baldo, Guilherme; Teixeira, Helder Ferreira

2018-01-01

Mucopolysaccharidosis type I (MPS I) is an inherited disease caused by the deficiency of alpha-L-iduronidase (IDUA). This study shows the use of nanoemulsions co-complexed with the plasmid of CRISPR/Cas9 system and a donor oligonucleotide aiming at MPS I gene editing in vitro. Nanoemulsions composed of MCT, DOPE, DOTAP, DSPE-PEG, and water were prepared by high-pressure homogenization. The DNA was complexed by adsorption (NA) or encapsulation (NE) of preformed DNA/DOTAP complexes with nanoemulsions at +4/-1 charge ratio. The incubation in pure DMEM or supplemented with serum showed that the complexation with DNA was stable after 1 h of incubation, but the complexes tended to release the adsorbed DNA after 24 h of incubation, while the encapsulated DNA remained complexed in the oil core of the nanoemulsions even 48 h after incubation with DMEM. The treatment of MPS I patient's fibroblasts homozygous for the p.Trp402 ∗ mutation led to a significant increase in IDUA activity at 2, 15, and 30 days when compared to MPS I untreated fibroblasts. Flow cytometry and confocal microscopy demonstrated that there was a reduction in the area of lysosomes to values similar to normal, an indicator of correction of the cellular phenotype. These results show that the nanoemulsions co-complexed with the CRISPR/Cas9 system and a donor oligonucleotide could effectively transfect MPS I p.Trp402 ∗ patient's fibroblasts, as well as enable the production of IDUA, and represent a potential new treatment option for MPS I. Copyright © 2017 Elsevier B.V. All rights reserved.

Liver‐Directed Human Amniotic Epithelial Cell Transplantation Improves Systemic Disease Phenotype in Hurler Syndrome Mouse Model

PubMed Central

Rodriguez, Natalie S.; Yanuaria, Lisa; Parducho, Kevin Murphy R.; Garcia, Irving M.; Varghese, Bino A.; Grubbs, Brendan H.

2017-01-01

Abstract Mucopolysaccharidosis type 1 (MPS1) is an inherited lysosomal storage disorder caused by a deficiency in the glycosaminoglycan (GAG)‐degrading enzyme α‐l‐iduronidase (IDUA). In affected patients, the systemic accumulation of GAGs results in skeletal dysplasia, neurological degeneration, multiple organ dysfunction, and early death. Current therapies, including enzyme replacement and bone marrow transplant, improve life expectancy but the benefits to skeletal and neurological phenotypes are limited. In this study, we tested the therapeutic efficacy of liver‐directed transplantation of a placental stem cell, which possesses multilineage differentiation potential, low immunogenicity, and high lysosomal enzyme activity. Unfractionated human amniotic epithelial cells (hAECs) were transplanted directly into the liver of immunodeficient Idua knockout mouse neonates. The hAECs engraftment was immunohistochemically confirmed with anti‐human mitochondria staining. Enzyme activity assays indicated that hAECs transplantation restored IDUA function in the liver and significantly decreased urinary GAG excretion. Histochemical and micro‐computed tomography analyses revealed reduced GAG deposition in the phalanges joints and composition/morphology improvement of cranial and facial bones. Neurological assessment in the hAEC treated mice showed significant improvement of sensorimotor coordination in the hAEC treated mice compared to untreated mice. Results confirm that partial liver cell replacement with placental stem cells can provide long‐term (>20 weeks) and systemic restoration of enzyme function, and lead to significant phenotypic improvement in the MPS1 mouse model. This preclinical data indicate that liver‐directed placental stem cell transplantation may improve skeletal and neurological phenotypes of MPS1 patients. Stem Cells Translational Medicine 2017;6:1583–1594 PMID:28585336

Liver-Directed Human Amniotic Epithelial Cell Transplantation Improves Systemic Disease Phenotype in Hurler Syndrome Mouse Model.

PubMed

Rodriguez, Natalie S; Yanuaria, Lisa; Parducho, Kevin Murphy R; Garcia, Irving M; Varghese, Bino A; Grubbs, Brendan H; Miki, Toshio

2017-07-01

Mucopolysaccharidosis type 1 (MPS1) is an inherited lysosomal storage disorder caused by a deficiency in the glycosaminoglycan (GAG)-degrading enzyme α-l-iduronidase (IDUA). In affected patients, the systemic accumulation of GAGs results in skeletal dysplasia, neurological degeneration, multiple organ dysfunction, and early death. Current therapies, including enzyme replacement and bone marrow transplant, improve life expectancy but the benefits to skeletal and neurological phenotypes are limited. In this study, we tested the therapeutic efficacy of liver-directed transplantation of a placental stem cell, which possesses multilineage differentiation potential, low immunogenicity, and high lysosomal enzyme activity. Unfractionated human amniotic epithelial cells (hAECs) were transplanted directly into the liver of immunodeficient Idua knockout mouse neonates. The hAECs engraftment was immunohistochemically confirmed with anti-human mitochondria staining. Enzyme activity assays indicated that hAECs transplantation restored IDUA function in the liver and significantly decreased urinary GAG excretion. Histochemical and micro-computed tomography analyses revealed reduced GAG deposition in the phalanges joints and composition/morphology improvement of cranial and facial bones. Neurological assessment in the hAEC treated mice showed significant improvement of sensorimotor coordination in the hAEC treated mice compared to untreated mice. Results confirm that partial liver cell replacement with placental stem cells can provide long-term (>20 weeks) and systemic restoration of enzyme function, and lead to significant phenotypic improvement in the MPS1 mouse model. This preclinical data indicate that liver-directed placental stem cell transplantation may improve skeletal and neurological phenotypes of MPS1 patients. Stem Cells Translational Medicine 2017;6:1583-1594. © 2017 The Authors Stem Cells Translational Medicine published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.

Genetic manipulation of murine embryonic stem cells with enhanced green fluorescence protein and sulfatase-modifying factor I genes.

PubMed

Zhao, Guoying; Karageorgos, Litsa; Hutchinson, Rhonda G; Hopwood, John J; Hemsley, Kim

2010-05-01

Mucopolysaccharidosis type IIIA (MPS IIIA) is a lysosomal storage disorder (LSD) in which an absence of sulfamidase results in incomplete degradation and subsequent accumulation of its substrate, heparan sulfate. Most neurodegenerative LSD remain untreatable. However, therapy options, such as gene, enzyme end cell therapy, are under investigation. Previously, we have constructed an embryonic stem (ES) cell line (NS21) that over-expresses human sulphamidase as a potential treatment for murine MPS IIIA. In the present study the sulfatase-modifying factor I (SUMF1) and enhanced green fluorescence protein (eGFP) genes were co-introduced under a cytomegalovirus (CMV) promoter into NS21 cells, to enhance further sulfamidase activity and provide a marker for in vivo cell tracking, respectively. eGFP was also introduced under the control of the human elongation factor-1alpha (hEF-1alpha) promoter to compare the stability of transgene expression. During differentiation of ES cells into glial precursors, SUMF1 was down-regulated and was hardly detectable by day 18 of differentiation. Likewise, eGFP expression was heterogeneous and highly unstable. Use of a human EF-1alpha promoter resulted in more homogeneous eGFP expression, with approximately 50% of cells eGFP positive following differentiation into glial precursors. Compared with NS21 cells, the outgrowth of eGFP-expressing cells was not as confluent when differentiated into glial precursors. Our data suggest that SUMF1 enhances sulfamidase activity in ES cells, hEF-1alpha is a stronger promoter than CMV for ES cells and over-expression of eGFP may affect cell growth and contribute to unstable gene expression.

Adeno-Associated Virus Vectors and Stem Cells: Friends or Foes?

PubMed

Brown, Nolan; Song, Liujiang; Kollu, Nageswara R; Hirsch, Matthew L

2017-06-01

The infusion of healthy stem cells into a patient-termed "stem-cell therapy"-has shown great promise for the treatment of genetic and non-genetic diseases, including mucopolysaccharidosis type 1, Parkinson's disease, multiple sclerosis, numerous immunodeficiency disorders, and aplastic anemia. Stem cells for cell therapy can be collected from the patient (autologous) or collected from another "healthy" individual (allogeneic). The use of allogenic stem cells is accompanied with the potentially fatal risk that the transplanted donor T cells will reject the patient's cells-a process termed "graft-versus-host disease." Therefore, the use of autologous stem cells is preferred, at least from the immunological perspective. However, an obvious drawback is that inherently as "self," they contain the disease mutation. As such, autologous cells for use in cell therapies often require genetic "correction" (i.e., gene addition or editing) prior to cell infusion and therefore the requirement for some form of nucleic acid delivery, which sets the stage for the AAV controversy discussed herein. Despite being the most clinically applied gene delivery context to date, unlike other more concerning integrating and non-integrating vectors such as retroviruses and adenovirus, those based on adeno-associated virus (AAV) have not been employed in the clinic. Furthermore, published data regarding AAV vector transduction of stem cells are inconsistent in regards to vector transduction efficiency, while the pendulum swings far in the other direction with demonstrations of AAV vector-induced toxicity in undifferentiated cells. The variation present in the literature examining the transduction efficiency of AAV vectors in stem cells may be due to numerous factors, including inconsistencies in stem-cell collection, cell culture, vector preparation, and/or transduction conditions. This review summarizes the controversy surrounding AAV vector transduction of stem cells, hopefully setting the stage for future elucidation and eventual therapeutic applications.

An Evidence-Based Approach to the Management of Children with Morquio A Syndrome Presenting with Craniocervical Pathology.

PubMed

Williams, Nicole; Narducci, Alessandro; Eastwood, Deborah M; Cleary, Maureen; Thompson, Dominic

2018-06-12

Retrospective case series OBJECTIVE.: To review clinical and radiological outcomes of craniovertebral surgery in children with Morquio A syndrome (Mucopolysaccharidosis type IVA) and develop an evidence-based management algorithm. Myelopathy secondary to craniovertebral pathology is a common cause of neurological disability in Morquio A syndrome. Previously unresolved surgical controversies include the value of surveillance, surgical indications and operative technique. A retrospective case-based review of children with Morquio A syndrome and craniovertebral pathology seen in a tertiary referral paediatric centre from 1992-2016 was performed. Patients treated non-operatively and operatively were included. Medical records and imaging were reviewed to determine clinical and radiological findings at initial assessment, prior to cervical spine surgery, early post-operative period and final follow-up. The clinical outcomes of interest were neurological status and mobility at follow-up, complications and need for further surgery. Twenty-seven patients were included. Surgical indications were radiological evidence of cervicomedullary compression alone (6 cases) or with clinical evidence of myelopathy (12 cases). Eighteen patients (median age 6.2 years, range 3.5 - 15.9 years) underwent surgery, with median follow-up of 8.5years. Occiput to upper cervical spine fusion with C1 decompression was performed in all cases with the addition of autologous calvarial graft in young patients (12 cases) and occipital-cervical plate fixation in older children (6 cases). Neurological improvement occurred in 38% of cases but by one functional level only. Six of 9 conservatively treated patients remained independent walkers. Surgery for craniovertebral pathology is required in the majority of children with Morquio A syndrome. Close clinical and radiological surveillance is essential for timely intervention. Occiput to cervical fusion is safe and feasible even in young patients and improves clinical and radiological parameters. 4.

Application and Miniaturization of Linear and Nonlinear Raman Microscopy for Biomedical Imaging

NASA Astrophysics Data System (ADS)

Mittal, Richa

Current diagnostics for several disorders rely on surgical biopsy or evaluation of ex vivo bodily fluids, which have numerous drawbacks. We evaluated the potential for vibrational techniques (both linear and nonlinear Raman) as a reliable and noninvasive diagnostic tool. Raman spectroscopy is an optical technique for molecular analysis that has been used extensively in various biomedical applications. Based on demonstrated capabilities of Raman spectroscopy we evaluated the potential of the technique for providing a noninvasive diagnosis of mucopolysaccharidosis (MPS). These studies show that Raman spectroscopy can detect subtle changes in tissue biochemistry. In applications where sub-micrometer visualization of tissue compositional change is required, a transition from spectroscopy to high quality imaging is necessary. Nonlinear vibrational microscopy is sensitive to the same molecular vibrations as linear Raman, but features fast imaging capabilities. Coherent Raman scattering when combined with other nonlinear optical (NLO) techniques (like two-photon excited fluorescence and second harmonic generation) forms a collection of advanced optical techniques that provide noninvasive chemical contrast at submicron resolution. This capability to examine tissues without external molecular agents is driving the NLO approach towards clinical applications. However, the unique imaging capabilities of NLO microscopy are accompanied by complex instrument requirements. Clinical examination requires portable imaging systems for rapid inspection of tissues. Optical components utilized in NLO microscopy would then need substantial miniaturization and optimization to enable in vivo use. The challenges in designing compact microscope objective lenses and laser beam scanning mechanisms are discussed. The development of multimodal NLO probes for imaging oral cavity tissue is presented. Our prototype has been examined for ex vivo tissue imaging based on intrinsic fluorescence and SHG contrast. These studies show a potential for multiphoton compact probes to be used for real time imaging in the clinic.

Diagnosis, quality of life, and treatment of patients with Hunter syndrome in the French healthcare system: a retrospective observational study.

PubMed

Guffon, Nathalie; Heron, Bénédicte; Chabrol, Brigitte; Feillet, François; Montauban, Vincent; Valayannopoulos, Vassili

2015-04-12

Mucopolysaccharidosis II (MPS II) is associated with a broad spectrum of chronic and progressive, life-limiting symptoms. Idursulfase is approved for MPS II enzyme replacement therapy (ERT) in over 50 countries. This retrospective study evaluated the MPS II burden, organization of clinical care, and effects of idursulfase treatment on the disease in France. MPS II patients who had received idursulfase ERT in the French healthcare system were enrolled. In addition to clinician and patient questionnaires, the Clinical Global Impression-Improvement (CGI-I); Patient Global Impression-Improvement (PGI-I); KIDSCREEN-27, and EuroQoL-5D for adult patients scales were used to assess quality of life (QoL) and efficacy. Fifty-two patients were enrolled from 5 sites in France. The majority of patients (69.2%) presented a severe MPS II phenotype with progressive neurocognitive impairment. Major impacts on QoL were apparent, with at least 1 member of the family having to reorganize working hours (45.5%) or to stop working (22.7%). KIDSCREEN-27 and EuroQoL-5D scale scores were well below those for referent (control) populations. Most families (70.0%) experienced a diagnostic delay of at least 3 years after the initial observation of symptoms. The MPS II diagnosis was often delivered without adequate sensitivity, psychological support, or comprehensive information about the disease. The study population had received a mean of 3.8 ± 1.3 years ERT. Forty-four percent of patients with the attenuated phenotype (without progressive neurocognitive impairment) showed symptom improvement during both the first year (Period 1) and from the end of the first year of treatment to "the present" (Period 2), as measured by CGI-I/PGI-I. 30.3% and 9.1% of severe patients experienced symptom improvement during Periods 1 and 2, respectively, while 63.6% and 51.5% displayed no change. The most common adverse reactions reported were skin rash and other infusion-associated reactions. MPS II adversely affects multiple domains of QoL for patients and families, requiring multiple healthcare services and social aid programs. The majority of patients with either phenotype experienced either improvement or stability in their symptoms during the first year of ERT, but this was clearly less so for patients with the severe phenotype after the first year of treatment.

Progression of multiple behavioral deficits with various ages of onset in a murine model of Hurler syndrome.

PubMed

Pan, Dao; Sciascia, Anthony; Vorhees, Charles V; Williams, Michael T

2008-01-10

Mucopolysaccharidosis type I (MPS I) is one of the most common lysosomal storage diseases with progressive neurological dysfunction. To characterize the chronological behavioral profiles and identify the onset of functional deficits in a MPS I mouse model (IDUA(-/-)), we evaluated anxiety, locomotor behavior, startle, spatial learning and memory with mice at 2, 4, 6 and 8 months of age. In automated open-field test, IDUA(-/-) mice showed hypoactivity as early as 2 months of age and altered anxiety starting from 6 months of age during the initial exploratory phase, even though normal habituation was observed at all ages. In the marble-burying task, the anxiety-like compulsive behavior was normal in IDUA(-/-) mice at almost all tested ages, but significantly reduced in 8-month old male IDUA(-/-) mice which coincided with the rapid death of IDUA(-/-) males starting from 7 months of age. In the Morris water maze, IDUA(-/-) mice exhibited impaired proficient learning only at 4 months of age during the acquisition phase. Spatial memory deficits were observed in IDUA(-/-) mice during both 1 and 7 days probe trials at 4 and 8 months of age. The IDUA(-/-) mice performed normally in a novel object recognition task at younger ages until 8 months old when reduced visual cognitive memory retention was noted in the IDUA(-/-) mice. In addition, 8-month-old IDUA(-/-) mice failed to habituate to repeated open-field exposure, suggesting deficits in non-aversive and non-associative memory. In acoustic startle assessment, significantly more non-responders were found in IDUA(-/-) mice, but normal performance was seen in those that did show a response. These results presented a temporal evaluation of phenotypic behavioral dysfunctions in IDUA(-/-) mice from adolescence to maturity, indicating the impairments, with different ages of onset, in locomotor and anxiety-like compulsive behaviors, spatial learning and memory, visual recognition and short-term non-associative memory retention. This study would also provide guidelines for the experimental designs of behavioral evaluation on innovative therapies for the treatment of MPS type I.

All Madelung deformities are not endocrine

PubMed Central

Kumar, Ajay; Rai, Gopal K.; Akhtar, Javed; Phillip, Rajeev; Gutch, Manish; Arya, T. V. S.

2013-01-01

Madelung deformity is a rare inherited disorder associated with endocrine disorders like Turner's syndrome, pseudohypoparathyroidism, but can be seen with short stature homeobox deficiency conditions such as Leri-Weill dyschondrosteosis (LWD) and Langers mesomelic dysplasia. It has also been reported following trauma to the distal radius epiphysis neoplasia mucopolysaccharidosis (MPS) and achondroplasia. Madelung deformity is an abnormality of distal radial epiphysis where in progressive ulnar and volar tilt of the articular surface occurring in association with distal subluxation of ulna. A 13-year-old girl was referred to us for evaluation of bilateral deformity of wrist and short stature. There was ulnar deviation and dorsal tilt of bilateral hands without history of pain to the joint trauma and family history of similar illness. On X-ray, wrist showed malformed distal radial epiphysis with dorsal and ulnar shift and with increased length of phalanges suggestive of Madelung deformity. X-ray spine was normal. Ultrasound abdomen showed normal uterus and ovary and her follicle stimulating hormone. Luteinizing hormone was normal and so was urine MPS screening. Based on the above points the diagnosis of LWD was made. PMID:24251169

All Madelung deformities are not endocrine.

PubMed

Kumar, Ajay; Rai, Gopal K; Akhtar, Javed; Phillip, Rajeev; Gutch, Manish; Arya, T V S

2013-10-01

Madelung deformity is a rare inherited disorder associated with endocrine disorders like Turner's syndrome, pseudohypoparathyroidism, but can be seen with short stature homeobox deficiency conditions such as Leri-Weill dyschondrosteosis (LWD) and Langers mesomelic dysplasia. It has also been reported following trauma to the distal radius epiphysis neoplasia mucopolysaccharidosis (MPS) and achondroplasia. Madelung deformity is an abnormality of distal radial epiphysis where in progressive ulnar and volar tilt of the articular surface occurring in association with distal subluxation of ulna. A 13-year-old girl was referred to us for evaluation of bilateral deformity of wrist and short stature. There was ulnar deviation and dorsal tilt of bilateral hands without history of pain to the joint trauma and family history of similar illness. On X-ray, wrist showed malformed distal radial epiphysis with dorsal and ulnar shift and with increased length of phalanges suggestive of Madelung deformity. X-ray spine was normal. Ultrasound abdomen showed normal uterus and ovary and her follicle stimulating hormone. Luteinizing hormone was normal and so was urine MPS screening. Based on the above points the diagnosis of LWD was made.

Prolonged Expression of Secreted Enzymes in Dogs After Liver-Directed Delivery of Sleeping Beauty Transposons: Implications for Non-Viral Gene Therapy of Systemic Disease.

PubMed

Aronovich, Elena L; Hyland, Kendra A; Hall, Bryan C; Bell, Jason B; Olson, Erik R; Rusten, Myra Urness; Hunter, David W; Ellinwood, N Matthew; McIvor, R Scott; Hackett, Perry B

2017-07-01

The non-viral, integrating Sleeping Beauty (SB) transposon system is efficient in treating systemic monogenic disease in mice, including hemophilia A and B caused by deficiency of blood clotting factors and mucopolysaccharidosis types I and VII caused by α-L-iduronidase (IDUA) and β-glucuronidase (GUSB) deficiency, respectively. Modified approaches of the hydrodynamics-based procedure to deliver transposons to the liver in dogs were recently reported. Using the transgenic canine reporter secreted alkaline phosphatase (cSEAP), transgenic protein in the plasma was demonstrated for up to 6 weeks post infusion. This study reports that immunosuppression of dogs with gadolinium chloride (GdCl 3 ) prolonged the presence of cSEAP in the circulation up to 5.5 months after a single vector infusion. Transgene expression declined gradually but appeared to stabilize after about 2 months at approximately fourfold baseline level. Durability of transgenic protein expression in the plasma was inversely associated with transient increase of liver enzymes alanine transaminase and aspartate transaminase in response to the plasmid delivery procedure, which suggests a deleterious effect of hepatocellular toxicity on transgene expression. GdCl 3 treatment was ineffective for repeat vector infusions. In parallel studies, dogs were infused with potentially therapeutic transposons. Activities of transgenic IDUA and GUSB in plasma peaked at 50-350% of wildtype, but in the absence of immunosuppression lasted only a few days. Transposition was detectable by excision assay only when the most efficient transposase, SB100X, was used. Dogs infused with transposons encoding canine clotting factor IX (cFIX) were treated with GdCl 3 and showed expression profiles similar to those in cSEAP-infused dogs, with expression peaking at 40% wt (2 μg/mL). It is concluded that GdCl 3 can support extended transgene expression after hydrodynamic introduction of SB transposons in dogs, but that alternative regimens will be required to achieve therapeutic levels of transgene products.

Production of MPS VII mouse (Gustm(hE540A·mE536A)Sly) doubly tolerant to human and mouse β-glucuronidase

PubMed Central

Tomatsu, Shunji; Orii, Koji O.; Vogler, Carole; Grubb, Jeffrey H.; Snella, Elizabeth M.; Gutierrez, Monica; Dieter, Tatiana; Holden, Christopher C.; Sukegawa, Kazuko; Orii, Tadao; Kondo, Naomi; Sly, William S.

2006-01-01

Mucopolysaccharidosis VII (MPS VII, Sly syndrome) is an autosomal recessive lysosomal storage disease caused by β-glucuronidase (GUS) deficiency. A naturally occurring mouse model of that disease has been very useful for studying experimental approaches to therapy. However, immune responses can complicate evaluation of the long-term benefits of enzyme replacement or gene therapy delivered to adult MPS VII mice. To make this model useful for studying the long-term effectiveness and side effects of experimental therapies delivered to adult mice, we developed a new MPS VII mouse model, which is tolerant to both human and murine GUS. To achieve this, we used homologous recombination to introduce simultaneously a human cDNA transgene expressing inactive human GUS into intron 9 of the murine Gus gene and a targeted active site mutation (E536A) into the adjacent exon 10. When the heterozygote products of germline transmission were bred to homozygosity, the homozygous mice expressed no GUS enzyme activity but expressed inactive human GUS protein highly and were tolerant to immune challenge with human enzyme. Expression of the mutant murine Gus gene was reduced to about 10% of normal levels, but the inactive murine GUS enzyme also conferred tolerance to murine GUS. This MPS VII mouse model should be useful to evaluate therapeutic responses in adult mice receiving repetitive doses of enzyme or mice receiving gene therapy as adults. Heterozygotes expressed only 9.5–26% of wild-type levels of murine GUS instead of the expected 50%, indicating a dominant-negative effect of the mutant enzyme monomers on the activity of GUS tetramers in different tissues. Corrective gene therapy in this model should provide high enough levels of expression of normal GUS monomers to overcome the dominant negative effect of mutant monomers on newly synthesized GUS tetramers in most tissues. PMID:12700165

Enzyme replacement therapy with galsulfase in 34 children younger than five years of age with MPS VI.

PubMed

Horovitz, Dafne D G; Magalhães, Tatiana S P C; Acosta, Angelina; Ribeiro, Erlane M; Giuliani, Liane R; Palhares, Durval B; Kim, Chong A; de Paula, Ana Carolina; Kerstenestzy, Marcelo; Pianovski, Mara A D; Costa, Maria Ione F; Santos, Francisca C; Martins, Ana Maria; Aranda, Carolina S; Correa Neto, Jordão; Holanda, Gervina Brady Moreira; Cardoso, Laércio; da Silva, Carlos A B; Bonatti, Renata C F; Ribeiro, Bethania F R; Rodrigues, Maria do Carmo S; Llerena, Juan C

2013-05-01

Mucopolysaccharidosis type VI (MPS VI) is a progressive, chronic and multisystem lysosomal storage disease with a wide disease spectrum. Clinical and biochemical improvements have been reported for MPS VI patients on enzyme replacement therapy (ERT) with rhASB (recombinant human arylsulfatase B; galsulfase, Naglazyme®, BioMarin Pharmaceutical Inc.), making early diagnosis and intervention imperative for optimal patient outcomes. Few studies have included children younger than five years of age. This report describes 34 MPS VI patients that started treatment with galsulfase before five years of age. Data from patients who initiated treatment at <5 years of age were collected from patients' medical records. Baseline and follow-up assessments of common symptoms that led to diagnosis and that were used to evaluate disease progression and treatment efficacy were evaluated. A significant negative correlation was seen with treatment with ERT and urinary GAG levels. Of those with baseline and follow-up growth data, 47% remained on their pre-treatment growth curve or moved to a higher percentile after treatment. Of the 9 patients with baseline and follow-up sleep studies, 5 remained unaffected and 1 patient initially with mild sleep apnea showed improvement. Data regarding cardiac, ophthalmic, central nervous system, hearing, surgical interventions and development are also reported. No patient discontinued treatment due to an adverse event and all that were treatment-emergent resolved. The prescribed dosage of 1mg/kg IV weekly with galsulfase ERT is shown to be safe and effective in slowing and/or improving certain aspects of the disease, although patients should be closely monitored for complications associated with the natural history of the disease, especially cardiac valve involvement and spinal cord compression. A long-term follow-up investigation of this group of children will provide further information on the benefits of early treatment as well as disease progression and treatment efficacy and safety in this young patient population. Copyright © 2013 Elsevier Inc. All rights reserved.

Assessment and diagnosis of suspected glaucoma in patients with mucopolysaccharidosis.

PubMed

Ashworth, Jane; Flaherty, Maree; Pitz, Susanne; Ramlee, Azura

2015-03-01

The mucopolysaccharidoses (MPS) are a group of rare lysosomal storage disorders, characterized by the accumulation of glycosaminoglycans within multiple organ systems including the eye. This study aimed to determine the prevalence of glaucoma in patients with MPS, as well as the characteristics, diagnosis and management of patients with MPS and glaucoma. A multicentre retrospective case-note review was carried out by ophthalmologists from four tertiary referral centres to identify patients with MPS who had been treated for glaucoma. Clinical ophthalmological data were collected using standardized data collection forms. Fourteen patients were identified (27 eyes) of 294 patients with MPS. The prevalence of glaucoma ranged from 2.1% to 12.5%. The median age at diagnosis of glaucoma was 8 years. Diagnostic evaluation of glaucoma was incomplete in many patients: intraocular pressure was documented in all eyes, but optic disc appearance was only assessed in 67%, central corneal thickness in 26%, visual fields in 19% and iridocorneal angle in 15%. Patients with MPS need regular assessment for possible glaucoma including during childhood. Multiple factors contribute to the challenges of assessment, diagnosis and monitoring of glaucoma in these patients. © 2015 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.

Spinal Cord Injury After Extremity Surgery in Children With Thoracic Kyphosis.

PubMed

Pruszczynski, Blazej; Mackenzie, William G; Rogers, Kenneth; White, Klane K

2015-10-01

Spinal cord injury is a rare complication after lower extremity surgery in children with skeletal dysplasia and thoracic kyphosis. We encountered two patients who had this complication, from among 51 (39 from Nemours/Alfred I. duPont Hospital for Children and 12 from Seattle Children's Hospital) who underwent lower extremity surgery during an 8.5-year period (June 2004 to December 2012). Because spinal cord injury is a devastating complication likely not known to most physicians treating patients with skeletal dysplasias, we sought to examine factors that may contribute to this rare complication. We performed a retrospective review of two patients with skeletal dysplasia who had paraplegia develop after extremity surgery. Outcome measures included operative time, vital signs, and postsurgery recovery of neurologic deficit. MR images were reviewed. Two patients were found-an 8.5-year-old boy with spondyloepiphyseal dysplasia congenita with a 76°-thoracic kyphosis apex at T4 and a 6.5-year-old boy with mucopolysaccharidosis type 1-H with an 80°-thoracic kyphosis apex at T2. Bilateral proximal femoral osteotomies or bilateral innominate and proximal femoral osteotomies had been performed. The spinal cord injuries occurred at the apex of the kyphosis as determined by clinical examination and MRI assessment. In both patients, the mean arterial blood pressure decreased below 50 mm Hg and might be a factor in the etiology of the paralysis. The first patient recovered motor function in 5 months; the second had no recovery. Paraplegia is extremely rare after nonspine operations. Many factors contribute to the risk for a spinal cord event: low mean arterial pressure, duration of the surgery, position on the operating table, the kyphotic spine deformity, or unappreciated vascular disease. Motor-evoked potentials and somatosensory-evoked potentials together potentially provide high sensitivity and specificity for predicting a postoperative neurologic deficit. Based on our two patients with skeletal dysplasia and a literature review of patients with hyperkyphosis undergoing extremity surgery, the surgeon must be aware of the risk of spinal cord injury. Careful preoperative assessment possibly including MRI of the spine is recommended. Mean arterial pressure should be maintained at a safe level; neuromonitoring should be considered.

Correlation between urinary GAG and anti-idursulfase ERT neutralizing antibodies during treatment with NICIT immune tolerance regimen: A case report☆,☆☆

PubMed Central

Kim, Sarah; Whitley, Chester B.; Jarnes Utz, Jeanine R.

2018-01-01

Introduction Antibodies to intravenous idursulfase enzyme replacement therapy (ERT) for patients with Hunter syndrome (mucopolysaccharidosis type II, MPS II) can have a harmful clinical impact, including both increasing risk of infusion reactions and inhibiting therapeutic activity. Thus, failure to monitor anti-idursulfase antibodies and neutralizing antibodies, and delays in reporting results, may postpone critical clinical decisions. Hypothesis Urinary glycosaminoglycan (GAG) levels may be used as a biomarker for anti-idursulfase antibodies and neutralizing antibodies to improve timeliness in monitoring and managing ERT. Methods This is a case report describing a patient with MPS II with high levels of neutralizing antibodies and worsened clinical status who was treated for five years with a non-immunosuppressive and non-cytotoxic immune tolerance (NICIT) regimen, consisting of intravenous immune globulin and frequent infusions of idursulfase. Neutralizing antibodies and total anti-idursulfase antibodies were measured by two different methods, the direct 1,9-dimethylmethylene blue (DMB) assay and cetylpyridinium chloride carbazole-borate (CPC) assay. Results Neutralizing antibodies, measured as percent inhibition of enzyme activity and also by total neutralizing antibody titer, were correlated with quantitative urinary GAG measured by DMB assay (p = 0.026, p = 0.0067), and quantitative urinary GAG by CPC assay with percent inhibition of enzyme activity by neutralizing antibodies (p = 0.0475). The NICIT regimen showed a sustained immune tolerance after five years and was well-tolerated. Conclusions Urinary GAG, measured by DMB assay, may be a biomarker for anti-idursulfase neutralizing antibodies and is useful for managing immune tolerance regimens for patients with MPS II who have high levels of anti-idursulfase neutralizing antibodies. This study highlights the importance of regular and frequent monitoring of urinary GAG in patients with MPS II who are receiving ERT. The NICIT regimen, with less drug toxicities, may be preferred in patients with MPS who have a high risk of infections and whose disease progresses less rapidly than some other lysosomal storage diseases, such as infantile Pompe disease. PMID:28610913

A selective screening program for the early detection of mucopolysaccharidosis: Results of the FIND project - a 2-year follow-up study.

PubMed

Colón, Cristóbal; Alvarez, J Victor; Castaño, Cristina; Gutierrez-Solana, Luís G; Marquez, Ana M; O'Callaghan, María; Sánchez-Valverde, Félix; Yeste, Carmen; Couce, María-Luz

2017-05-01

The mucopolysaccharidoses (MPSs) are underdiagnosed but they are evaluated in few newborn screening programs, probably due to the many challenges remaining, such as the identification of late-onset phenotypes. Systematic screening at the onset of clinical symptoms could help to early identify patients who may benefit from specific treatments. The aim of this prospective study was to assess a novel selective screening program, the FIND project, targeting patients aged 0 to 16 years with clinical manifestations of MPS. The project was designed to increase awareness of these diseases among pediatricians and allow early diagnosis.From July 2014 to June 2016, glycosaminoglycan (GAG) levels normalized to creatinine levels were determined in urine-impregnated analytical paper submitted by pediatricians who had patients with clinical signs and/or symptoms compatible with MPS. When high GAG concentrations were detected, a new liquid urine sample was requested to confirm and identify the GAG present. When a specific form of MPS was suspected, enzyme activity was analyzed using blood-impregnated paper to determine MPS type (I, IIIB, IIIC, IVA, IVB, VI, or VII). Age-specific reference values for GAG were previously established using 145 urine samples from healthy children.GAG levels were normal in 147 (81.7%) of the 180 initial samples received. A liquid sample was requested for the other 33 cases (18.3%); GAG levels were normal in 13 of these and slightly elevated in 12, although the electrophoresis study showed no evidence of MPS. Elevated levels with corresponding low enzymatic activity were confirmed in 8 cases. The mean time from onset of clinical symptoms to detection of MPS was 22 months, and just 2 cases were detected at the beginning of the project were detected with 35 and 71 months of evolution of clinical symptoms. Our screening strategy for MPS had a sensitivity of 100%, a specificity of 85%, and a positive predictive value of 24%.The FIND project is a useful and cost-effective screening method for increasing awareness of MPS among pediatricians and enabling the detection of MPS at onset of clinical symptoms.

Treatment of cuff-related tracheal stenosis with a fully covered retrievable expandable metallic stent.

PubMed

Chen, G; Wang, Z; Liang, X; Wang, Y; Wang, Y; Wang, Z; Xian, J

2013-04-01

To investigate the clinical effectiveness, complications, and optimal duration of use of covered retrievable expandable metallic stents in the management of cuff-related tracheal stenosis. Twenty-one patients with cuff-related tracheal stenosis, Meyer-Cotton grade II (29%) and III (71%), who underwent fluoroscopically guided placement of covered retrievable expandable metallic stents were studied. Sixty-four-section computed tomography (CT) and bronchovideoscopy were performed prior to stent insertion, 1 month after stent insertion, in the case of stent-related complications, and after stent removal. Clinical manifestations, Hugh-Jones classification, and forced expiratory volume in 1 s (FEV1) were used to evaluate respiratory function before and after stent insertion and removal. The diameter of the stricture and FEV1 changes before insertion and after removal were analysed using the paired samples t-test. A p-value of ≤0.05 was considered statistically significant. Twenty-one patients had 27 covered retrievable expandable metallic stents placed. Stents were electively removed from 20 patients. The median duration of stent placement was 5 months (range 4-12 months). One stent was not removed due to mucopolysaccharidosis type II (MPS II or Hunter syndrome) with tracheomalacia. After stent removal, airway dimensions increased and airway occlusion was symptomatically relieved in all patients. CT and bronchovideoscopy showed patent lumens with increased dimensions. Stent-related complications occurred in 19 (91%) patients, including granulation tissue formation (n = 18, 86%), stent migration and stent expectoration (n = 2, 10%), mucus plugging (n = 1, 5%), and halitosis (n = 6, 29%). Some patients experienced multiple complications, which were all managed effectively while the stent was still in place. There was a statistically significant difference in the diameter of the stricture and FEV1 between the time of stent insertion and removal. An improvement in Hugh-Jones classification of greater than one grade was seen in patients after stent removal. Temporary placement of a fully covered retrievable expandable metallic stent is safe and effective in cuff-related tracheal stenosis. The optimal duration of stent placement may be 4-8 months. Copyright © 2012 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.

The dog genome map and its use in mammalian comparative genomics.

PubMed

Switonski, Marek; Szczerbal, Izabela; Nowacka, Joanna

2004-01-01

The dog genome organization was extensively studied in the last ten years. The most important achievements are the well-developed marker genome maps, including over 3200 marker loci, and a survey of the DNA genome sequence. This knowledge, along with the most advanced map of the human genome, turned out to be very useful in comparative genomic studies. On the one hand, it has promoted the development of marker genome maps of other species of the family Canidae (red fox, arctic fox, Chinese raccoon dog) as well as studies on the evolution of their karyotype. But the most important approach is the comparative analysis of human and canine hereditary diseases. At present, causative gene mutations are known for 30 canine hereditary diseases. A majority of them have human counterparts with similar clinical and molecular features. Studies on identification of genes having a major impact on some multifactorial diseases (hip dysplasia, epilepsy) and cancers (multifocal renal cystadenocarcinoma and nodular dermatofibrosis) are advanced. Very promising are the results of gene therapy for certain canine monogenic diseases (haemophilia, hereditary retinal dystrophy, mucopolysaccharidosis), which have human equivalents. The above-mentioned examples prove a very important model role of the dog in studies of human genetic diseases. On the other hand, the identification of gene mutations responsible for hereditary diseases has a substantial impact on breeding strategy in the dog.

Immune tolerance improves the efficacy of enzyme replacement therapy in canine mucopolysaccharidosis I

PubMed Central

Dickson, Patricia; Peinovich, Maryn; McEntee, Michael; Lester, Thomas; Le, Steven; Krieger, Aimee; Manuel, Hayden; Jabagat, Catherine; Passage, Merry; Kakkis, Emil D.

2008-01-01

Mucopolysaccharidoses (MPSs) are lysosomal storage diseases caused by a deficit in the enzymes needed for glycosaminoglycan (GAG) degradation. Enzyme replacement therapy with recombinant human α-l-iduronidase successfully reduces lysosomal storage in canines and humans with iduronidase-deficient MPS I, but therapy usually also induces antibodies specific for the recombinant enzyme that could reduce its efficacy. To understand the potential impact of α-l-iduronidase–specific antibodies, we studied whether inducing antigen-specific immune tolerance to iduronidase could improve the effectiveness of recombinant iduronidase treatment in canines. A total of 24 canines with MPS I were either tolerized to iduronidase or left nontolerant. All canines received i.v. recombinant iduronidase at the FDA-approved human dose or a higher dose for 9–44 weeks. Nontolerized canines developed iduronidase-specific antibodies that proportionally reduced in vitro iduronidase uptake. Immune-tolerized canines achieved increased tissue enzyme levels at either dose in most nonreticular tissues and a greater reduction in tissue GAG levels, lysosomal pathology, and urinary GAG excretion. Tolerized MPS I dogs treated with the higher dose received some further benefit in the reduction of GAGs in tissues, urine, and the heart valve. Therefore, immune tolerance to iduronidase improved the efficacy of enzyme replacement therapy with recombinant iduronidase in canine MPS I and could potentially improve outcomes in patients with MPS I and other lysosomal storage diseases. PMID:18654665

Recombinant human N-acetylgalactosamine-6-sulfate sulfatase (GALNS) produced in the methylotrophic yeast Pichia pastoris

PubMed Central

Rodríguez-López, Alexander; Alméciga-Díaz, Carlos J.; Sánchez, Jhonnathan; Moreno, Jefferson; Beltran, Laura; Díaz, Dennis; Pardo, Andrea; Ramírez, Aura María; Espejo-Mojica, Angela J.; Pimentel, Luisa; Barrera, Luis A.

2016-01-01

Mucopolysaccharidosis IV A (MPS IV A, Morquio A disease) is a lysosomal storage disease (LSD) produced by mutations on N-acetylgalactosamine-6-sulfate sulfatase (GALNS). Recently an enzyme replacement therapy (ERT) for this disease was approved using a recombinant enzyme produced in CHO cells. Previously, we reported the production of an active GALNS enzyme in Escherichia coli that showed similar stability properties to that of a recombinant mammalian enzyme though it was not taken-up by culture cells. In this study, we showed the production of the human recombinant GALNS in the methylotrophic yeast Pichia pastoris GS115 (prGALNS). We observed that removal of native signal peptide and co-expression with human formylglycine-generating enzyme (SUMF1) allowed an improvement of 4.5-fold in the specific GALNS activity. prGALNS enzyme showed a high stability at 4 °C, while the activity was markedly reduced at 37 and 45 °C. It was noteworthy that prGALNS was taken-up by HEK293 cells and human skin fibroblasts in a dose-dependent manner through a process potentially mediated by an endocytic pathway, without any additional protein or host modification. The results show the potential of P. pastoris in the production of a human recombinant GALNS for the development of an ERT for Morquio A. PMID:27378276

Gelatinase activity in synovial fluid and synovium obtained from healthy and osteoarthritic joints of dogs.

PubMed

Volk, Susan W; Kapatkin, Amy S; Haskins, Mark E; Walton, Raquel M; D'Angelo, Marina

2003-10-01

To determine matrix metalloproteinase (MMP) activity in synovial fluid (SF) obtained from the joints of dogs with degenerative joint disease (DJD) secondary to various underlying conditions. 35 samples of SF obtained from 18 clinically normal (control) dogs and 34 samples of SF obtained from 17 dogs with DJD; dogs with DJD were from 2 populations (client-owned dogs and research dogs that had DJD secondary to the lysosomal storage disease mucopolysaccharidosis VII). MMP activity in samples of SF was semiquantitatively examined by use of gelatin or casein zymography. Western blot analysis was performed by use of antibodies for MMP-2 and MMP-9. In addition, in situ MMP activity was observed in sections of synovial membrane obtained from healthy and osteoarthritic joints. Samples of SF from osteoarthritic joints had higher MMP-2 activity and dramatically increased MMP-9 activity, compared with values for healthy joints. Substrate-overlay analyses indicated minimal gelatin-degrading activity in synoviocytes obtained from control dogs, whereas greater activity was seen in osteoarthritic synoviocytes, with additional activity in the underlying tissue. Higher MMP-2 activity and dramatic increases in MMP-9 activity were associated with the osteoarthritic state, even though MMP-2 activity was detected in healthy joints. This study expands information on MMP production in SF of osteoarthritic joints in other species and documents the similarity of MMP activity patterns regardless of the cause of DJD.

Address substrates as promising targets for laser histochemical surgery as a nontraditional line in medicine

NASA Astrophysics Data System (ADS)

Piruzyan, L. A.; Mikhailovskiy, Ye. M.; Piruzyan, A. L.

1999-12-01

The priority concept of the laser histochemical surgery as a potentially novel line in medicine is presented. The histochemical stains, selectively coloring some targets (address substrates), that are cells or their biochemical ingredients, sensitize them to the laser irradiation. Such sensitization to laser irradiation by staining turns the colored targets into targets for the laser beam. The action of the irradiation onto its specific targets beats out of the cell its ingredients which participate in a pathology process. In particular, the beating of a stained ferment out of the general stage of biochemical processes characteristic for the pathology interrupts their currence. The laser beam, when beating out its stained targets without any damage of the unstained tissues, acts like a scalpel that cuts off affected tissues not brushing healthy ones. A scheme for testing stains as sensitizers of the `address substrates' to the laser irradiation is presented. As the criterion of the stain sensitization the fact was chosen of absence or weakness of pathomorphologic and biochemical signs of the disease in an experimental model of the pathology irradiated with laser after a stain use, while the pathology signs are present in a control sample. The basis is done for study of the histochemical stains as potential means for the laser histochemical surgery of disseminated sclerosis, mucopolysaccharidosis, hypercholesterolemia, myocardial infarction, cardiosclerosis, caries and parodontosis.

A comparison of the effect of xinruibai versus filgrastim on hematopoietic reconstruction after allogeneic hematopoietic stem cell transplantation.

PubMed

Ye, Qixiang; Jiang, Hebi; Jiang, Hua

2018-05-31

To compare the effect of xinruibai (Pegfilgrastim) and filgrastim injections on white blood cell and platelet (PLT) recovery, adverse events, post-operative complications, and cost effectiveness after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Children who underwent allo-HSCT at our hospital from January 2014 to May 2017 due to thalassemia major, aplastic anemia, leukemia, and mucopolysaccharidosis were included. Among the children, 53 received xinruibai injections and 33 received filgrastim injections. There were no significant differences in the average time to neutrophil and platelet recovery, the incidence of post-operative complications after allo-HSCT, the number of red blood cell and PLT infusions, or the incidence of adverse events related to the injection between two groups (P >  0.05). The pain score was 3.06 (SD 0.41) for the xinruibai group and 25.18 (SD 6.22) for the filgrastim group, indicating significant differences between the two groups (P <  0.001). No difference was found in the hospitalization cost. The cost of the granulocyte-colony stimulating factor (G-CSF) was 257.11 ± 61.87 Euro in the xinruibai group and 214.79 ± 0.00 Euro in the filgrastim group, showing significant difference (P <  0.001). Xinruibai injection was more convenient, simple, effective, and safer than filgrastim.

Multivariate poisson lognormal modeling of crashes by type and severity on rural two lane highways.

PubMed

Wang, Kai; Ivan, John N; Ravishanker, Nalini; Jackson, Eric

2017-02-01

In an effort to improve traffic safety, there has been considerable interest in estimating crash prediction models and identifying factors contributing to crashes. To account for crash frequency variations among crash types and severities, crash prediction models have been estimated by type and severity. The univariate crash count models have been used by researchers to estimate crashes by crash type or severity, in which the crash counts by type or severity are assumed to be independent of one another and modelled separately. When considering crash types and severities simultaneously, this may neglect the potential correlations between crash counts due to the presence of shared unobserved factors across crash types or severities for a specific roadway intersection or segment, and might lead to biased parameter estimation and reduce model accuracy. The focus on this study is to estimate crashes by both crash type and crash severity using the Integrated Nested Laplace Approximation (INLA) Multivariate Poisson Lognormal (MVPLN) model, and identify the different effects of contributing factors on different crash type and severity counts on rural two-lane highways. The INLA MVPLN model can simultaneously model crash counts by crash type and crash severity by accounting for the potential correlations among them and significantly decreases the computational time compared with a fully Bayesian fitting of the MVPLN model using Markov Chain Monte Carlo (MCMC) method. This paper describes estimation of MVPLN models for three-way stop controlled (3ST) intersections, four-way stop controlled (4ST) intersections, four-way signalized (4SG) intersections, and roadway segments on rural two-lane highways. Annual Average Daily traffic (AADT) and variables describing roadway conditions (including presence of lighting, presence of left-turn/right-turn lane, lane width and shoulder width) were used as predictors. A Univariate Poisson Lognormal (UPLN) was estimated by crash type and severity for each highway facility, and their prediction results are compared with the MVPLN model based on the Average Predicted Mean Absolute Error (APMAE) statistic. A UPLN model for total crashes was also estimated to compare the coefficients of contributing factors with the models that estimate crashes by crash type and severity. The model coefficient estimates show that the signs of coefficients for presence of left-turn lane, presence of right-turn lane, land width and speed limit are different across crash type or severity counts, which suggest that estimating crashes by crash type or severity might be more helpful in identifying crash contributing factors. The standard errors of covariates in the MVPLN model are slightly lower than the UPLN model when the covariates are statistically significant, and the crash counts by crash type and severity are significantly correlated. The model prediction comparisons illustrate that the MVPLN model outperforms the UPLN model in prediction accuracy. Therefore, when predicting crash counts by crash type and crash severity for rural two-lane highways, the MVPLN model should be considered to avoid estimation error and to account for the potential correlations among crash type counts and crash severity counts. Copyright © 2016 Elsevier Ltd. All rights reserved.

Severity of post-stroke aphasia according to aphasia type and lesion location in Koreans.

PubMed

Kang, Eun Kyoung; Sohn, Hae Min; Han, Moon-Ku; Kim, Won; Han, Tai Ryoon; Paik, Nam-Jong

2010-01-01

To determine the relations between post-stroke aphasia severity and aphasia type and lesion location, a retrospective review was undertaken using the medical records of 97 Korean patients, treated within 90 days of onset, for aphasia caused by unilateral left hemispheric stroke. Types of aphasia were classified according to the validated Korean version of the Western Aphasia Battery (K-WAB), and severities of aphasia were quantified using WAB Aphasia Quotients (AQ). Lesion locations were classified as cortical or subcortical, and were determined by magnetic resonance imaging. Two-step cluster analysis was performed using AQ values to classify aphasia severity by aphasia type and lesion location. Cluster analysis resulted in four severity clusters: 1) mild; anomic type, 2) moderate; Wernicke's, transcortical motor, transcortical sensory, conduction, and mixed transcortical types, 3) moderately severe; Broca's aphasia, and 4) severe; global aphasia, and also in three lesion location clusters: 1) mild; subcortical 2) moderate; cortical lesions involving Broca's and/or Wernicke's areas, and 3) severe; insular and cortical lesions not in Broca's or Wernicke's areas. These results revealed that within 3 months of stroke, global aphasia was the more severely affected type and cortical lesions were more likely to affect language function than subcortical lesions.

Changes in skeletal muscle biochemistry and histology relative to fiber type in rats with heart failure.

PubMed

Delp, M D; Duan, C; Mattson, J P; Musch, T I

1997-10-01

One of the primary consequences of left ventricular dysfunction (LVD) after myocardial infarction is a decrement in exercise capacity. Several factors have been hypothesized to account for this decrement, including alterations in skeletal muscle metabolism and aerobic capacity. The purpose of this study was to determine whether LVD-induced alterations in skeletal muscle enzyme activities, fiber composition, and fiber size are 1) generalized in muscles or specific to muscles composed primarily of a given fiber type and 2) related to the severity of the LVD. Female Wistar rats were divided into three groups: sham-operated controls (n = 13) and rats with moderate (n = 10) and severe (n = 7) LVD. LVD was surgically induced by ligating the left main coronary artery and resulted in elevations (P < 0.05) in left ventricular end-diastolic pressure (sham, 5 +/- 1 mmHg; moderate LVD, 11 +/- 1 mmHg; severe LVD, 25 +/- 1 mmHg). Moderate LVD decreased the activities of phosphofructokinase (PFK) and citrate synthase in one muscle composed of type IIB fibers but did not modify fiber composition or size of any muscle studied. However, severe LVD diminished the activity of enzymes involved in terminal and beta-oxidation in muscles composed primarily of type I fibers, type IIA fibers, and type IIB fibers. In addition, severe LVD induced a reduction in the activity of PFK in type IIB muscle, a 10% reduction in the percentage of type IID/X fibers, and a corresponding increase in the portion of type IIB fibers. Atrophy of type I fibers, type IIA fibers, and/or type IIB fibers occurred in soleus and plantaris muscles of rats with severe LVD. These data indicate that rats with severe LVD after myocardial infarction exhibit 1) decrements in mitochondrial enzyme activities independent of muscle fiber composition, 2) a reduction in PFK activity in type IIB muscle, 3) transformation of type IID/X to type IIB fibers, and 4) atrophy of type I, IIA, and IIB fibers.

Changes in skeletal muscle biochemistry and histology relative to fiber type in rats with heart failure

NASA Technical Reports Server (NTRS)

Delp, M. D.; Duan, C.; Mattson, J. P.; Musch, T. I.

1997-01-01

One of the primary consequences of left ventricular dysfunction (LVD) after myocardial infarction is a decrement in exercise capacity. Several factors have been hypothesized to account for this decrement, including alterations in skeletal muscle metabolism and aerobic capacity. The purpose of this study was to determine whether LVD-induced alterations in skeletal muscle enzyme activities, fiber composition, and fiber size are 1) generalized in muscles or specific to muscles composed primarily of a given fiber type and 2) related to the severity of the LVD. Female Wistar rats were divided into three groups: sham-operated controls (n = 13) and rats with moderate (n = 10) and severe (n = 7) LVD. LVD was surgically induced by ligating the left main coronary artery and resulted in elevations (P < 0.05) in left ventricular end-diastolic pressure (sham, 5 +/- 1 mmHg; moderate LVD, 11 +/- 1 mmHg; severe LVD, 25 +/- 1 mmHg). Moderate LVD decreased the activities of phosphofructokinase (PFK) and citrate synthase in one muscle composed of type IIB fibers but did not modify fiber composition or size of any muscle studied. However, severe LVD diminished the activity of enzymes involved in terminal and beta-oxidation in muscles composed primarily of type I fibers, type IIA fibers, and type IIB fibers. In addition, severe LVD induced a reduction in the activity of PFK in type IIB muscle, a 10% reduction in the percentage of type IID/X fibers, and a corresponding increase in the portion of type IIB fibers. Atrophy of type I fibers, type IIA fibers, and/or type IIB fibers occurred in soleus and plantaris muscles of rats with severe LVD. These data indicate that rats with severe LVD after myocardial infarction exhibit 1) decrements in mitochondrial enzyme activities independent of muscle fiber composition, 2) a reduction in PFK activity in type IIB muscle, 3) transformation of type IID/X to type IIB fibers, and 4) atrophy of type I, IIA, and IIB fibers.

Severity of Post-stroke Aphasia According to Aphasia Type and Lesion Location in Koreans

PubMed Central

Kang, Eun Kyoung; Sohn, Hae Min; Han, Moon-Ku; Kim, Won; Han, Tai Ryoon

2010-01-01

To determine the relations between post-stroke aphasia severity and aphasia type and lesion location, a retrospective review was undertaken using the medical records of 97 Korean patients, treated within 90 days of onset, for aphasia caused by unilateral left hemispheric stroke. Types of aphasia were classified according to the validated Korean version of the Western Aphasia Battery (K-WAB), and severities of aphasia were quantified using WAB Aphasia Quotients (AQ). Lesion locations were classified as cortical or subcortical, and were determined by magnetic resonance imaging. Two-step cluster analysis was performed using AQ values to classify aphasia severity by aphasia type and lesion location. Cluster analysis resulted in four severity clusters: 1) mild; anomic type, 2) moderate; Wernicke's, transcortical motor, transcortical sensory, conduction, and mixed transcortical types, 3) moderately severe; Broca's aphasia, and 4) severe; global aphasia, and also in three lesion location clusters: 1) mild; subcortical 2) moderate; cortical lesions involving Broca's and/or Wernicke's areas, and 3) severe; insular and cortical lesions not in Broca's or Wernicke's areas. These results revealed that within 3 months of stroke, global aphasia was the more severely affected type and cortical lesions were more likely to affect language function than subcortical lesions. PMID:20052357

An evaluation framework for funding drugs for rare diseases.

PubMed

Winquist, Eric; Bell, Chaim M; Clarke, Joe T R; Evans, Gerald; Martin, Janet; Sabharwal, Mona; Gadhok, Anita; Stevenson, Helen; Coyle, Doug

2012-01-01

For rare diseases it may be difficult to generate data from randomized trials to support funding of a drug. Enzyme replacement therapies for diseases of inherited metabolic enzyme deficiency provide an example of this dilemma. The Ontario Public Drug Programs convened the Drugs for Rare Diseases Working Group to develop a policy for assessing these drugs. The Drugs for Rare Diseases Working Group developed terms of reference expecting that the ideal policy product would be transparent and consistent and address unique aspects of the treatment of a specific rare condition while being adaptable to other dissimilar conditions. The perspective was that of a public payer addressing requests for funding generated for a specific drug, and included respect for the principles of "accountability for reasonableness" of Daniels and Sabin. A seven-step framework was developed and tested by using the case study of idursulfase for mucopolysaccharidosis II (Hunter disease). Estimation of clinical effectiveness was done by using decision modeling. The model developed informed funding recommendations and ultimately led to an agreement with the manufacturer allowing funding of idursulfase in Ontario. This policy framework attempts to address the policy challenges of funding drugs for rare diseases. The framework will be used to assess other drugs in future and will inevitably require modification with experience. It is hoped that it may be of value to other policymakers. Copyright © 2012 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.

Evaluation of Disease Lesions in the Developing Canine MPS IIIA Brain.

PubMed

Winner, Leanne K; Marshall, Neil R; Jolly, Robert D; Trim, Paul J; Duplock, Stephen K; Snel, Marten F; Hemsley, Kim M

2018-06-20

Mucopolysaccharidosis IIIA (MPS IIIA) is an inherited neurodegenerative disease of childhood that results in early death. Post-mortem studies have been carried out on human MPS IIIA brain, but little is known about early disease development. Here, we utilised the Huntaway dog model of MPS IIIA to evaluate disease lesion development from 2 to 24 weeks of age. A significant elevation in primarily stored heparan sulphate was observed in all brain regions assessed in MPS IIIA pups ≤9.5 weeks of age. There was a significant elevation in secondarily stored ganglioside (GM3 36:1) in ≤9.5-week-old MPS IIIA pup cerebellum, and other brain regions also exhibited accumulation of this lipid with time. The number of neural stem cells and neuronal precursor cells was essentially unchanged in MPS IIIA dog brain (c.f. unaffected) over the time course assessed, a finding corroborated by neuron cell counts. We observed early neuroinflammatory changes in young MPS IIIA pup brain, with significantly increased numbers of activated microglia recorded in all but one brain region in MPS IIIA pups ≤9.5 weeks of age (c.f. age-matched unaffected pups). In conclusion, infant-paediatric-stage MPS IIIA canine brain exhibits substantial and progressive primary and secondary substrate accumulation, coupled with early and robust microgliosis. Whilst early initiation of treatment is likely to be required to maintain optimal neurological function, the brain's neurodevelopmental potential appears largely unaffected by the disease process; further investigations confirming this are warranted.

Classifying Adverse Events in the Dental Office.

PubMed

Kalenderian, Elsbeth; Obadan-Udoh, Enihomo; Maramaldi, Peter; Etolue, Jini; Yansane, Alfa; Stewart, Denice; White, Joel; Vaderhobli, Ram; Kent, Karla; Hebballi, Nutan B; Delattre, Veronique; Kahn, Maria; Tokede, Oluwabunmi; Ramoni, Rachel B; Walji, Muhammad F

2017-06-30

Dentists strive to provide safe and effective oral healthcare. However, some patients may encounter an adverse event (AE) defined as "unnecessary harm due to dental treatment." In this research, we propose and evaluate two systems for categorizing the type and severity of AEs encountered at the dental office. Several existing medical AE type and severity classification systems were reviewed and adapted for dentistry. Using data collected in previous work, two initial dental AE type and severity classification systems were developed. Eight independent reviewers performed focused chart reviews, and AEs identified were used to evaluate and modify these newly developed classifications. A total of 958 charts were independently reviewed. Among the reviewed charts, 118 prospective AEs were found and 101 (85.6%) were verified as AEs through a consensus process. At the end of the study, a final AE type classification comprising 12 categories, and an AE severity classification comprising 7 categories emerged. Pain and infection were the most common AE types representing 73% of the cases reviewed (56% and 17%, respectively) and 88% were found to cause temporary, moderate to severe harm to the patient. Adverse events found during the chart review process were successfully classified using the novel dental AE type and severity classifications. Understanding the type of AEs and their severity are important steps if we are to learn from and prevent patient harm in the dental office.

Type 2 diabetes mellitus in people with severe mental illness: inequalities by ethnicity and age. Cross-sectional analysis of 588 408 records from the UK.

PubMed

Das-Munshi, J; Ashworth, M; Dewey, M E; Gaughran, F; Hull, S; Morgan, C; Nazroo, J; Petersen, I; Schofield, P; Stewart, R; Thornicroft, G; Prince, M J

2017-07-01

To investigate whether the association of severe mental illness with Type 2 diabetes varies by ethnicity and age. We conducted a cross-sectional analysis of data from an ethnically diverse sample of 588 408 individuals aged ≥18 years, registered to 98% of general practices (primary care) in London, UK. The outcome of interest was prevalent Type 2 diabetes. Relative to people without severe mental illness, the relative risk of Type 2 diabetes in people with severe mental illness was greatest in the youngest age groups. In the white British group the relative risks were 9.99 (95% CI 5.34, 18.69) in those aged 18-34 years, 2.89 (95% CI 2.43, 3.45) in those aged 35-54 years and 1.16 (95% CI 1.04, 1.30) in those aged ≥55 years, with similar trends across all ethnic minority groups. Additional adjustment for anti-psychotic prescriptions only marginally attenuated the associations. Assessment of estimated prevalence of Type 2 diabetes in severe mental illness by ethnicity (absolute measures of effect) indicated that the association between severe mental illness and Type 2 diabetes was more marked in ethnic minorities than in the white British group with severe mental illness, especially for Indian, Pakistani and Bangladeshi individuals with severe mental illness. The relative risk of Type 2 diabetes is elevated in younger populations. Most associations persisted despite adjustment for anti-psychotic prescriptions. Ethnic minority groups had a higher prevalence of Type 2 diabetes in the presence of severe mental illness. Future research and policy, particularly with respect to screening and clinical care for Type 2 diabetes in populations with severe mental illness, should take these findings into account. © 2016 The Authors. Diabetic Medicine published by John Wiley & Sons Ltd on behalf of Diabetes UK.

Type D personality is related to severity of acute coronary syndrome in patients with recurrent cardiovascular disease.

PubMed

Garcia-Retamero, Rocio; Petrova, Dafina; Arrebola-Moreno, Antonio; Catena, Andrés; Ramírez-Hernández, José A

2016-09-01

To investigate the relationship between Type D (distressed) personality and cardiac biomarkers of disease severity in patients with acute coronary syndrome. To identify potential mechanisms behind the effect of Type D personality on cardiovascular disease (CVD). Cross-sectional. Patients (N = 215) with acute coronary syndrome completed a survey including a measure of Type D personality. Blood samples including a lipid profile and cardiac enzymes were taken within 3 days after the cardiovascular event. Data were analysed using simple correlations, multiple regressions, and mediation analyses. Type D personality was more predictive of severity of the acute coronary syndrome among patients with previous CVD compared to patients without previous CVD. Among patients with previous CVD, Type D personality was associated with the presence of ST elevation (R(2)  =.07) and more damage to the myocardium as indicated by higher troponin-I (R(2)  = .05) and myoglobin (R(2)  = .07) levels. These effects were independent from demographics, CV risk factors, and depression. Lower HDL cholesterol levels mediated the relationship between Type D personality and disease severity (Κ(2)  = .12 [95% CI 0.02, 0.28]) for myoglobin and Κ(2)  = .08 [95% CI 0.01, 0.21] for troponin-I). Type D personality was related to a worse lipid profile and more severe acute coronary syndrome in patients with previous history of CVD. Given the strong relationship between disease severity and subsequent mortality, these results suggest that severity of the myocardial infarction may be a potential mechanism explaining increased mortality in Type D patients with recurrent CVD. Statement of contribution What is already known on this subject? Type D personality has been related to worse outcomes in cardiac patients. However, recent studies show mixed results, suggesting the need to clarify potential mechanisms. What does this study add? Type D personality is related to severity of acute coronary syndrome in patients with previous history of cardiovascular disease. This effect is partially accounted for by lower HDL levels in Type D patients. Disease severity is a potential mechanism by which Type D personality may affect cardiovascular health of patients with recurrent CVD. © 2016 The British Psychological Society.

An Acoustic Study of the Relationships among Neurologic Disease, Dysarthria Type, and Severity of Dysarthria

ERIC Educational Resources Information Center

Kim, Yunjung; Kent, Raymond D.; Weismer, Gary

2011-01-01

Purpose: This study examined acoustic predictors of speech intelligibility in speakers with several types of dysarthria secondary to different diseases and conducted classification analysis solely by acoustic measures according to 3 variables (disease, speech severity, and dysarthria type). Method: Speech recordings from 107 speakers with…

Using data mining techniques to predict the severity of bicycle crashes.

PubMed

Prati, Gabriele; Pietrantoni, Luca; Fraboni, Federico

2017-04-01

To investigate the factors predicting severity of bicycle crashes in Italy, we used an observational study of official statistics. We applied two of the most widely used data mining techniques, CHAID decision tree technique and Bayesian network analysis. We used data provided by the Italian National Institute of Statistics on road crashes that occurred on the Italian road network during the period ranging from 2011 to 2013. In the present study, the dataset contains information about road crashes occurred on the Italian road network during the period ranging from 2011 to 2013. We extracted 49,621 road accidents where at least one cyclist was injured or killed from the original database that comprised a total of 575,093 road accidents. CHAID decision tree technique was employed to establish the relationship between severity of bicycle crashes and factors related to crash characteristics (type of collision and opponent vehicle), infrastructure characteristics (type of carriageway, road type, road signage, pavement type, and type of road segment), cyclists (gender and age), and environmental factors (time of the day, day of the week, month, pavement condition, and weather). CHAID analysis revealed that the most important predictors were, in decreasing order of importance, road type (0.30), crash type (0.24), age of cyclist (0.19), road signage (0.08), gender of cyclist (0.07), type of opponent vehicle (0.05), month (0.04), and type of road segment (0.02). These eight most important predictors of the severity of bicycle crashes were included as predictors of the target (i.e., severity of bicycle crashes) in Bayesian network analysis. Bayesian network analysis identified crash type (0.31), road type (0.19), and type of opponent vehicle (0.18) as the most important predictors of severity of bicycle crashes. Copyright © 2017 Elsevier Ltd. All rights reserved.

Video game addiction, ADHD symptomatology, and video game reinforcement.

PubMed

Mathews, Christine L; Morrell, Holly E R; Molle, Jon E

2018-06-06

Up to 23% of people who play video games report symptoms of addiction. Individuals with attention deficit hyperactivity disorder (ADHD) may be at increased risk for video game addiction, especially when playing games with more reinforcing properties. The current study tested whether level of video game reinforcement (type of game) places individuals with greater ADHD symptom severity at higher risk for developing video game addiction. Adult video game players (N = 2,801; Mean age = 22.43, SD = 4.70; 93.30% male; 82.80% Caucasian) completed an online survey. Hierarchical multiple linear regression analyses were used to test type of game, ADHD symptom severity, and the interaction between type of game and ADHD symptomatology as predictors of video game addiction severity, after controlling for age, gender, and weekly time spent playing video games. ADHD symptom severity was positively associated with increased addiction severity (b = .73 and .68, ps < 0.001). Type of game played or preferred the most was not associated with addiction severity, ps > .05. The relationship between ADHD symptom severity and addiction severity did not depend on the type of video game played or preferred most, ps > .05. Gamers who have greater ADHD symptom severity may be at greater risk for developing symptoms of video game addiction and its negative consequences, regardless of type of video game played or preferred most. Individuals who report ADHD symptomatology and also identify as gamers may benefit from psychoeducation about the potential risk for problematic play.

Effects of different types of moderate severity disturbance on forest structural complexity and ecosystem functioning: A story of ice and fire

NASA Astrophysics Data System (ADS)

Fahey, R. T.; Atkins, J.; Gough, C. M.; Hardiman, B. S.; Haber, L.; Stuart-Haentjens, E.; David, O.; Campbell, J. L.; Rustad, L.; Duffy, M.

2017-12-01

Disturbances that alter the structure and function of forest ecosystems occur along a continuum of severity. In contrast to the extremes of the disturbance gradient (i.e., stand-replacing disturbance and small gap formation), moderate severity disturbances are poorly understood, even though they make up the majority of the gradient and their spatial extent (and likely overall importance to regional disturbance regimes) often exceeds that of more severe disturbances. Moderate severity disturbances originate from a variety of causes, such as fires, ice storms, or pest and pathogen outbreaks, and each of these could reshape structure and function in different ways. Observational data from a limited number of sites shows that moderate disturbance can increase ecosystem complexity, but the generality of this effect has not been tested across a broad range of disturbance types and severities. Here, we utilize data from a set of five case studies of experimental or natural moderate disturbance to assess the effects of different types and severities of disturbance on forest canopy structural complexity (CSC) and the relationship of canopy structure with ecosystem functioning. Using pre- and post-disturbance measures of CSC derived from aerial and terrestrial LiDAR, UAV imagery, and Landsat data we quantified changes in CSC following an experimental ice storm, a low-severity surface fire, Beech Bark Disease and Hemlock Wooly Adelgid outbreaks, and experimental accelerated succession. Our initial findings indicate that different disturbance types have highly variable effects on CSC, and also that progressive increases in disturbance severity alter CSC differently among disturbance types. Differential effects of variable disturbance types on CSC has implications for the carbon cycle, as forest structure is strongly linked with both growth-limiting resource (e.g., nutrients and light) acquisition and net primary productivity. Understanding how different types and severities of moderate disturbance affect canopy structural complexity is thus crucial to informing and improving modeling the earth system and predicting how global shifts in moderate disturbance type, frequency, and severity will alter the land carbon sink.

Survival of Patients with Cystic Fibrosis Depending on Mutation Type and Nutritional Status.

PubMed

Szwed, A; John, A; Goździk-Spychalska, J; Czaiński, W; Czerniak, W; Ratajczak, J; Batura-Gabryel, H

2018-01-01

The purpose of the study was to evaluate the influence of nutrition and of the severity of mutation type on survival rate in cystic fibrosis (CF) patients. Data were longitudinally collected from 60 hospitalized adult CF patients, aged 18-50. The variables consisted of body mass index (BMI) ratio, Cole's BMI cut-off points, severity of mutation type, and survival rate of CF patients. We found that the mean BMI was strongly associated with the severity of mutation type and was significantly lower in patients with severe mutations of grade I and II. The mutation type significantly affected the patients' survival rate; survival was greater in patients with mild and undefined mutation types. The BMI and Cole's cut-off points also had a significant influence on survival rate. CF patients, who suffered from malnutrition and emaciation, had a shorter survival rate than those with proper nutritional status. In conclusion, the study findings confirmed a significant effect of nutritional status and of mutation type on survival rate of CF patients.

Histochemical stains as promising means for the laser histochemical surgery of a number of pathologies

NASA Astrophysics Data System (ADS)

Piruzyan, L. A.; Mikhailovskiy, Ye. M.; Piruzyan, A. L.

1999-12-01

The directions of laboratory and clinical studies oriented to experimental confirmation of the priority concept of `laser histochemical surgery' are presented. The goal of the studies is reproduction on experimental model of a number of pathologies (in vivo and in vitro) of the `sensitization to laser radiation by staining' effect. Testing of the histochemical stains as sensitizers to laser irradiation of their `address substrates', i.e. vitally stained intracellular structures which participate in the pathologic processes evolution is under planning. The processes include: (a) metabolic disorders in the brain cells, i.e. disseminated sclerosis; (b) generalized metabolic disorders- -mucopolysaccharidosis and collagenosises (periarteritis nodosa, rheumatism, rheumatoid arthritis, sclerodermia); (3) metabolic disorders in individual organs--vessel atherosclerosis, hypercholesterolemia, myocardial infarction, cardiosclerosis, caries and parodontosis. The conditions of the studies are detailed in the recommendations along the positions: (1) disease name; (2) disease characteristics: (a) pathomorphologic, (b) biochemical; (3) stains revealing the disease signs and recommended for testing; (4) `address substrates' of the stains that are targets for laser radiation; (5) lasers recommended for the testing after the cells staining in vivo in the corresponding pathology; (6) experimental models of the pathologies suggested for the testing; (7) criteria of the stain efficiency as target sensitizer to the laser light (criteria of the `laser sensitization by staining' efficiency). Possible perspectives for the experimental clinical medicine are indicated of common histochemical stains and lasers use and of practice introduction of the `laser histochemical surgery' in the case the described concept is confirmed in experiments and clinically.

A novel explanation of corneal clouding in a bone marrow transplant-treated patient with Hurler syndrome

PubMed Central

Yuan, Ching; Bothun, Erick D.; Hardten, David R.; Tolar, Jakub; McLoon, Linda K.

2016-01-01

One common complication of mucopolysaccharidosis I-Hurler (MPS1-H) is corneal clouding, which occurs despite current treatments, including bone marrow transplantation. Human corneas were obtained from a 14 year old subject with MPS1-H and visual disability from progressive corneal clouding despite a prior bone marrow transplant at age 2. This was compared to a cornea from a 17 year old donated to our eye bank after his accidental death. The corneas were analyzed microscopically after staining with Alcian blue, antibodies to collagen I, IV, VI, and α-smooth muscle actin. Differences in levels of expression of the indicated molecules were assessed. Corneas from Hurler and control mice were examined similarly to determine potential mechanistic overlap. The MPS1-H subject cornea showed elevations in mucopolysaccharide deposition. The MPS1-H and Hurler mice corneas showed increased and disorganized expression of collagen I and IV relative to the control corneas. The MPS1-H corneas also showed increased and disordered expression of collagen VI. Positive expression of α-smooth muscle actin indicated myofibroblast conversion within the MPS1-H cornea in both the patient and mutant mouse material compared to normal human and control mouse cornea. Increased deposition of collagens and smooth muscle actin correlate with corneal clouding, providing a potential mechanism for corneal clouding despite bone marrow transplantation in MPS1-H patients. It might be possible to prevent or slow the onset of corneal clouding by treating the cornea with drugs known to prevent myofibroblast conversion. PMID:27235795

A pseudodeficiency allele (D152N) of the human {beta}-glucuronidase gene

DOE Office of Scientific and Technical Information (OSTI.GOV)

Vervoort, R.; Liebaers, I.; Lissens, W.

1995-10-01

We present evidence that a 480G{r_arrow}A transition in the coding region of the {Beta}glucuronidase gene, which results in an aspartic-acid-to-asparagine substitution at amino acid position 152 (D152N), produces a pseudodeficiency allele (GUSBp) that leads to greatly reduced levels of {Beta}-glucuronidase activity without apparent deleterious consequences. The 48OG{r_arrow}A mutation was found initially in the pseudodeficient mother of a child with mucopolysaccharidosis VII (MPSVII), but it was not on her disease-causing allele, which carried the L176F mutation. The 480G{r_arrow}A change was also present in an unrelated individual with another MPSVII allele who had unusually low {Beta}-glucuronidase activity, but whose clinical symptoms weremore » probably unrelated to {Beta}-glucuronidase deficiency. This individual also had an R357X mutation, probably on his second allele. We screened 100 unrelated normal individuals for the 480G{r_arrow}A mutation with a PCR method and detected one carrier. Reduced {Beta}-glucuronidase activity following transfection of COS cells with the D152N cDNA supported the causal relationship between the D152N allele and pseudodeficiency. The mutation reduced the fraction of expressed enzyme that was secreted. Pulse-chase experiments indicated that the reduced activity in COS cells was due to accelerated intracellular turnover of the D152N enzyme. They also suggested that a potential glycosylation site created by the mutation is utilized in {approximately}50% of the enzyme expressed. 25 refs., 3 figs., 3 tabs.« less

Therapeutic Potential of Mesenchymal Stem Cell-Derived Exosomes in the Treatment of Eye Diseases.

PubMed

Harrell, C Randall; Simovic Markovic, Bojana; Fellabaum, Crissy; Arsenijevic, Aleksandar; Djonov, Valentin; Arsenijevic, Nebojsa; Volarevic, Vladislav

2018-05-18

Mesenchymal stem cells (MSCs) were, due to their immunomodulatory and pro-angiogenic characteristics, extensively explored as new therapeutic agents in cell-based therapy of uveitis, glaucoma, retinal and ocular surface diseases.Since it was recently revealed that exosomes play an important role in biological functions of MSCs, herewith we summarized current knowledge about the morphology, structure, phenotype and functional characteristics of MSC-derived exosomes emphasizing their therapeutic potential in the treatment of eye diseases.MSC-derived exosomes were as efficient as transplanted MSCs in limiting the extent of eye injury and inflammation. Immediately after intravitreal injection, MSC-derived exosomes, due to nano-dimension, diffused rapidly throughout the retina and significantly attenuated retinal damage and inflammation. MSC-derived exosomes successfully delivered trophic and immunomodulatory factors to the inner retina and efficiently promoted survival and neuritogenesis of injured retinal ganglion cells. MSC-derived exosomes efficiently suppressed migration of inflammatory cells, attenuated detrimental Th1 and Th17 cell-driven immune response and ameliorated experimental autoimmune uveitis. MSC-derived exosomes were able to fuse with the lysosomes within corneal cells, enabling delivering of MSC-derived active β-glucuronidase and consequent catabolism of accumulated glycosaminoglycans, indicating their therapeutic potential in the treatment of Mucopolysaccharidosis VII (Sly Syndrome). Importantly, beneficent effects were noticed only in animals that received MSC-derived exosomes and were not seen after therapy with fibroblasts-derived exosomes confirming specific therapeutic potential of MSCs and their products in the treatment of eye diseases.In conclusion, MSC-derived exosomes represent potentially new therapeutic agents in the therapy of degenerative and inflammatory ocular diseases.

Unintentional injuries among Chinese children with different types and severity of disability

PubMed Central

Zhu, Huiping; Xiang, Huiyun; Xia, Xin; Yang, Xia; Li, Dan; Stallones, Lorann; Du, Yukai

2014-01-01

Purpose Little research has been done in China to study injury in individuals with disability. We investigated impact of type and severity of disability on injury among children with disability in Hubei Province of China. Methods A sample of 1201 children with disability were matched with 1201 healthy children on gender, age, and neighborhood. Disability type and severity were determined using the Chinese national standards. Caregivers were interviewed face-to-face about nonfatal unintentional injuries suffered by the child in the past 12 months prior to the interview. Univariate Chi-square test and logistic regression models were used to investigate association between disability type/severity and nonfatal unintentional injuries. Results Injury rate among children with disability was significantly higher than that among children without disability (10.2% vs. 4.4%; P <.001). Children with multiple disabilities had the highest risk of injury after controlling for confounding variables (OR=4.54; 95% CI=2.82, 7.30; P<.001). The magnitude of the association between disability and injury varied by type and severity of disability. Conclusions The magnitude of the association between the presence or absence of disability in children and their risk of injury was large and significant, regardless of the type or severity of the children's disabilities. PMID:24331162

Vital signs, QT prolongation, and newly diagnosed cardiovascular disease during severe hypoglycemia in type 1 and type 2 diabetic patients.

PubMed

Tsujimoto, Tetsuro; Yamamoto-Honda, Ritsuko; Kajio, Hiroshi; Kishimoto, Miyako; Noto, Hiroshi; Hachiya, Remi; Kimura, Akio; Kakei, Masafumi; Noda, Mitsuhiko

2014-01-01

OBJECTIVE To assess vital signs, QT intervals, and newly diagnosed cardiovascular disease during severe hypoglycemia in diabetic patients. RESEARCH DESIGN AND METHODS From January 2006 to March 2012, we conducted a retrospective cohort study to assess type 1 and type 2 diabetic patients with severe hypoglycemia at a national center in Japan. Severe hypoglycemia was defined as the presence of any hypoglycemic symptoms that could not be resolved by the patients themselves in prehospital settings. RESULTS A total of 59,602 cases that visited the emergency room by ambulance were screened, and 414 cases of severe hypoglycemia were analyzed. The median (interquartile range) blood glucose levels were not significantly different between the type 1 diabetes mellitus (T1DM) (n = 88) and type 2 diabetes mellitus (T2DM) (n = 326) groups (32 [24-42] vs. 31 [24-39] mg/dL, P = 0.59). During severe hypoglycemia, the incidences of severe hypertension (≥180/120 mmHg), hypokalemia (<3.5 mEq/L), and QT prolongation were 19.8 and 38.8% (P = 0.001), 42.4 and 36.3% (P = 0.30), and 50.0 and 59.9% (P = 0.29) in the T1DM and T2DM groups, respectively. Newly diagnosed cardiovascular disease during severe hypoglycemia and death were only observed in the T2DM group (1.5 and 1.8%, respectively). Blood glucose levels between the deceased and surviving patients in the T2DM group were significantly different (18 [14-33] vs. 31 [24-39] mg/dL, P = 0.02). CONCLUSIONS T1DM and T2DM patients with severe hypoglycemia experienced many critical problems that could lead to cardiovascular disease, fatal arrhythmia, and death.

Are the binary typology models of alcoholism valid in polydrug abusers?

PubMed

Pombo, Samuel; da Costa, Nuno F; Figueira, Maria L

2015-01-01

To evaluate the dichotomy of type I/II and type A/B alcoholism typologies in opiate-dependent patients with a comorbid alcohol dependence problem (ODP-AP). The validity assessment process comprised the information regarding the history of alcohol use (internal validity), cognitive-behavioral variables regarding substance use (external validity), and indicators of treatment during 6-month follow-up (predictive validity). ODP-AP subjects classified as type II/B presented an early and much more severe drinking problem and a worse clinical prognosis when considering opiate treatment variables as compared with ODP-AP subjects defined as type I/A. Furthermore, type II/B patients endorse more general positive beliefs and expectancies related to the effect of alcohol and tend to drink heavily across several intra- and interpersonal situations as compared with type I/A patients. These findings confirm two different forms of alcohol dependence, recognized as a low-severity/vulnerability subgroup and a high-severity/vulnerability subgroup, in an opiate-dependent population with a lifetime diagnosis of alcohol dependence.

Fetal-onset Congenital Dyserythropoietic Anemia Type 1 due to a Novel Mutation With Severe Iron Overload and Severe Cholestatic Liver Disease.

PubMed

Chin, Hui-Lin; Lee, Le Ye; Koh, Pei Lin

2018-04-17

We report a rare case of severe congenital dyserythropoietic anemia type 1 with fetal onset. Our patient presented with fetal hydrops from 19 weeks of gestation, requiring multiple intrauterine transfusions. At birth, she had severe hemolytic anemia with severe jaundice, and was subsequently transfusion dependent. She eventually developed severe iron overload and fulminant liver failure before her demise at 5 months of age. Genetic testing revealed a novel mutation in CDAN1.

A graduated food addiction classification approach significantly differentiates obesity among people with type 2 diabetes.

PubMed

Raymond, Karren-Lee; Kannis-Dymand, Lee; Lovell, Geoff P

2016-10-01

This study examined a graduated severity level approach to food addiction classification against associations with World Health Organization obesity classifications (body mass index, kg/m 2 ) among 408 people with type 2 diabetes. A survey including the Yale Food Addiction Scale and several demographic questions demonstrated four distinct Yale Food Addiction Scale symptom severity groups (in line with Diagnostic and Statistical Manual of Mental Disorders (5th ed.) severity indicators): non-food addiction, mild food addiction, moderate food addiction and severe food addiction. Analysis of variance with post hoc tests demonstrated each severity classification group was significantly different in body mass index, with each grouping being associated with increased World Health Organization obesity classifications. These findings have implications for diagnosing food addiction and implementing treatment and prevention methodologies of obesity among people with type 2 diabetes.

The Effects of Lamp Spectral Distribution on Sky Glow over Observatories

DTIC Science & Technology

2015-01-01

overhead sky glow as a function of distance up to 300 km, from a variety of lamp types, including common gas discharge lamps and several types of LED...distance up to 300 km, from a variety of lamp types, in- cluding common gas discharge lamps and several types of LED lamps . We conclude for both...MAR 2015 2. REPORT TYPE 3. DATES COVERED 00-00-2015 to 00-00-2015 4. TITLE AND SUBTITLE The Effects of Lamp Spectral Distribution on Sky Glow

The effect of recurrent severe hypoglycemia on cognitive performance in children with type 1 diabetes: a meta-analysis.

PubMed

Blasetti, Annalisa; Chiuri, Rosa Maria; Tocco, Anna Maria; Di Giulio, Concetta; Mattei, Peter A; Ballone, Enzo; Chiarelli, Francesco; Verrotti, Alberto

2011-11-01

The purpose of this study was to investigate the existence and extent of cognitive impairment in type 1 diabetic children with episodes of recurrent severe hypoglycemia, using meta-analysis to synthesize data across studies. The meta-analysis sample included: 441 children with diabetes and recurrent severe hypoglycemia, 560 children with diabetes and without recurrent severe hypoglycemia. Overall, children with type 1 diabetes and recurrent severe hypoglycemia had slightly lower performance than diabetic children without severe hypoglycemia, only in some cognitive domains: intelligence, memory, learning, and verbal fluency/language. Greater impairment was found in memory and learning. No impairment was found for motor speed. Our results seem to confirm the hypothesis that recurrent severe hypoglycemia has a selective negative effect on the children's cognitive functions. However, these results must be considered with caution taking into account factors such as small sample sizes, the different definitions of severe hypoglycemia, and the variety of neuropsychological tests used.

Types, Subtypes, and Severity of Substantiated Child Neglect in U.S. Army Communities.

PubMed

Cozza, Stephen J; Ortiz, Claudio D; Fullerton, Carol S; McCarroll, James E; Holmes, Allison K; Harris, April M; Wryter, Christina L; Ursano, Robert J

2015-11-01

Neglect has been linked to short-term and long-term deleterious outcomes in children, but has received little attention in the research literature. Identify types, subtypes, and severity of child neglect in a sample of substantiated cases at 4 U.S. Army installations. Describe demographic correlates of victims and offenders by type and subtype. Data were collected from archived clinical records. A stratified random sample of 100 substantiated child neglect case files were selected per site (N = 400). Data from a single child per case file were used. 5 types and 17 subtypes of neglect were represented, singly or in combination, with varying severity. Lack of Supervision was most common (n = 177, 35.3%), followed by Emotional Neglect (n = 159, 31.8%), Failure to Provide Physical Needs (n = 131, 26.2%), Moral-Legal Neglect (n = 20, 4%), and Educational Neglect (n = 13; 2.6%). Child neglect occurred mostly among young children and in young enlisted families. Current results highlight the need to focus on types, subtypes, and severity of neglect incidents that provide specific understanding of child risk to better inform policy. Further study should examine specific risk factors and their relationship to neglect types and severity outcomes. Reprint & Copyright © 2015 Association of Military Surgeons of the U.S.

The relationship between type D personality and chronic heart failure is not confounded by disease severity as assessed by BNP.

PubMed

Pelle, Aline J; van den Broek, Krista C; Szabó, Balázs; Kupper, Nina

2010-11-05

Psychological factors, like Type D personality (i.e., the tendency to experience negative emotions and to inhibit emotional distress) have been linked to impaired health outcomes. Criticism on the role of psychological factors in cardiac disease has postulated that such constructs may be confounded by disease severity. Hence, we examined whether Type D personality is associated with brain natriuretic peptide (BNP), a sensitive marker of disease severity in chronic heart failure (CHF), in 202 consecutive CHF outpatients. No differences in logBNP levels were found between Type D and non-Type D patients (t(200) = -1.03, p = .30). After adjusting for demographic and clinical confounders, Type D personality remained unassociated with logBNP levels (β=.04, p = .55), whereas older age (β = .27, p<.001), being prescribed beta-blockers (β = .15, p = .02), lower left ventricular ejection fraction (β = -.38, p<.0001), and kidney dysfunction (β = .17, p = .01) were associated with higher logBNP. To conclude, Type D personality was not associated with BNP in CHF outpatients, whereas clinical variables were associated with BNP. These findings oppose the suggestion that Type D personality is confounded by indicators of disease severity. Copyright © 2009 Elsevier Ireland Ltd. All rights reserved.

Hemolytic disease of the newborn

MedlinePlus

... much less common, types of mismatch between minor blood group antigens. These can also cause severe problems. ... tests are done depends on the type of blood group incompatibility and the severity of symptoms, but may ...

Blood typing

MedlinePlus

... matching; Rh typing; ABO blood typing; Blood group; Anemia - immune hemolytic blood type; ABO blood type; A ... during pregnancy. Careful testing can prevent a severe anemia in the newborn and jaundice .

Reporting Severe Hypoglycemia in Type 1 Diabetes: Facts and Pitfalls.

PubMed

Pedersen-Bjergaard, Ulrik; Thorsteinsson, Birger

2017-10-28

To describe potential factors influencing reporting of severe hypoglycemia in adult patients with type 1 diabetes and to analyze their effect on reported rates of severe hypoglycemia. Reported rates of severe hypoglycemia defined as need for third party assistance vary between 0.3-3.0 events per patient-year in unselected cohorts, corresponding to a yearly prevalence range of 10-53%. When defined as need for parenteral therapy with glucose or glucagon or need for admission to an emergency unit or hospitalization, incidence and prevalence rates of severe hypoglycemia are 0.02-0.5 events per patient-year and 1-29%, respectively. When subjects with recurrent severe hypoglycemia in the past or suffering from impaired hypoglycemia awareness are excluded from participation in studies, lower rates are reported. Studies applying anonymous reporting or reporting by partners report higher rates of severe hypoglycemia. There is a large variation between studies reporting incidence and prevalence of severe hypoglycemia in patients with type 1 diabetes, mainly explained by definition of severity, methods of reporting, and patient selection. These findings call for consensus about hypoglycemia definition and reporting in future research.

Severe vulvovaginitis as a presenting problem of type 2 diabetes in adolescent girls: a case series.

PubMed

Curran, Jacqueline; Hayward, Jenette; Sellers, Elizabeth; Dean, Heather

2011-04-01

This article describes the presentation of 4 adolescent girls who sought medical attention for severe vulvovaginitis and were subsequently found to have type 2 diabetes. Symptomatic vulvovaginitis is rare in adolescent girls, and its presence should alert health care providers to test for underlying hyperglycemia. These 4 girls represent 8.5% of the females with new-onset type 2 diabetes during a 3-year period (2007-2009). The 4 cases fulfilled the current Canadian Diabetes Association screening criteria for type 2 diabetes in youth, yet none of these girls had been screened. These cases highlight the need for better awareness of screening criteria for type 2 diabetes in adolescents. Consideration should be given in clinical practice guidelines to including the presence of unusual or severe infections as a risk factor for type 2 diabetes in youth.

Cerebro-costo-mandibular syndrome: prognosis and proposal for classification.

PubMed

Nagasawa, Hiroyuki; Yamamoto, Yutaka; Kohno, Yoshinori

2010-09-01

Cerebro-costo-mandibular syndrome (CCMS) is a very rare syndrome characterized by micrognathia and posterior rib gap, with a poor prognosis. To date, only 75 cases have been reported worldwide. The overall survival rate for patients with this disorder has not been reported, and a classification of the patients on the basis of the prognosis is not yet available. The present study analyzed the figures and prognoses of past patients and documented a new case of CCMS. Formerly published case reports and personal communications were used to reveal the prognosis and classification of CCMS. The occurrence ratios of rib gap defects and of missing ribs were examined. Patients were divided into the following three groups according to their life span: lethal type, where the patients died before 1 month; severe type, where the patients lived for 1-12 months; and mild type, where they survived for more than 1 year. A comparison was made of the number of rib gaps, missing ribs, and the rib gap ratio (defined as the number of rib gaps divided by the number of all existing ribs) among these three groups. A significant difference in the number of rib defects between the lethal type and other types was noted. Short life span of severe type patients, compared to mild type, was attributed to their subjection to severe respiratory infection. CCMS can be classified into three categories--lethal, severe, and mild--according to the severity of the symptoms and prognosis.

Variability of simulants used in recreating stab events.

PubMed

Carr, D J; Wainwright, A

2011-07-15

Forensic investigators commonly use simulants/backing materials to mount fabrics and/or garments on when recreating damage due to stab events. Such work may be conducted in support of an investigation to connect a particular knife to a stabbing event by comparing the severance morphology obtained in the laboratory to that observed in the incident. There does not appear to have been a comparison of the effect of simulant type on the morphology of severances in fabrics and simulants, nor on the variability of simulants. This work investigates three simulants (pork, gelatine, expanded polystyrene), two knife blades (carving, bread), and how severances in the simulants and an apparel fabric typically used to manufacture T-shirts (single jersey) were affected by (i) simulant type and (ii) blade type. Severances were formed using a laboratory impact apparatus to ensure a consistent impact velocity and hence impact energy independently of the other variables. The impact velocity was chosen so that the force measured was similar to that measured in human performance trials. Force-time and energy-time curves were analysed and severance morphology (y, z directions) investigated. Simulant type and knife type significantly affected the critical forensic measurements of severance length (y direction) in the fabric and 'skin' (Tuftane). The use of EPS resulted in the lowest variability in data, further the severances recorded in both the fabric and Tuftane more accurately reflected the dimensions of the impacting knives. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Is typing speed proportional to the severity of pain in keyboard workers with work-related upper limb disorder

PubMed Central

Povlsen, Bo

2012-01-01

Objectives To investigate if typing speed is proportional to the severity of pain in keyboard workers with work-related upper limb disorder (WRULD). Design Standardized functional typing test with participants scoring pain before and after typing; calculation of typing speed. Participants Fifty-nine patients and six controls. Setting Tertiary hospital centre for hand and upper limb pain. Main outcome measures Pain (VAS 0–10) and calculation of typing speed as words per minute. Results Three subgroups of patients were found based on their typing speed: fast, slow and intermediate. Two-tailed student T-test with P level at 0.05 was used for evaluation. The typing speeds were significantly different between all three patient groups (P < 0.05). The typing speed was significantly faster in the fastest patient group than in the control group (P = 0.04) and the slow and middle groups (P = < 0.0001). The pain before typing was highest in the ‘slow’ group, in both hands but this difference was not statistically significant. Conclusion Typing speed is not proportional to the severity of pain in keyboard workers with WRULD. Patients with statistically significant slower or faster typing speeds do not have statistically different levels of pain. PMID:22299070

Causes, types and severity of injury among army soldiers hospitalized with alcohol comorbidity.

PubMed

Howland, Jonathan; Bell, Nicole S; Hollander, Ilyssa E

2007-09-01

To examine the relationship between alcohol use and the cause, type and severity of hospitalized injuries. We used the Total Army Injury and Health Outcomes Database (TAIHOD) to conduct cross-sectional analyses of the association between alcohol comorbidity and the cause, type and severity of soldiers' non-combat injuries requiring hospitalization. Subjects were active-duty US army soldiers (n = 211 790) hospitalized with a primary diagnosis of injury between 1980 and 2002. Alcohol comorbidity was positively associated with hospitalized injuries resulting from fights and falls and negatively associated with sports injuries; positively associated with hospitalized cases of head injury, open wounds and poisonings and negatively associated with musculoskeletal injury; and, overall, associated with shorter length of stay. Controlling for demographic factors did not moderate the association between alcohol and cause, type or severity of injury. Alcohol comorbidity is specifically associated with injuries related to impairment and antisocial behavior.

Pilot study of newborn screening for six lysosomal storage diseases using Tandem Mass Spectrometry☆

PubMed Central

Elliott, Susan; Buroker, Norman; Cournoyer, Jason J.; Potier, Anna M.; Trometer, Joseph D.; Elbin, Carole; Schermer, Mack J.; Kantola, Jaana; Boyce, Aaron; Turecek, Frantisek; Gelb, Michael H.; Scott, C. Ronald

2017-01-01

Background There is current expansion of newborn screening (NBS) programs to include lysosomal storage disorders because of the availability of treatments that produce an optimal clinical outcome when started early in life. Objective To evaluate the performance of a multiplex-tandem mass spectrometry (MS/MS) enzymatic activity assay of 6 lysosomal enzymes in a NBS laboratory for the identification of newborns at risk for developing Pompe, Mucopolysaccharidosis-I (MPS-I), Fabry, Gaucher, Niemann Pick-A/B, and Krabbe diseases. Methods and Results Enzyme activities (acid α-glucosidase (GAA), galactocerebrosidase (GALC), glucocerebrosidase (GBA), α-galactosidase A (GLA), α-iduronidase (IDUA) and sphingomyeline phosphodiesterase-1 (SMPD-1)) were measured on ~43,000 de-identified dried blood spot (DBS) punches, and screen positive samples were submitted for DNA sequencing to obtain genotype confirmation of disease risk. The 6-plex assay was efficiently performed in the Washington state NBS laboratory by a single laboratory technician at the bench using a single MS/MS instrument. The number of screen positive samples per 100,000 newborns were as follows: GAA (4.5), IDUA (13.6), GLA (18.2), SMPD1 (11.4), GBA (6.8), and GALC (25.0). Discussion A 6-plex MS/MS assay for 6 lysosomal enzymes can be successfully performed in a NBS laboratory. The analytical ranges (enzyme-dependent assay response for the quality control HIGH sample divided by that for all enzyme-independent processes) for the 6-enzymes with the MS/MS is 5- to 15-fold higher than comparable fluorimetric assays using 4-methylumbelliferyl substrates. The rate of screen positive detection is consistently lower for the MS/MS assay compared to the fluorimetric assay using a digital microfluidics platform. PMID:27238910

Molecular analysis of Hurler syndrome in Druze and Muslim Arab patients in Israel: Multiple allelic mutations of the IDUA gene in a small geographic area

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bach, G.; Moskowitz, S.M.; Tieu, P.T.

1993-08-01

The mutations underlying Hurler syndrome (mucopolysaccharidosis IH) in Druze and Muslim Israeli Arab patients have been characterized. Four alleles were identified, using a combination of (a) PCR amplification of reverse-transcribed RNA or genomic DNA segments, (b) cycle sequencing of PCR products, and (c) restriction-enzyme analysis. One allele has two amino acid substitutions, Gly[sub 409][yields]Arg in exon 9 and Ter[yields]Cys in exon 14. The other three alleles have mutations in exon 2 (Tyr[sub 64][yields]Ter), exon 7 (Gln[sub 310][yields]Ter), or exon 8 (Thr[sub 366][yields]Pro). Transfection of mutagenized cDNAs into Cos-1 cells showed that two missense mutations, Thr[sub 366][yields]Pro and Ter[yields]Cys, permitted themore » expression of only trace amounts of [alpha]-L-iduronidase activity, whereas Gly[sub 409][yields]Arg permitted the expression of 60% as much enzyme as did the normal cDNA. The nonsense mutations were associated with abnormalities of RNA processing: (1) both a very low level of mRNA and skipping of exon 2 for Tyr[sub 64][yields]Ter and (2) utilization of a cryptic splice site for Gln[sub 310][yields]Ter. In all instances, the probands were found homozygous, and the parents heterozygous, for the mutant alleles, as anticipated from the consanguinity in each family. The two-mutation allele was identified in a family from Gaza; the other three alleles were found in seven families, five of them Druze, residing in a very small area of northern Israel. Since such clustering suggests a classic founder effect, the presence of three mutant alleles of the IDUA gene was unexpected. 28 refs., 4 figs., 3 tabs.« less

Quality-of-life impairment in neurofibromatosis type 1: a cross-sectional study of 128 cases.

PubMed

Wolkenstein, P; Zeller, J; Revuz, J; Ecosse, E; Leplège, A

2001-11-01

Neurofibromatosis type 1 affects quality of life (QoL) through association with severe complications, impact on cosmetic features, and uncertainty of the effects of the disorder. To evaluate the impact of the severity and visibility of neurofibromatosis type 1 on QoL. Monocenter, cross-sectional study. One French academic dermatological and neurofibromatoses clinic. A total of 128 adult patients with neurofibromatosis type 1. Evaluation of severity and visibility using, respectively, the Riccardi and Ablon scales. Evaluation of skin disease-specific and general QoL using, respectively, Skindex-France and SF-36 (Short Form 36 health survey) profiles controlled for sex, age, severity, and visibility. In a multiple regression model controlling for sex, age, and visibility, visibility remained independently associated with the alteration of 3 aspects of the skin disease-specific QoL (Skindex-France): emotions, physical symptoms, and functioning (P =.03, P =.009, and P =.002, respectively). Patients with more severe neurofibromatosis reported more effects on the following domains of their general health QoL (SF-36): physical function, bodily pain, general health perception, and vitality (P =.006, P =.03, P =.01, and P =.04, respectively). Neurofibromatosis type 1 has a significant impact on QoL through alteration of health and appearance. The consequences of visibility and severity from the viewpoint of patients can be evaluated using Skindex and the SF-36, respectively.

Planned diversity: The case for a system with several types of wilderness

Treesearch

David N. Cole

2011-01-01

Although the U.S. Wilderness Act of 1964 legally designated only one type of wilderness, the full array of wilderness values might be better protected by setting aside several important and different types of wilderness. Wilderness serves many different needs, having multiple and varied values and purposes (Cordell et al. 2005). Although many assume that these values...

Using Factor Mixture Models to Evaluate the Type A/B Classification of Alcohol Use Disorders in a Heterogeneous Treatment Sample

PubMed Central

Hildebrandt, Tom; Epstein, Elizabeth E.; Sysko, Robyn; Bux, Donald A.

2017-01-01

Background The type A/B classification model for alcohol use disorders (AUDs) has received considerable empirical support. However, few studies examine the underlying latent structure of this subtyping model, which has been challenged as a dichotomization of a single drinking severity dimension. Type B, relative to type A, alcoholics represent those with early age of onset, greater familial risk, and worse outcomes from alcohol use. Method We examined the latent structure of the type A/B model using categorical, dimensional, and factor mixture models in a mixed gender community treatment-seeking sample of adults with an AUD. Results Factor analytic models identified 2-factors (drinking severity/externalizing psychopathology and internalizing psychopathology) underlying the type A/B indicators. A factor mixture model with 2-dimensions and 3-classes emerged as the best overall fitting model. The classes reflected a type A class and two type B classes (B1 and B2) that differed on the respective level of drinking severity/externalizing pathology and internalizing pathology. Type B1 had a greater prevalence of women and more internalizing pathology and B2 had a greater prevalence of men and more drinking severity/externalizing pathology. The 2-factor, 3-class model also exhibited predictive validity by explaining significant variance in 12-month drinking and drug use outcomes. Conclusions The model identified in the current study may provide a basis for examining different sources of heterogeneity in the course and outcome of AUDs. PMID:28247423

Severe Infections with Human Adenovirus 7d in 2 Adults in Family, Illinois, USA, 2014

PubMed Central

Ison, Michael G.

2016-01-01

Human adenovirus 7d, a genomic variant with no reported circulation in the United States, was isolated from 2 adults with severe respiratory infections in Illinois. Molecular typing identified a close relationship with strains of the same genome type isolated from cases of respiratory disease in several provinces of China since 2009. PMID:26982199

Glucose-6-phosphate dehydrogenase deficiency and reduced haemoglobin levels in African children with severe malaria.

PubMed

Nguetse, Christian N; Meyer, Christian G; Adegnika, Ayola Akim; Agbenyega, Tsiri; Ogutu, Bernhards R; Kremsner, Peter G; Velavan, Thirumalaisamy P

2016-07-07

Extensive studies investigating the role of host genetic factors during malaria associate glucose-6-phosphate dehydrogenase deficiency with relative protection. G6PD deficiency had been reported to associate with anti-malarial drug induced with haemolytic anaemia. A total of 301 Gabonese, Ghanaian, and Kenyan children aged 6-120 months with severe malaria recruited in a multicentre trial on artesunate were included in this sub-study. G6PD normal (type B), heterozygous (type A(+)) and deficient (type A(-)) genotypes were determined by direct sequencing of the common African mutations G202A and A376G. Furthermore, multivariate analyses were executed to associate possible contributions of G6PD deficiency with baseline haemoglobin levels, parasitaemia and with severe malarial anaemia. Two hundred and seventy-eight children (132 females and 146 males) were successfully genotyped for G6PD variants. The overall prevalence of G6PD deficiency was 13 % [36/278; 3 % (4/132) female homozygous and 22 % (32/146) male hemizygous], 14 % (40/278) children were female heterozygous while 73 % (202/278) were G6PD normal [67 % (88/132) females and 78 % (114/146) males] individuals. Multivariate regression revealed a significant association of moderately and severely deficient G6PD genotypes with haemoglobin levels according to the baseline data (p < 0.0001; G6PD heterozygous: p < 0.0001; G6PD deficient: p = 0.009), but not with severe malarial anaemia (p = 0.66). No association of G6PD genotypes with baseline parasitaemia. In this study, moderately (type A(+)) and severely (type A(-)) G6PD deficiency showed significant association with lower haemoglobin concentrations at baseline in African children with severe malaria without leading to severe malarial anaemia. In addition, there was no association of G6PD variant types with parasite densities on admission.

Prioritizing prevention opportunities in the Washington State construction industry, 2003-2007.

PubMed

Schoonover, Todd; Bonauto, David; Silverstein, Barbara; Adams, Darrin; Clark, Randy

2010-06-01

This study compares construction industry groups in Washington State by injury severity and cost, and ranks industry groups according to potential for prevention. All Washington State workers' compensation compensable claims with date of injury between 2003 and 2007 were classified into North American Industrial Classification System (NAICS) industry groups. Claims were then aggregated by injury type and industry groups were ranked according to a prevention index (PI). The PI is the average of the rank orders of the claim count and the claim incidence rate. A lower PI indicates a higher need for prevention activities. The severity rate was calculated as the number of days of time loss per 10,000 full-time equivalents (FTEs). For all injury types, construction industry groups occupy 7 of the top 15 PI ranks in Washington State. The severity rate among construction industry groups was twice that for non-construction groups for all injury types. Foundation, structure, and building exterior contractors (NAICS 2381) ranked highest in prevention potential and severity among construction industry groups for most common injury types including falls from elevation, fall on same level, struck by/against, and musculo-skeletal disorders of the neck, back, and upper extremity (WMSDs). Median claim costs by injury type were generally higher among construction industry groups. The construction industry in Washington State has a high severity rate and potential for prevention. The methods used for characterizing these industry groups can be adapted for comparison within and between other industries and states. These data can be used by industry groups and employers to identify higher cost and higher severity injury types. Knowledge about the relative frequencies and costs associated with different injury types will help employers and construction industry associations make better informed decisions about where prevention efforts are most needed and may have the greatest impact. The results of this study can also be used by industry stakeholders to cooperatively focus on high cost and high severity injuries and explore best practices, interventions, and solutions as demonstrated by efforts to prevent musculoskeletal disorders in masonry (Entzel, Albers, & Welch, 2007). Initiating construction industry groups to focus on high cost and high severity injuries may also help prevent other types of injuries. (c) 2010 National Safety Council. Published by Elsevier Ltd. All rights reserved.

Multidisciplinary Treatment of Severe Osteogenesis Imperfecta: Functional Outcomes at Skeletal Maturity.

PubMed

Montpetit, Kathleen; Palomo, Telma; Glorieux, Francis H; Fassier, François; Rauch, Frank

2015-10-01

To determine the functional outcomes associated with long-term multidisciplinary treatment, intravenous bisphosphonate treatment, orthopedic surgery, and rehabilitation in children with severe osteogenesis imperfecta (OI) (diagnosed clinically as OI types III or IV). Retrospective study where outcomes were measured prospectively. Pediatric orthopedic hospital. Adolescents (N=41; age range, 15-21y) with severe OI (OI type III: n=17; OI type IV: n=24) who had started therapy before the age of 6 years, had received treatment for at least 10 years, and had achieved final height. Intravenous bisphosphonate treatment, orthopedic surgery, and rehabilitation. Pediatric Evaluation of Disability Inventory. At the time of the last available follow-up examination, none of the individuals diagnosed with OI type III (most severely affected group) was able to ambulate without ambulation aids, whereas 20 (83%) patients with OI type IV were able to ambulate without ambulation aids. Regarding self-care, we specifically assessed 8 skills that we deemed essential for living independently (grooming; dressing; toileting; bed, chair, toilet, tub, and car transfers). Only 6 (35%) of the youths with OI type III were able to complete all 8 items, whereas 23 (96%) individuals with OI type IV managed to perform all tasks. Teens with OI type III often needed assistance for the transfer to toilet, tub, and car and for personal hygiene and clothing management associated with toileting, usually because of limitations in upper-extremity function. These observations suggest that further improvements in the functional status of the most severely affected children with OI are contingent on advances in the clinical management of upper-extremity issues. Copyright © 2015 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.

Gender differences in injury severity risks in crashes at signalized intersections.

PubMed

Obeng, K

2011-07-01

This paper analyzes gender differences in crash risk severities using data for signalized intersections. It estimates gender models for injury severity risks and finds that driver condition, type of crash, type of vehicle driven and vehicle safety features have different effects on females' and males' injury severity risks. Also, it finds some variables which are significantly related to females' injury severity risks but not males' and others which affect males' injury severity risks but not females'. It concludes that better and more in-depth information about gender differences in injury severity risks is gained by estimating separate models for females and males. Copyright © 2011 Elsevier Ltd. All rights reserved.

Severe hypoglycaemia in elderly patients with type 2 diabetes and coexistence of cardiovascular history.

PubMed

Piątkiewicz, Paweł; Buraczewska-Leszczyńska, Bożena; Kuczerowski, Roman; Bernat-Karpińska, Małgorzata; Rabijewski, Michał; Kowrach, Marek

2016-01-01

Hypoglycaemia is a condition that occurs when blood glucose levels fall below 3.9 mmol/L (70 mg/dL), while hypoglycaemic coma is usually associated with glycaemia around 1.1 mmol/L (20 mg/dL). Recurrent severe hypoglycaemia may result in permanent neurological disorders and also has a negative impact on the cardiovascular system. To evaluate the causes of severe hypoglycaemia in elderly patients with type 2 diabetes and coexistence of cardiovascular history. We analysed retrospectively the history of 33 elderly patients with type 2 diabetes and coexistence of cardiovascular history, who were admitted to our clinic due to severe hypoglycaemia with loss of consciousness. The mean age of the patients was 76.0 ± 11.1 years, and the mean duration of diabetes was 12.0 ± 9.8 years. Glycated haemoglobin (HbA1c) was measured and the prevalence of cardiovascular diseases and therapeutic procedures were evaluated. In the group of patients with severe hypoglycaemia, the mean value of HbA1c was 6.3 ± 1.2% (44 ± 13.1 mmol/mol), which indicates a mean glucose value below 7.8 mmol/L (140 mg/dL). Ischaemic heart disease was diagnosed in 18 patients (eight had a history of myocardial infarction), and 22 patients had arterial hypertension. Severe hypoglycaemia requiring hospitalisation in elderly patients with type 2 diabetes and coexistence of cardiovascular history was related to insulin or sulfonylurea therapy. A low HbA1c level indicates inappropriate intensification of therapy and was associated with high risk of severe hypoglycaemic episodes in older people. The majority of severe hypoglycaemic episodes were observed in sulphonylurea or insulin-treated type 2 diabetic patients.

Human rotavirus vaccine Rotarix™ provides protection against diverse circulating rotavirus strains in African infants: a randomized controlled trial.

PubMed

Steele, Andrew Duncan; Neuzil, Kathleen M; Cunliffe, Nigel A; Madhi, Shabir A; Bos, Pieter; Ngwira, Bagrey; Witte, Desiree; Todd, Stacy; Louw, Cheryl; Kirsten, Mari; Aspinall, Sanet; Van Doorn, Leen Jan; Bouckenooghe, Alain; Suryakiran, Pemmaraju V; Han, Htay Htay

2012-09-13

Rotaviruses are the most important cause of severe acute gastroenteritis worldwide in children <5 years of age. The human, G1P[8] rotavirus vaccine Rotarix™ significantly reduced severe rotavirus gastroenteritis episodes in a Phase III clinical trial conducted in infants in South Africa and Malawi. This paper examines rotavirus vaccine efficacy in preventing severe rotavirus gastroenteritis, during infancy, caused by the various G and P rotavirus types encountered during the first rotavirus-season. Healthy infants aged 5-10 weeks were enrolled and randomized into three groups to receive either two (10 and 14 weeks) or three doses of Rotarix™ (together forming the pooled Rotarix™ group) or three doses of placebo at a 6,10,14-week schedule. Weekly home visits were conducted to identify gastroenteritis episodes. Rotaviruses were detected by ELISA and genotyped by RT-PCR and nucleotide sequencing. The percentage of infants with severe rotavirus gastroenteritis caused by the circulating G and P types from 2 weeks post-last dose until one year of age and the corresponding vaccine efficacy was calculated with 95% CI. Overall, 4939 infants were vaccinated and 4417 (pooled Rotarix™ = 2974; placebo = 1443) were included in the per protocol efficacy cohort. G1 wild-type was detected in 23 (1.6%) severe rotavirus gastroenteritis episodes from the placebo group. This was followed in order of detection by G12 (15 [1%] in placebo) and G8 types (15 [1%] in placebo). Vaccine efficacy against G1 wild-type, G12 and G8 types were 64.1% (95% CI: 29.9%; 82%), 51.5% (95% CI:-6.5%; 77.9%) and 64.4% (95% CI: 17.1%; 85.2%), respectively. Genotype P[8] was the predominant circulating P type and was detected in 38 (2.6%) severe rotavirus gastroenteritis cases in placebo group. The remaining circulating P types comprised of P[4] (20 [1.4%] in placebo) and P[6] (13 [0.9%] in placebo). Vaccine efficacy against P[8] was 59.1% (95% CI: 32.8%; 75.3%), P[4] was 70.9% (95% CI: 37.5%; 87.0%) and P[6] was 55.2% (95% CI: -6.5%; 81.3%) Rotarix™ vaccine demonstrated efficacy against severe gastroenteritis caused by diverse circulating rotavirus types. These data add to a growing body of evidence supporting heterotypic protection provided by Rotarix™. NCT00241644.

Capillary cerebral amyloid angiopathy in Alzheimer's disease: association with allocortical/hippocampal microinfarcts and cognitive decline.

PubMed

Hecht, Moritz; Krämer, Lara Maria; von Arnim, Christine A F; Otto, Markus; Thal, Dietmar Rudolf

2018-05-01

Cerebral amyloid angiopathy (CAA) is caused by the deposition of the amyloid β-protein (Aβ) in the wall of cerebral and leptomeningeal blood vessels and is related to Alzheimer's disease (AD). Capillary Aβ deposition is observed in a subset of CAA cases and represents a distinct type of CAA named capillary CAA or CAA type 1. This type of CAA is strongly associated with the presence of the apolipoprotein E ε4 allele. CAA type 1-associated AD cases often exhibit a more severe Aβ plaque pathology but less widespread neurofibrillary tangle (NFT) pathology. The objective of this study was to analyze whether capillary CAA and its effects on cerebral blood flow have an impact on dementia. To address this objective, we performed neuropathological evaluation of 284 autopsy cases of demented and non-demented individuals. We assessed the presence of CAA and its subtypes as well as for that of hemorrhages and infarcts. Capillary CAA and CAA severity were associated with allocortical microinfarcts, comprising the CA1 region of the hippocampus. Allocortical microinfarcts, capillary CAA and CAA severity were, thereby, associated with cognitive decline. In conclusion, allocortical microinfarcts, CAA severity, and the capillary type of CAA were associated with one another and with the development of cognitive decline. Thus, AD cases with CAA type 1 (capillary CAA) appear to develop dementia symptoms not only due to AD-related Aβ plaque and NFT pathology but also due to hippocampal microinfarcts that are associated with CAA type 1 and CAA severity, and that damage a brain region important for memory function.

Exploring the Phenotype of Phonological Reading Disability as a Function of the Phonological Deficit Severity: Evidence from the Error Analysis Paradigm in Arabic

ERIC Educational Resources Information Center

Taha, Haitham; Ibrahim, Raphiq; Khateb, Asaid

2014-01-01

The dominant error types were investigated as a function of phonological processing (PP) deficit severity in four groups of impaired readers. For this aim, an error analysis paradigm distinguishing between four error types was used. The findings revealed that the different types of impaired readers were characterized by differing predominant error…

The impact of blood type O on mortality of severe trauma patients: a retrospective observational study.

PubMed

Takayama, Wataru; Endo, Akira; Koguchi, Hazuki; Sugimoto, Momoko; Murata, Kiyoshi; Otomo, Yasuhiro

2018-05-02

Recent studies have implicated the differences in the ABO blood system as a potential risk for various diseases, including hemostatic disorders and hemorrhage. In this study, we evaluated the impact of the difference in the ABO blood type on mortality in patients with severe trauma. A retrospective observational study was conducted in two tertiary emergency critical care medical centers in Japan. Patients with trauma with an Injury Severity Score (ISS) > 15 were included. The association between the different blood types (type O versus other blood types) and the outcomes of all-cause mortality, cause-specific mortalities (exsanguination, traumatic brain injury, and others), ventilator-free days (VFD), and total transfusion volume were evaluated using univariate and multivariate competing-risk regression models. Moreover, the impact of blood type O on the outcomes was assessed using regression coefficients in the multivariate analysis adjusted for age, ISS, and the Revised Trauma Score (RTS). A total of 901 patients were included in this study. The study population was divided based on the ABO blood type: type O, 284 (32%); type A, 285 (32%); type B, 209 (23%); and type AB, 123 (13%). Blood type O was associated with high mortality (28% in patients with blood type O versus 11% in patients with other blood types; p <  0.001). Moreover, this association was observed in a multivariate model (adjusted odds ratio = 2.86, 95% confidence interval 1.84-4.46; p <  0.001). The impact of blood type O on all-cause in-hospital mortality was comparable to 12 increases in the ISS, 1.5 decreases in the RTS, and 26 increases in age. Furthermore, blood type O was significantly associated with higher cause-specific mortalities and shorter VFD compared with the other blood types; however, a significant difference was not observed in the transfusion volume between the two groups. Blood type O was significantly associated with high mortality in severe trauma patients and might have a great impact on outcomes. Further studies elucidating the mechanism underlying this association are warranted to develop the appropriate intervention.

Tremor associated with focal and segmental dystonia.

PubMed

Rudzińska, M; Krawczyk, M; Wójcik-Pędziwiatr, M; Szczudlik, A; Wasielewska, A

2013-01-01

Tremor occurs in 10-85% of patients with focal dystonia as so-called dystonic tremor or tremor associated with dystonia. The aim of this study was to assess the incidence and to characterize parameters of tremor accompanying focal and segmental dystonia. One hundred and twenty-three patients with diagnosis of focal and segmental dystonia together with 51 healthy controls were included in the study. For each participant, clinical examination and objective assessment (accelerometer, electromyography, graphic tablet) of hand tremor was performed. Frequency and severity of tremor were assessed in three positions: at rest (rest tremor); with hands extended (postural tremor); during 'finger-to-nose' test and during Archimedes spiral drawing (kinetic tremor). Based on the mass load test, type of tremor was determined as essential tremor type or enhanced physiological type. The incidence of tremor was significantly higher in dystonic patients as compared to controls (p = 0.0001). In clinical examination, tremor was found in 50% of dystonic patients, and in instrumental assessment in an additional 10-20%. The most frequent type of tremor was postural and kinetic tremor with 7 Hz frequency and featured essential tremor type. In the control group, tremor was detected in about 10% of subjects as 9-Hz postural tremor of enhanced physiological tremor type. No differences were found between patients with different types of dystonia with respect to the tremor incidence, type and parameters (frequency and severity). No correlations between tremor severity and dystonia severity were found either.

Clinical profile and outcomes of acute cardiorenal syndrome type-5 in sepsis: An eight-year cohort study.

PubMed

Vallabhajosyula, Saraschandra; Sakhuja, Ankit; Geske, Jeffrey B; Kumar, Mukesh; Kashyap, Rahul; Kashani, Kianoush; Jentzer, Jacob C

2018-01-01

To evaluate the clinical features and outcomes of acute cardiorenal syndrome type-5 in patients with severe sepsis and septic shock. Historical cohort study of all adult patients with severe sepsis and septic shock admitted to the intensive care units (ICU) at Mayo Clinic Rochester from January 1, 2007 through December 31, 2014. Patients with prior renal or cardiac dysfunction were excluded. Patients were divided into groups with and without cardiorenal syndrome type-5. Acute Kidney Injury (AKI) was defined by both serum creatinine and urine output criteria of the AKI Network and the cardiac injury was determined by troponin-T levels. Outcomes included in-hospital mortality, ICU and hospital length of stay, and one-year survival. Of 602 patients meeting the study inclusion criteria, 430 (71.4%) met criteria for acute cardiorenal syndrome type-5. Patients with cardiorenal syndrome type-5 had higher severity of illness, greater vasopressor and mechanical ventilation use. Cardiorenal syndrome type-5 was associated higher unadjusted in-hospital mortality, ICU and hospital lengths of stay, and lower one-year survival. When adjusted for age, gender, severity of illness and mechanical ventilation, cardiorenal syndrome type-5 was independently associated with 1.7-times greater odds of in-hospital mortality (p = .03), but did not predict one-year survival (p = .06) compared to patients without cardiorenal syndrome. In sepsis, acute cardiorenal syndrome type-5 is associated with worse in-hospital mortality compared to patients without cardiorenal syndrome.

Morphology, severity, and distribution of growth anomalies in the coral, Montipora capitata, at Wai`ōpae, Hawai`i

NASA Astrophysics Data System (ADS)

Burns, J. H. R.; Rozet, N. K.; Takabayashi, M.

2011-09-01

This study investigated the morphology, severity, and distribution of growth anomalies (GAs) in the coral, Montipora capitata, from Wai`ōpae tide pools, southeast Hawai`i Island. A macro-image analysis of skeletal microstructure placed GAs into two definable categories; Type A and Type B. Type A GAs had polyp density reduced by 43.05 ± 0.80% (mean ± SE) compared to healthy M. capitata tissue, with many fused and protrusive tuberculae. Type B GAs had no discernable polyps or calices and fused protuberant coenosteum. The prevalence of Type A and Type B GAs among all M. capitata colonies ( n = 1,093) in 8 tide pools at Wai`ōpae was 22.1% (range 2.8-33.7%) and 8.2% (range 0.0-16.9%), respectively. The proportion of colony surface area occupied by GA (relative GA cover) was quantified to assess the severity of this disease among all surveyed colonies. The relative GA cover was significantly greater on colonies larger than 1 m in diameter than smaller colonies and in the central portion of colonies than in the periphery. Furthermore, relative GA cover was negatively related to water motion ( R 2 = 0.748, P < 0.01). Developing field diagnostic criteria of M. capitata GA allowed for a detailed epizootiological assessment that determined several cofactors associated with disease severity. Such epizootiological analysis is applicable to future studies of GAs elsewhere.

Type A behavior and the thallium stress test

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kahn, J.P.; Kornfeld, D.S.; Blood, D.K.

1982-11-01

Several recent studies have examined the association between Type A personality and coronary artery disease (CAD) by coronary angiography. Most of these studies have reported a significant association. The present study is an attempt at further confirmation, using a new non-invasive technique for measuring CAD. Subjects were 53 patients undergoing routine exercise stress tests with concomitant thallium-201 myocardial perfusion studies. Five aspects of Type A behavior were assessed by the use of the Rosenman-Friedman Semistructured Interview, and each was rated on a three-point scale. Severity of CAD was independently estimated on a four-point scale. Pearson correlation coefficients were separately computedmore » for patients with and without reported history of myocardial infarction (MI). For 37 patients without reported MI, CAD severity was significantly correlated with Overall Type A (r . -0.53), Vocal Characteristics (r . -0.53), Job Involvement (r . -0.36) and Aggressiveness (r . -0.48), but not Time Urgency (r . -0.25). For 16 patients with reported MI, CAD severity was significantly correlated with Job Involvement only (r . +0.49). The data are consistent with the association of Type A personality and coronary atherogenesis, but may also reflect Type A psychological and physiological characteristics. Future studies may be able to examine these and other aspects of Type A behavior using this noninvasive technique in more diverse patient populations.« less

Characteristics of cyclist crashes in Italy using latent class analysis and association rule mining

PubMed Central

De Angelis, Marco; Marín Puchades, Víctor; Fraboni, Federico; Pietrantoni, Luca

2017-01-01

The factors associated with severity of the bicycle crashes may differ across different bicycle crash patterns. Therefore, it is important to identify distinct bicycle crash patterns with homogeneous attributes. The current study aimed at identifying subgroups of bicycle crashes in Italy and analyzing separately the different bicycle crash types. The present study focused on bicycle crashes that occurred in Italy during the period between 2011 and 2013. We analyzed categorical indicators corresponding to the characteristics of infrastructure (road type, road signage, and location type), road user (i.e., opponent vehicle and cyclist’s maneuver, type of collision, age and gender of the cyclist), vehicle (type of opponent vehicle), and the environmental and time period variables (time of the day, day of the week, season, pavement condition, and weather). To identify homogenous subgroups of bicycle crashes, we used latent class analysis. Using latent class analysis, the bicycle crash data set was segmented into 19 classes, which represents 19 different bicycle crash types. Logistic regression analysis was used to identify the association between class membership and severity of the bicycle crashes. Finally, association rules were conducted for each of the latent classes to uncover the factors associated with an increased likelihood of severity. Association rules highlighted different crash characteristics associated with an increased likelihood of severity for each of the 19 bicycle crash types. PMID:28158296

Accelerated decline of renal function in type 2 diabetes following severe hypoglycemia.

PubMed

Tsujimoto, Tetsuro; Yamamoto-Honda, Ritsuko; Kajio, Hiroshi; Kishimoto, Miyako; Noto, Hiroshi; Hachiya, Remi; Kimura, Akio; Kakei, Masafumi; Noda, Mitsuhiko

2016-01-01

This study aimed to evaluate whether the pronounced elevation in blood pressure during severe hypoglycemia is associated with subsequent renal insufficiency. We conducted a 3-year cohort study to assess the clinical course of renal function in type 2 diabetes patients with or without blood pressure surge during severe hypoglycemia. Of 111 type 2 diabetes patients with severe hypoglycemia, 76 exhibited an extremely high systolic blood pressure before treatment, whereas 35 demonstrated no such increase (179.1 ± 27.7 mmHg vs. 131.1 ± 20.2 mmHg, P<0.001). At 12h after treatment, systolic blood pressure did not differ significantly (131.5 ± 30.7 mmHg vs. 123.5 ± 20.7 mmHg; P=0.39). The estimated glomerular filtration rate (GFR) before and at the time of severe hypoglycemia did not significantly differ between both groups. A multivariate Cox proportional hazards regression analysis revealed that blood pressure surge during severe hypoglycemia was independently associated with a composite outcome of a more than 15 mL/min/1.73 m(2) decrease in the estimated GFR and initiation of chronic dialysis (hazard ratio, 2.68; 95% confidence interval, 1.12-6.38; P=0.02). Renal function after severe hypoglycemia was significantly worse in type 2 diabetes patients with blood pressure surge during severe hypoglycemia than those without blood pressure surge. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Healthcare Provider Type and Switch to Biologics in Psoriasis: Evidence from Real-World Practice.

PubMed

Calara, Paul S; Norlin, Jenny M; Althin, Rikard; Carlsson, Katarina Steen; Schmitt-Egenolf, Marcus

2016-04-01

Previous research indicates an uneven uptake of biologics in patients with moderate-to-severe psoriasis in Sweden. Therefore, it is essential to scrutinise variations in treatment patterns. The aim of this study was to evaluate the extent to which the uptake of biologics for psoriasis differs between types of healthcare provider. Three types of provider were identified within 52 units participating in the Swedish National Registry for Systemic Psoriasis Treatment (PsoReg): university hospitals, non-university hospitals and individual practices. Biologics-naïve patients (n = 3165) were included in analyses to investigate the probability of switch to biologics. The numbers of patients fulfilling the criteria for moderate-to-severe psoriasis [Psoriasis Area and Severity Index (PASI) ≥10 and Dermatology Life Quality Index (DLQI) ≥10] among patients who switched to biologics and patients who did not switch were reported. A logistic regression model was used to calculate how healthcare provider type influenced the probability of switch to biologics whilst adjusting for patient characteristics and disease severity. During registration, 16% of patients switched to biologics while 84% remained on conventional systemic treatment. In 7% of patients, the criteria PASI ≥10 and DLQI ≥10 was fulfilled at their last visit without switching to biologics, whereas in 10% of patients the criteria was not fulfilled prior to switch. After controlling for patient characteristics and disease severity, small or no difference in the probability of switch was observed between provider types. Disease severity does not explain the decision to switch or not to switch to biologics for a disproportionate number of patients. There seems to be an uneven uptake of biologics in Swedish clinical practice, but the type of healthcare provider cannot explain this variation. More research is needed on what factors influence the prescription of biologics.

Behavior of scoliosis during growth in children with osteogenesis imperfecta.

PubMed

Anissipour, Alireza K; Hammerberg, Kim W; Caudill, Angela; Kostiuk, Theodore; Tarima, Sergey; Zhao, Heather Shi; Krzak, Joseph J; Smith, Peter A

2014-02-05

Spinal deformities are common in patients with osteogenesis imperfecta, a heritable disorder that causes bone fragility. The purpose of this study was to describe the behavior of spinal curvature during growth in patients with osteogenesis imperfecta and establish its relationship to disease severity and medical treatment with bisphosphonates. The medical records and radiographs of 316 patients with osteogenesis imperfecta were retrospectively reviewed. The severity of osteogenesis imperfecta was classified with the modified Sillence classification. Serial curve measurements were recorded throughout the follow-up period for each patient with scoliosis. Regression analysis was used to determine the effect of disease severity (Sillence type), patient age, and bisphosphonate treatment on the progression of scoliosis as measured with the Cobb method. Of the 316 patients with osteogenesis imperfecta, 157 had associated scoliosis, a prevalence of 50%. Scoliosis prevalence (68%) and mean progression rate (6° per year) were the highest in the group of patients with the most severe osteogenesis imperfecta (modified Sillence type III). A group with intermediate osteogenesis imperfecta severity, modified Sillence type IV, demonstrated intermediate scoliosis values (54%, 4° per year). The patient group with the mildest form of osteogenesis imperfecta, modified Sillence type I, had the lowest scoliosis prevalence (39%) and rate of progression (1° per year). Early treatment-before the patient reached the age of six years-of type-III osteogenesis imperfecta with bisphosphonate therapy decreased the curve progression rate by 3.8° per year, which was a significant decrease. Bisphosphonate treatment had no demonstrated beneficial effect on curve behavior in patients with other types of osteogenesis imperfecta or in patients of older age. The prevalence of scoliosis in association with osteogenesis imperfecta is high. Progression rates of scoliosis in children with osteogenesis imperfecta are variable, depending on the Sillence type of osteogenesis imperfecta. High rates of scoliosis progression in type-III and type-IV osteogenesis imperfecta contrast with a benign course in type I. Bisphosphonate therapy initiated before the patient reaches the age of six years can modulate curve progression in type-III osteogenesis imperfecta.

Features that exacerbate fatigue severity in joint hypermobility syndrome/Ehlers-Danlos syndrome - hypermobility type.

PubMed

Krahe, Anne Maree; Adams, Roger David; Nicholson, Leslie Lorenda

2018-08-01

To assess the prevalence, severity and impact of fatigue on individuals with joint hypermobility syndrome (JHS)/Ehlers-Danlos syndrome - hypermobility type (EDS-HT) and establish potential determinants of fatigue severity in this population. Questionnaires on symptoms and signs related to fatigue, quality of life, mental health, physical activity participation and sleep quality were completed by people with JHS/EDS-HT recruited through two social media sites. Multiple regression analysis was performed to identify predictors of fatigue in this population. Significant fatigue was reported by 79.5% of the 117 participants. Multiple regression analysis identified five predictors of fatigue severity, four being potentially modifiable, accounting for 52.3% of the variance in reported fatigue scores. Predictors of fatigue severity were: the self-perceived extent of joint hypermobility, orthostatic dizziness related to heat and exercise, levels of participation in personal relationships and community, current levels of physical activity and dissatisfaction with the diagnostic process and management options provided for their condition. Fatigue is a significant symptom associated with JHS/EDS-HT. Assessment of individuals with this condition should include measures of fatigue severity to enable targeted management of potentially modifiable factors associated with fatigue severity. Implications for rehabilitation Fatigue is a significant symptom reported by individuals affected by joint hypermobility syndrome/Ehlers-Danlos syndrome - hypermobility type. Potentially modifiable features that contribute to fatigue severity in this population have been identified. Targeted management of these features may decrease the severity and impact of fatigue in joint hypermobility syndrome/Ehlers-Danlos syndrome - hypermobility type.

A population-based study of risk factors for severe hypoglycaemia in a contemporary cohort of childhood-onset type 1 diabetes.

PubMed

Cooper, Matthew N; O'Connell, Susan M; Davis, Elizabeth A; Jones, Timothy W

2013-10-01

Severe hypoglycaemia is a major barrier to optimising glycaemic control. Recent changes in therapy, however, may have altered the epidemiology of severe hypoglycaemia and its associated risk factors. The aim of this study was to examine the incidence rates and risk factors associated with severe hypoglycaemia in a contemporary cohort of children and adolescents with type 1 diabetes. Subjects were identified from a population-based register containing data on >99% of patients (<16 years of age) who were being treated for type 1 diabetes in Western Australia. Patients attend the clinic approximately every 3 months, where data pertaining to diabetes management, demographics and complications including hypoglycaemia are prospectively recorded. A severe hypoglycaemic event was defined as an episode of coma or convulsion associated with hypoglycaemia. Risk factors assessed included age, duration of diabetes, glycaemic control, sex, insulin therapy, socioeconomic status and calendar year. Clinical visit data from 1,770 patients, providing 8,214 patient-years of data between 2000 and 2011 were analysed. During follow-up, 841 episodes of severe hypoglycaemia were observed. No difference in risk of severe hypoglycaemia was observed between age groups. Good glycaemic control (HbA1c <7% [53 mmol/mol]) compared with the cohort average (HbA1c 8-9% [64-75 mmol/mol]) was not associated with an increased risk of severe hypoglycaemia. When compared with patients on injection regimens, subjects aged 12-18 years on pump therapy were at reduced risk of severe hypoglycaemia (incidence risk ratio 0.6; 95% CI 0.4, 0.9). In this population-based sample of children and adolescents with type 1 diabetes, contemporary therapy is associated with a changed pattern and incidence of severe hypoglycaemia.

Ruthenium-catalyzed regioselective allylic amination of 2,3,3-trifluoroallylic carbonates.

PubMed

Isobe, Shin-Ichi; Terasaki, Shou; Hanakawa, Taisyun; Mizuno, Shota; Kawatsura, Motoi

2017-04-05

We demonstrated the ruthenium-catalyzed allylic amination of 2,3,3-trifluoroallylic carbonates with several types of amines. The reactions proceeded with several types of amines, and succeeded in obtaining polyfluorinated terminal alkenes possessing branched allylic amines as a single regioisomer.

Causes, types and severity of injury among army soldiers hospitalized with alcohol comorbidity*

PubMed Central

Howland, Jonathan; Bell, Nicole S.; Hollander, Ilyssa E.

2007-01-01

Aim To examine the relationship between alcohol use and the cause, type and severity of hospitalized injuries. Design/setting We used the Total Army Injury and Health Outcomes Database (TAIHOD) to conduct cross-sectional analyses of the association between alcohol comorbidity and the cause, type and severity of soldiers’ non-combat injuries requiring hospitalization. Participants Subjects were active-duty US army soldiers (n = 211 790) hospitalized with a primary diagnosis of injury between 1980 and 2002. Findings Alcohol comorbidity was positively associated with hospitalized injuries resulting from fights and falls and negatively associated with sports injuries; positively associated with hospitalized cases of head injury, open wounds and poisonings and negatively associated with musculoskeletal injury; and, overall, associated with shorter length of stay. Controlling for demographic factors did not moderate the association between alcohol and cause, type or severity of injury. Conclusion Alcohol comorbidity is specifically associated with injuries related to impairment and antisocial behavior. PMID:17697276

Severe gingival enlargement associated with aggressive periodontitis

PubMed Central

Padmanabhan, Shyam; Dwarakanath, C. D.

2013-01-01

Enlargement of the gingiva can be due to various causes. Most prevalent are the inflammatory type and drug-induced type of gingival hyperplasia. However, sever enlargement associated with an aggressive type of periodontitis is an infrequent finding. Reported here is a case of a female patient aged 18 years who presented with severe enlargement of the maxillary and mandibular gingiva. Examination revealed enlargement extending up to the incisal edge of all the teeth and also an associated generalized loss of attachment with radiographic evidence of reduced bone height resembling an aggressive type of periodontitis. There were no associated systemic signs and symptoms or any family history except that there was generalized vitiligo of the skin and oral mucous membrane. The case was treated by gross electrosection of the gingiva. PMID:23633785

DNA sequence analysis in 598 individuals with a clinical diagnosis of osteogenesis imperfecta: diagnostic yield and mutation spectrum.

PubMed

Bardai, G; Moffatt, P; Glorieux, F H; Rauch, F

2016-12-01

We detected disease-causing mutations in 585 of 598 individuals (98 %) with typical features of osteogenesis imperfecta (OI). In mild OI, only collagen type I encoding genes were involved. In moderate to severe OI, mutations in 12 different genes were found; 11 % of these patients had mutations in recessive genes. OI is usually caused by mutations in COL1A1 or COL1A2, the genes encoding collagen type I alpha chains, but mutations in at least 16 other genes have also been associated with OI. It is presently unknown what proportion of individuals with clinical features of OI has a disease-causing mutation in one of these genes. DNA sequence analysis was performed on 598 individuals from 487 families who had a typical OI phenotype. OI type I was diagnosed in 43 % of individuals, and 57 % had moderate to severe OI, defined as OI types other than type I. Disease-causing variants were detected in 97 % of individuals with OI type I and in 99 % of patients with moderate to severe OI. All mutations found in OI type I were dominant and exclusively affected COL1A1 or COL1A2. In moderate to severe OI, dominant mutations were found in COL1A1/COL1A2 (77 %), IFITM5 (9 %), and P4HB (0.6 %). Mutations in one of the recessive OI-associated gene were observed in 12 % of individuals with moderate to severe OI. The genes most frequently involved in recessive OI were SERPINF1 (4.0 % of individuals with moderate to severe OI) and CRTAP (2.9 %). DNA sequence analysis of currently known OI-associated genes identifies disease-causing variants in almost all individuals with a typical OI phenotype. About 20 % of individuals with moderate to severe OI had mutations in genes other than COL1A1/COL1A2.

Associations of financial stressors and physical intimate partner violence perpetration.

PubMed

Schwab-Reese, Laura M; Peek-Asa, Corinne; Parker, Edith

2016-12-01

Contextual factors, such as exposure to stressors, may be antecedents to IPV perpetration. These contextual factors may be amenable to modification through intervention and prevention. However, few studies have examined specific contextual factors. To begin to address this gap, we examined the associations between financial stressors and three types of physical IPV perpetration. This analysis used data from Wave IV of The National Longitudinal Study of Adolescent to Adult Health. We used logistic regression to examine the associations of financial stressors and each type of IPV (minor, severe, causing injury), and multinomial logit regression to examine the associations of financial stressors and patterns of co-occurring types of IPV perpetration (only minor; only severe; minor and severe; minor, severe, and causing injury; compared with no perpetration). Fewer men perpetrated threats/minor physical IPV (6.7 %) or severe physical IPV (3.4 %) compared with women (11.4 % and 8.8 %, respectively). However, among physical IPV perpetrators, a higher percentage of men (32.0 %) than women (21.0 %) reported their partner was injured as a result of the IPV. In logistic regression models of each type of IPV perpetration, both the number of stressors experienced and several types of financial stressors were associated with perpetrating each type of IPV. Utilities nonpayment, housing nonpayment, food insecurity, and no phone service were associated with increased odds of perpetrating each form of IPV in adjusted analysis. Eviction was associated with perpetrating severe physical IPV but not threats/minor IPV or IPV causing injury. In multinomial logit regression comparing patterns of IPV perpetration to perpetrating no physical IPV, the relationships of financial stressors were less consistent. Food insecurity was associated with perpetrating only minor physical IPV. Comparatively, overall number of financial stressors and four types of financial stressors (utilities nonpayment, housing nonpayment, food insecurity, and disconnected phone service) were associated with perpetrating all three forms of physical IPV. Combined with prior research, our results suggested interventions to improve financial well-being may be a novel way to reduce physical IPV perpetration.

Associations of financial stressors and physical intimate partner violence perpetration.

PubMed

Schwab-Reese, Laura M; Peek-Asa, Corinne; Parker, Edith

Contextual factors, such as exposure to stressors, may be antecedents to IPV perpetration. These contextual factors may be amenable to modification through intervention and prevention. However, few studies have examined specific contextual factors. To begin to address this gap, we examined the associations between financial stressors and three types of physical IPV perpetration. This analysis used data from Wave IV of The National Longitudinal Study of Adolescent to Adult Health. We used logistic regression to examine the associations of financial stressors and each type of IPV (minor, severe, causing injury), and multinomial logit regression to examine the associations of financial stressors and patterns of co-occurring types of IPV perpetration ( only minor; only severe; minor and severe; minor, severe, and causing injury; compared with no perpetration). Fewer men perpetrated threats/minor physical IPV (6.7 %) or severe physical IPV (3.4 %) compared with women (11.4 % and 8.8 %, respectively). However, among physical IPV perpetrators, a higher percentage of men (32.0 %) than women (21.0 %) reported their partner was injured as a result of the IPV. In logistic regression models of each type of IPV perpetration, both the number of stressors experienced and several types of financial stressors were associated with perpetrating each type of IPV. Utilities nonpayment, housing nonpayment, food insecurity, and no phone service were associated with increased odds of perpetrating each form of IPV in adjusted analysis. Eviction was associated with perpetrating severe physical IPV but not threats/minor IPV or IPV causing injury. In multinomial logit regression comparing patterns of IPV perpetration to perpetrating no physical IPV, the relationships of financial stressors were less consistent. Food insecurity was associated with perpetrating only minor physical IPV. Comparatively, overall number of financial stressors and four types of financial stressors (utilities nonpayment, housing nonpayment, food insecurity, and disconnected phone service) were associated with perpetrating all three forms of physical IPV. Combined with prior research, our results suggested interventions to improve financial well-being may be a novel way to reduce physical IPV perpetration.

ABO Blood Type A Is Associated With Increased Risk of ARDS in Whites Following Both Major Trauma and Severe Sepsis

PubMed Central

Meyer, Nuala J.; Shashaty, Michael G. S.; Feng, Rui; Lanken, Paul N.; Gallop, Robert; Kaplan, Sandra; Herlim, Maximilian; Oz, Nathaniel L.; Hiciano, Isabel; Campbell, Ana; Holena, Daniel N.; Reilly, Muredach P.; Christie, Jason D.

2014-01-01

Background: ABO glycosyltransferases catalyze antigen modifications on various glycans and glycoproteins and determine the ABO blood types. Blood type A has been associated with increased risk of vascular diseases and differential circulating levels of proteins related to inflammation and endothelial function. The objective of this study was to determine the association of ABO blood types with ARDS risk in patients with major trauma and severe sepsis. Methods: We conducted prospective cohort studies in two populations at an urban tertiary referral, level I trauma center. Critically ill patients (n = 732) presenting after major trauma were followed for 5 days for ARDS development. Additionally, 976 medical patients with severe sepsis were followed for 5 days for ARDS. Multivariable logistic regression was used to adjust for confounders. Results: ARDS developed in 197 of the 732 trauma patients (27%). Blood type A was associated with increased ARDS risk among whites (37% vs 24%; adjusted OR, 1.88; 95% CI, 1.14-3.12; P = .014), but not blacks (adjusted OR, 0.61; 95% CI, 0.33-1.13; P = .114). ARDS developed in 222 of the 976 patients with severe sepsis (23%). Blood type A was also associated with an increased ARDS risk among whites (31% vs 21%; adjusted OR, 1.67; 95% CI, 1.08-2.59; P = .021) but, again, not among blacks (adjusted OR, 1.17; 95% CI, 0.59-2.33; P = .652). Conclusions: Blood type A is associated with an increased risk of ARDS in white patients with major trauma and severe sepsis. These results suggest a role for ABO glycans and glycosyltransferases in ARDS susceptibility. PMID:24385226

[Symbrachydactyly--a roentgenographic and clinical study of 126 cases].

PubMed

Senrui, H

1984-07-01

One hundred and twenty-six cases of symbrachydactyly were analyzed roentgenographically and clinically. This curious anomaly of the hand is sporadic and of unknown etiology. It is predominantly one-sided, either isolated or combined with ipsilateral pectoral muscle defect (fifty-one cases). On X-ray pictures, the skeletal abnormalities of the hands ranged from mild involvement featured with hypoplastic or aplastic middle phalanges to the most severe involvement in which all the phalanges were missing, providing a continuous spectrum. Even in the mildly affected hands hypoplasia involves all the phalanges and metacarpals, most severely in the middle phanges followed by distal, proximal phalanges and metacarpals in turn. The forearms and arms are less affected than the hands. The tendency is observed in the severely affected hands. In the most severely affected hand all the digits are missing, but there exist several finger-buds which carry often nail rudiments. Synostosis is seen in the remaining hypoplastic metacarpals often and in carpals infrequently. Although remarkable shortening and curving forearm bones are observed often, the humeral involvement remains mild. Abnormalities of muscles and tendons are frequently observed in the hand and forearm. The anomaly is classified roentgenographically into three types: Type I (brachydactyly type) which is featured with fingers having three or two phalanges (fifty-four hands), Type II (partial ectrodactyly type) in which one to four digits have only one phalanx or none(thirty-nine hands), and Type III(total ectrodactyly type) in which all the digits have only one phalanx or none (thirty-five hands). The symbrachydactyly seems to be caused by a extensive defect in an undifferentiated mesenchyme of the arm bud at about developmental stage 16, which may later cause a failure of separation of skeletal and muscular tissues of the hand and forearm or an arrest in their development.

Evaluation of the effects of several zoanthamine-type alkaloids on the aggregation of human platelets.

PubMed

Villar, Rosa M; Gil-Longo, José; Daranas, Antonio H; Souto, María L; Fernández, José J; Peixinho, Solange; Barral, Miguel A; Santafé, Gilmar; Rodríguez, Jaime; Jiménez, Carlos

2003-05-15

Ten zoanthamine-type alkaloids from two marine zoanthids belonging to the Zoanthus genus (Zoanthus nymphaeus and Zoanthus sp.) along with one semisynthetic derivative were evaluated for their antiplatelet activities on human platelet aggregation induced by several stimulating agents. 11-Hydroxyzoanthamine (11) and a synthetic derivative of norzoanthamine (16) showed strong inhibition against thrombin-, collagen- and arachidonic acid-induced aggregation, zoanthenol (15) displayed a selective inhibitory activity induced by collagen, while zoanthaminone (10) behaved as a potent aggregant agent. These evaluations allowed us to deduce several structure-activity relationships and suggest some mechanisms of action for this type of compounds.

Using multiclass classification to automate the identification of patient safety incident reports by type and severity.

PubMed

Wang, Ying; Coiera, Enrico; Runciman, William; Magrabi, Farah

2017-06-12

Approximately 10% of admissions to acute-care hospitals are associated with an adverse event. Analysis of incident reports helps to understand how and why incidents occur and can inform policy and practice for safer care. Unfortunately our capacity to monitor and respond to incident reports in a timely manner is limited by the sheer volumes of data collected. In this study, we aim to evaluate the feasibility of using multiclass classification to automate the identification of patient safety incidents in hospitals. Text based classifiers were applied to identify 10 incident types and 4 severity levels. Using the one-versus-one (OvsO) and one-versus-all (OvsA) ensemble strategies, we evaluated regularized logistic regression, linear support vector machine (SVM) and SVM with a radial-basis function (RBF) kernel. Classifiers were trained and tested with "balanced" datasets (n_ Type  = 2860, n_ SeverityLevel  = 1160) from a state-wide incident reporting system. Testing was also undertaken with imbalanced "stratified" datasets (n_ Type  = 6000, n_ SeverityLevel =5950) from the state-wide system and an independent hospital reporting system. Classifier performance was evaluated using a confusion matrix, as well as F-score, precision and recall. The most effective combination was a OvsO ensemble of binary SVM RBF classifiers with binary count feature extraction. For incident type, classifiers performed well on balanced and stratified datasets (F-score: 78.3, 73.9%), but were worse on independent datasets (68.5%). Reports about falls, medications, pressure injury, aggression and blood products were identified with high recall and precision. "Documentation" was the hardest type to identify. For severity level, F-score for severity assessment code (SAC) 1 (extreme risk) was 87.3 and 64% for SAC4 (low risk) on balanced data. With stratified data, high recall was achieved for SAC1 (82.8-84%) but precision was poor (6.8-11.2%). High risk incidents (SAC2) were confused with medium risk incidents (SAC3). Binary classifier ensembles appear to be a feasible method for identifying incidents by type and severity level. Automated identification should enable safety problems to be detected and addressed in a more timely manner. Multi-label classifiers may be necessary for reports that relate to more than one incident type.

Relationship between brain lesion characteristics and communication in preschool children with cerebral palsy.

PubMed

Coleman, Andrea; Fiori, Simona; Weir, Kelly A; Ware, Robert S; Boyd, Roslyn N

2016-11-01

MRI shows promise as a prognostic tool for clinical findings such as gross motor function in children with cerebral palsy(CP), however the relationship with communication skills requires exploration. To examine the relationship between the type and severity of brain lesion on MRI and communication skills in children with CP. 131 children with CP (73 males(56%)), mean corrected age(SD) 28(5) months, Gross Motor Functional Classification System distribution: I=57(44%), II=14(11%), III=19(14%), IV=17(13%), V=24(18%). Children were assessed on the Communication and Symbolic Behavioral Scales Developmental Profile (CSBS-DP) Infant-Toddler Checklist. Structural MRI was analysed with reference to type and semi-quantitative assessment of the severity of brain lesion. Children were classified for motor type, distribution and GMFCS. The relationships between type/severity of brain lesion and communication ability were analysed using multivariable tobit regression. Children with periventricular white matter lesions had better speech than children with cortical/deep grey matter lesions (β=-2.6, 95%CI=-5.0, -0.2, p=0.04). Brain lesion severity on the semi-quantitative scale was related to overall communication skills (β=-0.9, 95%CI=-1.4, -0.5, p<0.001). Motor impairment better accounted for impairment in overall communication skills than brain lesion severity. Structural MRI has potential prognostic value for communication impairment in children with CP. WHAT THIS PAPER ADDS?: This is the first paper to explore important aspects of communication in relation to the type and severity of brain lesion on MRI in a representative cohort of preschool-aged children with CP. We found a relationship between the type of brain lesion and communication skills, children who had cortical and deep grey matter lesions had overall communication skills>1 SD below children with periventricular white matter lesions. Children with more severe brain lesions on MRI had poorer overall communication skills. Children with CP born at term had poorer communication than those born prematurely and were more likely to have cortical and deep grey matter lesions. Gross motor function better accounted for overall communication skills than the type of brain lesion or brain lesion severity. Copyright © 2016. Published by Elsevier Ltd.

The current status of treatment-related severe hypoglycemia in Japanese patients with diabetes mellitus: A report from the committee on a survey of severe hypoglycemia in the Japan Diabetes Society.

PubMed

Namba, Mitsuyoshi; Iwakura, Toshio; Nishimura, Rimei; Akazawa, Kohei; Matsuhisa, Munehide; Atsumi, Yoshihito; Satoh, Jo; Yamauchi, Toshimasa

2018-03-02

Despite great strides in pharmacotherapy for diabetes, there is increasing concern over the risk of hypoglycemia in patients with diabetes receiving pharmacotherapy as they become increasingly older. This has prompted the Japan Diabetes Society (JDS) to initiate a survey on the current status of severe hypoglycemia in clinical settings. In July 2015, following approval from the JDS Scientific Survey/Research Ethics Committee, the JDS extended an invitation to executive educators, who represented a total of 631 healthcare facilities accredited by the JDS for diabetes education, to participate in the proposed survey. Of these, those who expressed their willingness to participate in the survey were sent an application form required for obtaining ethical approval at these healthcare facilities and were then asked, following approval, to enter relevant clinical data on an unlinked, anonymous basis in a web-based registry. The current survey was fully funded by the JDS Scientific Survey/Research Committee. A case registry (clinical case database) was launched after facility-specific information (healthcare facility database) was collected from all participating facilities and after informed consent was obtained from all participating patients. With severe hypoglycemia defined as the "presence of hypoglycemic symptoms requiring assistance from another person to treat and preferably venous plasma glucose levels at onset/diagnosis of disease or at presentation clearly less than 60 mg/dL (capillary whole blood glucose, less than 50 mg/dL)", the current survey was conducted between April 1, 2014 and March 31, 2015, during which facility-specific information was collected from a total of 193 facilities with a total of 798 case reports collected from 113 facilities. Of the 193 respondent facilities, 149 reported having an emergency department as well, with the median number of patients who required emergency transportation services to reach these facilities totaling 4,962 annually, of which those with severe hypoglycemia accounted for 0.34% (17). The respondent facilities accommodated a total of 2,237 patients with severe hypoglycemia annually, with the number of patients thus accommodated being 6.5 patients per site. A total of 1,171 patients were admitted for severe hypoglycemia, with the number of patients thus admitted being 4.0 per site, who accounted for 52.3% of all patients visiting annually for severe hypoglycemia. A review of the 798 case reports collected during the survey revealed that 240, 480 and 78 patients had type 1 diabetes, type 2 diabetes, and other types of diabetes, respectively; those with type 2 diabetes were shown to be significantly older (median [interquartile range], 77.0 [68.0-83.0]) than those with type 1 diabetes (54.0 [41.0-67.0]) (P < 0.001); and the BMI was shown to be significantly higher for those with type 2 diabetes (22.0 [19.5-24.8] kg/m 2 ) than for those with type 1 diabetes (21.3 [18.9-24.0] kg/m 2 ) (P = 0.003). It was also found that the median estimated glomerular filtration rate (eGFR) was significantly lower among those with type 2 diabetes (50.6 mL [31.8-71.1]/min/1.73 m 2 ) than among those with type 1 diabetes (73.3 [53.5-91.1] mL/min/1.73 m 2 ) (P < 0.001). Again, the median HbA1c value at onset of severe hypoglycemia was shown to be 7.0 (6.3-8.1)% among all patients examined, 7.5 (6.9-8.6)% among those with type 1 diabetes, and 6.8 (6.1-7.6)% among those with type 2 diabetes, with the HbA1c value at onset of hypoglycemia being significantly lower among those with type 2 diabetes (P < 0.001). Antecedent symptoms of severe hypoglycemia were shown to be present, absent and unknown in 35.5, 35.6, and 28.9% of all patients, respectively, with the incidence of symptomatic hypoglycemia being significantly lower among those with type 1 diabetes (41.0%) than among those with type 2 diabetes (56.9%). The antidiabetic agents used in those with type 2 diabetes were insulin preparations (292 patients including 29 receiving concomitant sulfonylureas [SUs]) (60.8%), SUs (159 insulin-naïve patients) (33.1%), and no insulin preparations or SUs (29 patients) (6.0%). Of the 798 patients surveyed, 296 patients (37.2%) were shown to have required emergency transportation services for severe hypoglycemia before. Thus, the survey revealed, for the first time, the current status of treatment-related severe hypoglycemia in Japan and clearly highlights the acute need for implementing preventive measures against hypoglycemia not only through education on hypoglycemia but through optimization of antidiabetic therapy for those at high risk of severe hypoglycemia or those with a history of severe hypoglycemia. © 2018 Japan Diabetes Society (JDS). Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.

Profiles of Childhood Trauma in Patients with Alcohol Dependence and Their Associations with Addiction-Related Problems.

PubMed

Lotzin, Annett; Haupt, Lena; von Schönfels, Julia; Wingenfeld, Katja; Schäfer, Ingo

2016-03-01

The high occurrence of childhood trauma in individuals with alcohol dependence is well-recognized. Nevertheless, researchers have rarely studied which types of childhood trauma often co-occur and how these combinations of different types and severities of childhood trauma are related to the patients' current addiction-related problems. We aimed to identify childhood trauma profiles in patients with alcohol dependence and examined relations of these trauma profiles with the patients' current addiction-related problems. In 347 alcohol-dependent patients, 5 types of childhood trauma (sexual abuse, physical abuse, emotional abuse, emotional neglect, and physical neglect) were measured using the Childhood Trauma Questionnaire. Childhood trauma profiles were identified using cluster analysis. The patients' current severity of addiction-related problems was assessed using the European Addiction Severity Index. We identified 6 profiles that comprised different types and severities of childhood trauma. The patients' trauma profiles predicted the severity of addiction-related problems in the domains of psychiatric symptoms, family relationships, social relationships, and drug use. Childhood trauma profiles may provide more useful information about the patient's risk of current addiction-related problems than the common distinction between traumatized versus nontraumatized patients. Copyright © 2016 by the Research Society on Alcoholism.

Intracranial pressure monitoring in severe blunt head trauma: does the type of monitoring device matter?

PubMed

Aiolfi, Alberto; Khor, Desmond; Cho, Jayun; Benjamin, Elizabeth; Inaba, Kenji; Demetriades, Demetrios

2018-03-01

OBJECTIVE Intracranial pressure (ICP) monitoring has become the standard of care in the management of severe head trauma. Intraventricular devices (IVDs) and intraparenchymal devices (IPDs) are the 2 most commonly used techniques for ICP monitoring. Despite the widespread use of these devices, very few studies have investigated the effect of device type on outcomes. The purpose of the present study was to compare outcomes between 2 types of ICP monitoring devices in patients with isolated severe blunt head trauma. METHODS This retrospective observational study was based on the American College of Surgeons Trauma Quality Improvement Program database, which was searched for all patients with isolated severe blunt head injury who had an ICP monitor placed in the 2-year period from 2013 to 2014. Extracted variables included demographics, comorbidities, mechanisms of injury, head injury specifics (epidural, subdural, subarachnoid, intracranial hemorrhage, and diffuse axonal injury), Abbreviated Injury Scale (AIS) score for each body area, Injury Severity Score (ISS), vital signs in the emergency department, and craniectomy. Outcomes included 30-day mortality, complications, number of ventilation days, intensive care unit and hospital lengths of stay, and functional independence. RESULTS During the study period, 105,721 patients had isolated severe traumatic brain injury (head AIS score ≥ 3). Overall, an ICP monitoring device was placed in 2562 patients (2.4%): 1358 (53%) had an IVD and 1204 (47%) had an IPD. The severity of the head AIS score did not affect the type of ICP monitoring selected. There was no difference in the median ISS; ISS > 15; head AIS Score 3, 4, or 5; or the need for craniectomy between the 2 device groups. Unadjusted 30-day mortality was significantly higher in the group with IVDs (29% vs 25.5%, p = 0.046); however, stepwise logistic regression analysis showed that the type of ICP monitoring was not an independent risk factor for death, complications, or functional outcome at discharge. CONCLUSIONS This study demonstrated that compliance with the Brain Trauma Foundation guidelines for ICP monitoring is poor. In isolated severe blunt head injuries, the type of ICP monitoring device does not have any effect on survival, systemic complications, or functional outcome.

Human rotavirus vaccine Rotarix™ provides protection against diverse circulating rotavirus strains in African infants: a randomized controlled trial

PubMed Central

2012-01-01

Background Rotaviruses are the most important cause of severe acute gastroenteritis worldwide in children <5 years of age. The human, G1P[8] rotavirus vaccine Rotarix™ significantly reduced severe rotavirus gastroenteritis episodes in a Phase III clinical trial conducted in infants in South Africa and Malawi. This paper examines rotavirus vaccine efficacy in preventing severe rotavirus gastroenteritis, during infancy, caused by the various G and P rotavirus types encountered during the first rotavirus-season. Methods Healthy infants aged 5–10 weeks were enrolled and randomized into three groups to receive either two (10 and 14 weeks) or three doses of Rotarix™ (together forming the pooled Rotarix™ group) or three doses of placebo at a 6,10,14-week schedule. Weekly home visits were conducted to identify gastroenteritis episodes. Rotaviruses were detected by ELISA and genotyped by RT-PCR and nucleotide sequencing. The percentage of infants with severe rotavirus gastroenteritis caused by the circulating G and P types from 2 weeks post-last dose until one year of age and the corresponding vaccine efficacy was calculated with 95% CI. Results Overall, 4939 infants were vaccinated and 4417 (pooled Rotarix™ = 2974; placebo = 1443) were included in the per protocol efficacy cohort. G1 wild-type was detected in 23 (1.6%) severe rotavirus gastroenteritis episodes from the placebo group. This was followed in order of detection by G12 (15 [1%] in placebo) and G8 types (15 [1%] in placebo). Vaccine efficacy against G1 wild-type, G12 and G8 types were 64.1% (95% CI: 29.9%; 82%), 51.5% (95% CI:-6.5%; 77.9%) and 64.4% (95% CI: 17.1%; 85.2%), respectively. Genotype P[8] was the predominant circulating P type and was detected in 38 (2.6%) severe rotavirus gastroenteritis cases in placebo group. The remaining circulating P types comprised of P[4] (20 [1.4%] in placebo) and P[6] (13 [0.9%] in placebo). Vaccine efficacy against P[8] was 59.1% (95% CI: 32.8%; 75.3%), P[4] was 70.9% (95% CI: 37.5%; 87.0%) and P[6] was 55.2% (95% CI: -6.5%; 81.3%) Conclusions Rotarix™ vaccine demonstrated efficacy against severe gastroenteritis caused by diverse circulating rotavirus types. These data add to a growing body of evidence supporting heterotypic protection provided by Rotarix™. Trial registration number NCT00241644 PMID:22974466

How Do Le Fort-Type Fractures Present in a Pediatric Cohort?

PubMed

Macmillan, Alexandra; Lopez, Joseph; Luck, J D; Faateh, Muhammad; Manson, Paul; Dorafshar, Amir H

2018-05-01

Le Fort-type fractures are very rare in children, and there is a paucity of literature presenting their frequency and characteristics. The purpose of this study was to determine the etiology, frequency, and fracture patterns of children with severe facial trauma associated with pterygoid plate fractures in a pediatric cohort. We performed a retrospective cohort study of all children aged younger than 16 years with pterygoid plate and facial fractures who presented to our institute between 1990 and 2010. Patient charts and radiologic records were reviewed for demographic and fracture characteristics. Patients were categorized into 2 groups as per facial fracture pattern: non-Le Fort-type fractures (group A) and Le Fort-type fractures (group B). Other variables including dentition age, frontal sinus development, mechanism of injury, injury severity, and concomitant injuries were recorded. Univariate methods were used to compare groups. We identified 24 children; 25% were girls, and 20.8% were of nonwhite race. Most presented with Le Fort-type fracture patterns (group B, 66.7%). Age was significantly different between group A and group B (mean, 5.9 years and 9.9 years, respectively; P = .009). No significant differences in Injury Severity Score, rate of operative repair, and length of stay were found between groups. Most children with severe facial fractures and pterygoid plate fractures presented with Le Fort-type fracture patterns in our cohort. The mean age of children with Le Fort-type fractures was greater than in those with non-Le Fort-type patterns. However, Le Fort-type fractures did occur in younger children with deciduous and mixed dentition. Copyright © 2017 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.

An Observational Study on Quantifying the Distance of Supercell-Boundary Interaction in the Great Plains

NASA Astrophysics Data System (ADS)

Magee, Kathleen Marie

Several case studies and numerical simulations have confirmed that baroclinic boundaries provide enhanced horizontal and vertical vorticity, wind shear, helicity, and moisture that induce stronger updrafts, higher reflectivity, and stronger low-level rotation in supercells. However, the distance at which a boundary will provide such enhancement is less well-defined. Previous studies have identified distances ranging from 5 km to 200 km, and only focused on tornadogenesis rather than all forms of severe weather. To better aid short-term forecasts, the actual distances at which supercells produce severe weather in proximity to a boundary needs to be assessed. In this study, the distance between a large number of supercells and nearby surface boundaries (including warm fronts, stationary fronts, and outflow boundaries) is measured throughout the lifetime of each storm; the distance at which associated reports of large hail, strong winds, and tornadoes is also collected. Data is gathered from SPC storm reports, WPC surface analyses, ASOS archives, and NCDC radar archives. The Integrated Data Viewer (IDV) from Unidata is used to analyze the distance of the supercell from the boundary every twenty minutes. These distances are then used to interpolate the distance at which severe and significantly severe reports occurred; reports are grouped by severe type (tornado, hail, or wind), then by boundary type (warm front, stationary front, or outflow). Using these distributions, the range from the boundary at which each type of severe weather is produced is identified per boundary type to assist forecasters. Overall, the range at which tornadoes are more likely to be produced is generally closer to the boundary than hail and wind reports for all three boundary types, likely owing to the enhanced helicity present near a boundary. Statistical analyses are used to assess the sensitivity of report distributions to report type, boundary type, distance from the boundary, and boundary strength. The distance of different report types near the same boundary surprisingly did not test as statistically different, except for warm fronts; however, when comparing the distances of the same report type associated with different boundaries, statistically significant differences were found for different boundaries in which different report types are maximally produced. Temperature gradients are not as statistically different between boundaries, but the temperature gradient within the same boundary is statistically significant for the occurrence of tornadoes vs. hail. Additional analyses were conducted to complement the distributions of severe report distances. Previous research has demonstrated that the angle at which supercells interact with boundaries impacts tornado production; in the present dataset, supercells interacting at an angle less than 45° are not only more likely to produce tornadoes, but also more likely to produce significantly severe tornadoes. Additionally, other studies have suggested that the temperature gradient of a boundary is of minimal importance with regards to tornado production. Interestingly, the tornadoes in this study were associated with stronger temperature gradients than for hail or wind production, thus v implying that a stronger amount of baroclinically-generated horizontal vorticity is required for tornadogenesis, likely due to the enhanced low-level rotation.

Regional variations in definitions and rates of hypoglycaemia: findings from the global HAT observational study of 27 585 people with Type 1 and insulin-treated Type 2 diabetes mellitus.

PubMed

Khunti, K; Cigrovski Berković, M; Ludvik, B; Moberg, E; Barner Lekdorf, J; Gydesen, H; Pedersen-Bjergaard, U

2018-05-05

To determine participant knowledge and reporting of hypoglycaemia in the non-interventional Hypoglycaemia Assessment Tool (HAT) study. HAT was conducted in 24 countries over a 6-month retrospective/4-week prospective period in 27 585 adults with Type 1 or insulin-treated Type 2 diabetes mellitus. Participants recorded whether hypoglycaemia was based on blood glucose levels, symptoms or both. Hypoglycaemia rates were consistently higher in the prospective compared with the retrospective period. Most respondents (96.8% Type 1 diabetes; 85.6% Type 2 diabetes) knew the American Diabetes Association/European Association for the Study of Diabetes hypoglycaemia definition, but there were regional differences in the use of blood glucose measurements and/or symptoms to define events. Confirmed symptomatic hypoglycaemia rates were highest in Northern Europe/Canada for Type 1 diabetes (63.9 events/year) and in Eastern Europe for Type 2 diabetes (19.4 events/year), and lowest in South East Asia (Type 1 diabetes: 6.0 events/year; Type 2 diabetes: 3.2 events/year). Unconfirmed symptomatic hypoglycaemia rates were highest in Eastern Europe for Type 1 diabetes (5.6 events/year) and South East Asia for Type 2 diabetes (4.7 events/year), and lowest for both in Russia (Type 1 diabetes: 2.1 events/year; Type 2 diabetes: 0.4 events/year). Participants in Latin America reported the highest rates of severe hypoglycaemia (Type 1 diabetes: 10.8 events/year; Type 2 diabetes 3.7 events/year) and severe hypoglycaemia requiring hospitalization (Type 1 diabetes: 0.56 events/year; Type 2 diabetes: 0.44 events/year). The lowest rates of severe hypoglycaemia were reported in South East Asia (Type 1 diabetes: 2.0 events/year) and Northern Europe/Canada (Type 2 diabetes: 1.3 events/year), and the lowest rates of severe hypoglycaemia requiring hospitalization were in Russia (Type 1 diabetes: 0.15 events/year; Type 2 diabetes: 0.09 events/year). The blood glucose cut-off used to define hypoglycaemia varied between regions (Type 1 diabetes: 3.1-3.6 mmol/l; Type 2 diabetes: 3.5-3.8 mmol/l). Under-reporting of hypoglycaemia rates in retrospective recall and regional variations in participant definitions of hypoglycaemia may contribute to the global differences in reported rates. Discrepancies between participant definitions and guidelines may highlight a need to redefine hypoglycaemia criteria. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

A comparison of type 2 diabetes outcomes among persons with and without severe mental illnesses.

PubMed

Dixon, Lisa B; Kreyenbuhl, Julie A; Dickerson, Faith B; Donner, Thomas W; Brown, Clayton H; Wohlheiter, Karen; Wolheiter, Karen; Postrado, Leticia; Goldberg, Richard W; Fang, LiJuan; Marano, Christopher; Messias, Erick

2004-08-01

Type 2 diabetes is an important comorbid medical condition associated with schizophrenia. The objective of this study was to compare glycosylated hemoglobin (HbA(1c)) levels of patients who had type 2 diabetes and schizophrenia with those of patients who had type 2 diabetes and major mood disorders and those who had type 2 diabetes but who did not have severe mental illness. A sample of 300 patients with type 2 diabetes was recruited from community mental health centers in the greater Baltimore region and nearby primary care clinics. Of these, 100 had schizophrenia, 101 had a major mood disorder, and 99 had no identified severe mental illness. HbA(1c), the main outcome measure, was compared between the group with schizophrenia and the other two groups. All three groups had HbA(1c) values above recommended levels. HbA(1c) levels were significantly lower among patients with schizophrenia than among patients who did not have severe mental illness but were not significantly different from those of patients who had major mood disorders. Patients for whom olanzapine was prescribed had higher HbA(1c) levels than those for whom other antipsychotic agents were prescribed. All three groups of patients require improved diabetes treatment to achieve acceptable HbA(1c) levels. There may be previously unrecognized benefits for diabetes management among persons with severe mental illnesses who are receiving regular mental heath care, but these individuals may also have risk factors that can influence diabetes outcomes and HbA(1c) levels.

Type 0 Spinal Muscular Atrophy: Further Delineation of Prenatal and Postnatal Features in 16 Patients.

PubMed

Grotto, Sarah; Cuisset, Jean-Marie; Marret, Stéphane; Drunat, Séverine; Faure, Patricia; Audebert-Bellanger, Séverine; Desguerre, Isabelle; Flurin, Vincent; Grebille, Anne-Gaëlle; Guerrot, Anne-Marie; Journel, Hubert; Morin, Gilles; Plessis, Ghislaine; Renolleau, Sylvain; Roume, Joëlle; Simon-Bouy, Brigitte; Touraine, Renaud; Willems, Marjolaine; Frébourg, Thierry; Verspyck, Eric; Saugier-Veber, Pascale

2016-11-29

Spinal muscular atrophy (SMA) is caused by homozygous inactivation of the SMN1 gene. The SMN2 copy number modulates the severity of SMA. The 0SMN1/1SMN2 genotype, the most severe genotype compatible with life, is expected to be associated with the most severe form of the disease, called type 0 SMA, defined by prenatal onset. The aim of the study was to review clinical features and prenatal manifestations in this rare SMA subtype. SMA patients with the 0SMN1/1SMN2 genotype were retrospectively collected using the UMD-SMN1 France database. Data from 16 patients were reviewed. These 16 patients displayed type 0 SMA. At birth, a vast majority had profound hypotonia, severe muscle weakness, severe respiratory distress, and cranial nerves involvement (inability to suck/swallow, facial muscles weakness). They showed characteristics of fetal akinesia deformation sequence and congenital heart defects. Recurrent episodes of bradycardia were observed. Death occurred within the first month. At prenatal stage, decreased fetal movements were frequently reported, mostly only by mothers, in late stages of pregnancy; increased nuchal translucency was reported in about half of the cases; congenital heart defects, abnormal amniotic fluid volume, or joint contractures were occasionally reported. Despite a prenatal onset attested by severity at birth and signs of fetal akinesia deformation sequence, prenatal manifestations of type 0 SMA are not specific and not constant. As illustrated by the frequent association with congenital heart defects, type 0 SMA physiopathology is not restricted to motor neuron, highlighting that SMN function is critical for organogenesis.

Thinking about gender types: cognitive organization of female and male types.

PubMed

Vonk, Roos; Ashmore, Richard D

2003-06-01

We examined the content and dimensional structure of a large and representative sample of gender types. In Study 1, using an open-ended procedure, participants generated 306 different labels for female types (e.g. housewife, feminist, femme fatale, secretary, slob) and 310 for male types (e.g. workaholic, family man, sissy, womanizer, labourer). In Study 2A, a multidimensional configuration of 229 of these male and female types was derived from a free sorting task among a new set of participants. In Study 2B, a subset of types was judged on several dimensions of meaning, which were then fitted into the configuration of types. The most important dimensions in describing the structure of gender types were: young-old, masculine-feminine and traditional-modern. The masculine-feminine dimension showed that the male and female types were largely separated from each other; within each gender category, the types were ordered by their position on the masculine-feminine dimension. Several other aspects of current thinking about men and women are discussed.

Sequential N-Terminal Pro-B-Type Natriuretic Peptide and High-Sensitivity Cardiac Troponin Measurements During Albumin Replacement in Patients With Severe Sepsis or Septic Shock.

PubMed

Masson, Serge; Caironi, Pietro; Fanizza, Caterina; Carrer, Sara; Caricato, Anselmo; Fassini, Paola; Vago, Tarcisio; Romero, Marilena; Tognoni, Gianni; Gattinoni, Luciano; Latini, Roberto

2016-04-01

Myocardial dysfunction is a frequent complication in patients with severe sepsis and can worsen the prognosis. We investigated whether circulating biomarkers related to myocardial function and injury predicted outcome and were associated with albumin replacement. A multicenter, randomized clinical trial about albumin replacement in severe sepsis or septic shock (the Albumin Italian Outcome Sepsis trial). Forty ICUs in Italy. Nine hundred and ninety-five patients with severe sepsis or septic shock. Randomization to albumin and crystalloid solutions or crystalloid solutions alone. Plasma concentrations of N- terminal pro-B-type natriuretic peptide and high-sensitivity cardiac troponin T were measured 1, 2, and 7 days after enrollment. We tested the relationship of single marker measurements or changes over time with clinical events, organ dysfunctions, albumin replacement, and ICU or 90-day mortality in the overall population and after stratification by shock. N-terminal pro-B-type natriuretic peptide levels were abnormal in 97.4% of the patients and high-sensitivity cardiac troponin T in 84.5%, with higher concentrations in those with shock. After extensive adjustments, N-terminal pro-B-type natriuretic peptide concentrations predicted ICU or 90-day mortality, better than high-sensitivity cardiac troponin T. Early changes in N-terminal pro-B-type natriuretic peptide or high-sensitivity cardiac troponin T concentrations were independently associated with subsequent mortality in patients with shock. Patients given albumin had significantly higher N-terminal pro-B-type natriuretic peptide levels; in addition, early rise in N-terminal pro-B-type natriuretic peptide was associated with a better outcome in this subgroup. Circulating N-terminal pro-B-type natriuretic peptide and high-sensitivity cardiac troponin T are frequently elevated in severe sepsis or septic shock and have relevant prognostic value, which may be important in monitoring the clinical efficacy of supporting therapy.

Prevalence and risk factors for diabetic maculopathy, and its relationship to diabetic retinopathy in elderly Japanese patients with type 2 diabetes mellitus.

PubMed

Yamamoto, Teiko; Iimuro, Satoshi; Ohashi, Yasuo; Sone, Hirohito; Yamashita, Hidetoshi; Ito, Hideki

2012-04-01

To determine the prevalence of diabetic retinopathy and diabetic maculopathy in Japanese patients older than 65 years-of-age with type 2 diabetes mellitus. In addition, to determine the relationship between the severity of retinopathy and maculopathy, and the risk factors for these conditions in Japanese patients with the same characteristics. This was a cross-sectional study carried out at the enrolment of patients who participated in a randomized controlled trial. A total of 960 eyes of 960 Japanese patients with type 2 diabetes who were ≥ 65 years-of-age were analyzed. Our data showed that there was a correlation between the severity of retinopathy and the severity of maculopathy. The risk factors for the severity of retinopathy were different from the risk factors for the severity of maculopathy. The age, duration of diabetes, systemic pulse pressure, fasting insulin, insulin treatment of diabetes, high-density lipoprotein cholesterol, microalbumin-to-creatinine ratio and history of cerebrovascular disease all contributed significantly to the severity of retinopathy. The duration of diabetes, insulin treatment and microalbumin-to-creatinine ratio were correlated with the severity of maculopathy. The risk factors related to diabetic retinopathy and maculopathy in Japanese patients with type 2 diabetes mellitus aged ≥ 65 years were different from that in other countries. Our data also showed that the certain risk factors for retinopathy differ from those associated with maculopathy. © 2012 Japan Geriatrics Society.

An analysis of high-impact, low-predictive skill severe weather events in the northeast U.S

NASA Astrophysics Data System (ADS)

Vaughan, Matthew T.

An objective evaluation of Storm Prediction Center slight risk convective outlooks, as well as a method to identify high-impact severe weather events with poor-predictive skill are presented in this study. The objectives are to assess severe weather forecast skill over the northeast U.S. relative to the continental U.S., build a climatology of high-impact, low-predictive skill events between 1980--2013, and investigate the dynamic and thermodynamic differences between severe weather events with low-predictive skill and high-predictive skill over the northeast U.S. Severe storm reports of hail, wind, and tornadoes are used to calculate skill scores including probability of detection (POD), false alarm ratio (FAR) and threat scores (TS) for each convective outlook. Low predictive skill events are binned into low POD (type 1) and high FAR (type 2) categories to assess temporal variability of low-predictive skill events. Type 1 events were found to occur in every year of the dataset with an average of 6 events per year. Type 2 events occur less frequently and are more common in the earlier half of the study period. An event-centered composite analysis is performed on the low-predictive skill database using the National Centers for Environmental Prediction Climate Forecast System Reanalysis 0.5° gridded dataset to analyze the dynamic and thermodynamic conditions prior to high-impact severe weather events with varying predictive skill. Deep-layer vertical shear between 1000--500 hPa is found to be a significant discriminator in slight risk forecast skill where high-impact events with less than 31-kt shear have lower threat scores than high-impact events with higher shear values. Case study analysis of type 1 events suggests the environment over which severe weather occurs is characterized by high downdraft convective available potential energy, steep low-level lapse rates, and high lifting condensation level heights that contribute to an elevated risk of severe wind.

Genotyping and clinical factors in pediatric diarrhea caused by rotaviruses: one-year surveillance in Surabaya, Indonesia.

PubMed

Sudarmo, Subijanto Marto; Shigemura, Katsumi; Athiyyah, Alpha Fardah; Osawa, Kayo; Wardana, Oktavian Prasetia; Darma, Andy; Ranuh, Reza; Raharjo, Dadik; Arakawa, Soichi; Fujisawa, Masato; Shirakawa, Toshiro

2015-01-01

Rotavirus infections are a major cause of diarrhea in children in both developed and developing countries. Rotavirus genetics, patient immunity, and environmental factors are thought to be related to the severity of acute diarrhea due to rotavirus in infants and young children. The objective of this study was to provide a correlation between rotavirus genotypes, clinical factors and degree of severity of acute diarrhea in children under 5 years old in Surabaya, Indonesia. A cross-sectional study was conducted in children aged 1-60 months with acute diarrhea hospitalized in Soetomo Hospital, Surabaya, Indonesia from April to December 2013. Rotavirus in stool specimens was identified by ELISA and genotyping (G-type and P-type) using multiplex reverse transcription PCR. Severity was measured using the Ruuska and Vesikari scoring system. The clinical factors were investigated included patient's age (months), hydration, antibiotic administration, nutritional state, co-bacterial infection and co-viral infection. A total of 88 children met the criteria; 80.7% were aged 6-24 months, watery diarrhea was the most common type (77.3%) and 73.6% of the subjects were co-infected with bacteria, of which pathogenic Escherichia coli was the most common (42.5%). The predominant VP7 genotyping (G-type) was G2 (31.8%) and that of VP4 genotyping (P-type) was P[4] (31.8%). The predominant rotavirus genotype was G2P[4] (19.3%); G1P[4] and G9P[4] were uncommon with a prevalence of 4.5%. There were significant differences between the common genotype and uncommon genotype with respect to the total severity score of diarrhea (p <0.05). G3, G4 and G9 were significantly correlated with severe diarrhea (p = 0.009) in multivariate analyses and with frequency of diarrhea (>10 times a day) (p = 0.045) in univariate analyses, but there was no significant correlation between P typing and severity of diarrhea. For combination genotyping of G and P, G2P[4] was significantly correlated with severe diarrhea in multivariate analyses (p = 0.029). There is a correlation between rotavirus genotype and severity of acute diarrhea in children. Genotype G2P[4] has the highest prevalence. G3, G4, G9 and G2P[4] combination genotype were found to be associated with severe diarrhea.

P-type gallium nitride

DOEpatents

Rubin, M.; Newman, N.; Fu, T.; Ross, J.; Chan, J.

1997-08-12

Several methods have been found to make p-type gallium nitride. P-type gallium nitride has long been sought for electronic devices. N-type gallium nitride is readily available. Discovery of p-type gallium nitride and the methods for making it will enable its use in ultraviolet and blue light-emitting diodes and lasers. pGaN will further enable blue photocathode elements to be made. Molecular beam epitaxy on substrates held at the proper temperatures, assisted by a nitrogen beam of the proper energy produced several types of p-type GaN with hole concentrations of about 5{times}10{sup 11} /cm{sup 3} and hole mobilities of about 500 cm{sup 2} /V-sec, measured at 250 K. P-type GaN can be formed of unintentionally-doped material or can be doped with magnesium by diffusion, ion implantation, or co-evaporation. When applicable, the nitrogen can be substituted with other group III elements such as Al. 9 figs.

P-type gallium nitride

DOEpatents

Rubin, Michael; Newman, Nathan; Fu, Tracy; Ross, Jennifer; Chan, James

1997-01-01

Several methods have been found to make p-type gallium nitride. P-type gallium nitride has long been sought for electronic devices. N-type gallium nitride is readily available. Discovery of p-type gallium nitride and the methods for making it will enable its use in ultraviolet and blue light-emitting diodes and lasers. pGaN will further enable blue photocathode elements to be made. Molecular beam epitaxy on substrates held at the proper temperatures, assisted by a nitrogen beam of the proper energy produced several types of p-type GaN with hole concentrations of about 5.times.10.sup.11 /cm.sup.3 and hole mobilities of about 500 cm.sup.2 /V-sec, measured at 250.degree. K. P-type GaN can be formed of unintentionally-doped material or can be doped with magnesium by diffusion, ion implantation, or co-evaporation. When applicable, the nitrogen can be substituted with other group III elements such as Al.

Correlation Between the Integrity of the Circle of Willis and the Severity of Initial Noncardiac Cerebral Infarction and Clinical Prognosis

PubMed Central

Zhou, Houshi; Sun, Jian; Ji, Xiaotan; Lin, Jing; Tang, Shujin; Zeng, Jinsheng; Fan, Yu-hua

2016-01-01

Abstract The quality of collateral circulation affects the severity and prognosis of stroke patients. The effect of the circle of Willis, which is the primary collateral circulation, on ischemic stroke has attracted significant attention. This study was designed to investigate the effect of different circles of Willis types on stroke severity and prognosis in patients with noncardiac stroke. A total of 376 patients with noncardiac ischemic stroke, who were treated by the specialty team of cerebrovascular diseases at the First Affiliated Hospital of Sun Yat-sen Hospital, were successively enrolled in this study. The detailed clinical characteristics of the patients were recorded upon admission, including risk factors of vascular disease and National Institutes of Health Stroke Scale (NIHSS) scores. The patients were divided into groups of different circles of Willis types based on magnetic resonance angiography (MRA) that was performed within 3 days of admission—type I: complete circle of Willis; type II: complete anterior half of the circle of Willis and incomplete posterior half of the circle of Willis; type III: incomplete anterior half of the circle of Willis and complete posterior half of the circle of Willis; and type IV: incomplete anterior and posterior halves of the circle of Willis. Patients were re-evaluated for NIHSS scores at discharge and after discharge. The modified Rankin score (mRS) was recorded for 90 days, and stroke recurrence and death after 90 days were also recorded until the end of the study. The 376 patients were divided into 4 groups based on the MRA—type I group: 92 patients (24.5%); type II group: 215 patients (57.2%); type III group: 12 patients (3.2%), and type IV group: 57 patients (15.2%). NIHSS scores at admission and discharge were significantly lower for the type I group compared with those for the type II and type IV groups (P < 0.05). NIHSS scores were higher in the groups with an incomplete circle of Willis compared with the group with a complete circle of Willis. A poor recovery rate was highest for the type IV group, whereas a good recovery rate was highest for the type I group. The logistic regression analysis showed that a complete circle of Willis was one of the predictors of suitable recovery (odds ratio [OR] = 0.708, 95% confidence interval [CI]: 0.554–0.906). Circle of Willis type was associated with stroke severity and patient prognosis, whereas an incomplete circle of Willis was associated with more severe conditions and a higher 90-day poor diagnosis rate. A complete circle of Willis was an independent predictor of good prognosis. PMID:26962785

Behavioral Assessment of Feeding Problems of Individuals with Severe Disabilities.

ERIC Educational Resources Information Center

Munk, Dennis D.; Repp, Alan C.

1994-01-01

A behavioral assessment procedure was evaluated with five children with severe/profound mental retardation who exhibited feeding problems of limited intake. Subjects were fed various types of foods. Results indicated each subject fit into one of four categories: (1) total food refusal, (2) food type selectivity, (3) food texture selectivity, or…

Effectiveness of lifestyle interventions for individuals with severe obesity and type 2 diabetes

USDA-ARS?s Scientific Manuscript database

OBJECTIVEdRates of severe obesity (BMI$40 kg/m2) are on the rise, and effective treatment options are needed.We examined the effect of an intensive lifestyle intervention (ILI) on weight loss, cardiovascular disease (CVD) risk, and program adherence in participants with type 2 diabetes who were seve...

21. VALVES, GAUGES, AND SEVERAL TYPES OF LIGHTING ALONG ROAD ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

21. VALVES, GAUGES, AND SEVERAL TYPES OF LIGHTING ALONG ROAD AT SOUTH REAR OF TEST STAND 1-A. RP1 TANK FARM IN MIDDLE DISTANCE. Looking northeast. - Edwards Air Force Base, Air Force Rocket Propulsion Laboratory, Test Stand 1-A, Test Area 1-120, north end of Jupiter Boulevard, Boron, Kern County, CA

Monograph on the use of the multivariate Gram Charlier series Type A

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hatayodom, T.; Heydt, G.

1978-01-01

The Gram-Charlier series in an infinite series expansion for a probability density function (pdf) in which terms of the series are Hermite polynomials. There are several Gram-Charlier series - the best known is Type A. The Gram-Charlier series, Type A (GCA) exists for both univariate and multivariate random variables. This monograph introduces the multivariate GCA and illustrates its use through several examples. A brief bibliography and discussion of Hermite polynomials is also included. 9 figures, 2 tables.

Charring temperatures are driven by the fuel types burned in a peatland wildfire

PubMed Central

Hudspith, Victoria A.; Belcher, Claire M.; Yearsley, Jonathan M.

2014-01-01

Peatlands represent a globally important carbon store; however, the human exploitation of this ecosystem is increasing both the frequency and severity of fires on drained peatlands. Yet, the interactions between the hydrological conditions (ecotopes), the fuel types being burned, the burn severity, and the charring temperatures (pyrolysis intensity) remain poorly understood. Here we present a post-burn assessment of a fire on a lowland raised bog in Co. Offaly, Ireland (All Saints Bog). Three burn severities were identified in the field (light, moderate, and deeply burned), and surface charcoals were taken from 17 sites across all burn severities. Charcoals were classified into two fuel type categories (either ground or aboveground fuel) and the reflectance of each charcoal particle was measured under oil using reflectance microscopy. Charcoal reflectance shows a positive relationship with charring temperature and as such can be used as a temperature proxy to reconstruct minimum charring temperatures after a fire event. Resulting median reflectance values for ground fuels are 1.09 ± 0.32%Romedian, corresponding to estimated minimum charring temperatures of 447°C ± 49°C. In contrast, the median charring temperatures of aboveground fuels were found to be considerably higher, 646°C ± 73°C (3.58 ± 0.77%Romedian). A mixed-effects modeling approach was used to demonstrate that the interaction effects of burn severity, as well as ecotope classes, on the charcoal reflectance is small compared to the main effect of fuel type. Our findings reveal that the different fuel types on raised bogs are capable of charring at different temperatures within the same fire, and that the pyrolysis intensity of the fire on All Saints Bog was primarily driven by the fuel types burning, with only a weak association to the burn severity or ecotope classes. PMID:25566288

Social Disadvantage, Severe Child Abuse, and Biological Profiles in Adulthood.

PubMed

Lee, Chioun; Coe, Christopher L; Ryff, Carol D

2017-09-01

Guided by the stress process model and the life course perspective, we hypothesize: (1) that childhood abuse is concentrated, in terms of type and intensity, among socially disadvantaged individuals, and (2) that experiencing serious abuse contributes to poor biological profiles in multiple body systems in adulthood. Data came from the Biomarker subsample of Midlife in the United States (2004-2006). We used latent class analysis to identify distinct profiles of childhood abuse, each reflecting a combination of type and severity. Results indicate that disadvantaged groups, women, and those from disadvantaged families are at greater risk of experiencing more severe and multiple types of abuse. Those with more severe and multifaceted childhood abuse show greater physiological dysregulation. Childhood abuse experiences partially accounted for the social status differences in physiological profiles. Our findings underscore that differential exposure to serious childhood stressors plays a significant role in gender and class inequalities in adult health.

Intimate partner violence against women in Maputo city, Mozambique

PubMed Central

2012-01-01

Background There is limited research about IPV against women and associated factors in Sub-Saharan Africa, not least Mozambique. The objective of this study was to examine the occurrence, severity, chronicity and “predictors” of IPV against women in Maputo City (Mozambique). Methods Data were collected during a 12 month-period (consecutive cases, with each woman seen only once) from 1,442 women aged 15–49 years old seeking help for abuse by an intimate partner at the Forensic Services at the Maputo Central Hospital, Maputo City, Mozambique. Interviews were conducted by trained female interviewers, and data collected included demographics and lifestyle variables, violence (using the previously validated Revised Conflict Tactics Scale (CTS2), and control (using the Controlling Behaviour Scale Revised (CBS-R). The data were analysed using bivariate and multivariate methods. Results The overall experienced IPV during the past 12 months across severity (one or more types, minor and severe) was 70.2% (chronicity, 85.8 ± 120.9).a Severe IPV varied between 26.3-45.9% and chronicity between 3.1 ± 9.1-12.8 ± 26.9, depending on IPV type. Severity and chronicity figures were higher in psychological aggression than in the other IPV types. Further, 26.8% (chronicity, 55.3 ± 117.6) of women experienced all IPV types across severity. The experience of other composite IPV types across severity (4 combinations of 3 types of IPV) varied between 27.1-42.6% and chronicity between 35.7 ± 80.3-64.9 ± 110.9, depending on the type of combination. The combination psychological aggression, physical assault and sexual coercion had the highest figures compared with the other combinations. The multiple regressions showed that controlling behaviours, own perpetration and co-occurring victimization were more important in “explaining” the experience of IPV than other variables (e.g. abuse as a child). Conclusions In our study, controlling behaviours over/by partner, own perpetration, co-occurring victimization and childhood abuse were more important factors in “explaining” sustained IPV. More investigation into women’s IPV exposure and its “predictors” is warranted in Sub-Saharan Africa, particularly Mozambique. PMID:23241146

Two-vehicle injury severity models based on integration of pavement management and traffic engineering factors.

PubMed

Jiang, Ximiao; Huang, Baoshan; Yan, Xuedong; Zaretzki, Russell L; Richards, Stephen

2013-01-01

The severity of traffic-related injuries has been studied by many researchers in recent decades. However, the evaluation of many factors is still in dispute and, until this point, few studies have taken into account pavement management factors as points of interest. The objective of this article is to evaluate the combined influences of pavement management factors and traditional traffic engineering factors on the injury severity of 2-vehicle crashes. This study examines 2-vehicle rear-end, sideswipe, and angle collisions that occurred on Tennessee state routes from 2004 to 2008. Both the traditional ordered probit (OP) model and Bayesian ordered probit (BOP) model with weak informative prior were fitted for each collision type. The performances of these models were evaluated based on the parameter estimates and deviances. The results indicated that pavement management factors played identical roles in all 3 collision types. Pavement serviceability produces significant positive effects on the severity of injuries. The pavement distress index (PDI), rutting depth (RD), and rutting depth difference between right and left wheels (RD_df) were not significant in any of these 3 collision types. The effects of traffic engineering factors varied across collision types, except that a few were consistently significant in all 3 collision types, such as annual average daily traffic (AADT), rural-urban location, speed limit, peaking hour, and light condition. The findings of this study indicated that improved pavement quality does not necessarily lessen the severity of injuries when a 2-vehicle crash occurs. The effects of traffic engineering factors are not universal but vary by the type of crash. The study also found that the BOP model with a weak informative prior can be used as an alternative but was not superior to the traditional OP model in terms of overall performance.

Self-reported sitting time and prevalence of erectile dysfunction in Japanese patients with type 2 diabetes mellitus: The Dogo Study.

PubMed

Furukawa, Shinya; Sakai, Takenori; Niiya, Tetsuji; Miyaoka, Hiroaki; Miyake, Teruki; Yamamoto, Shin; Kanzaki, Sayaka; Maruyama, Koutatsu; Tanaka, Keiko; Ueda, Teruhisa; Senba, Hidenori; Torisu, Masamoto; Minami, Hisaka; Tanigawa, Takeshi; Matsuura, Bunzo; Hiasa, Yoichi; Miyake, Yoshihiro

2017-01-01

No evidence exists regarding the association between sitting time and erectile dysfunction (ED) among patients with type 2 diabetes mellitus. The aim of this study was to evaluate the association between self-reported sitting time and ED among patients with type 2 diabetes mellitus. Study subjects were 430 male Japanese patients with type 2 diabetes mellitus (mean age, 60.5years). A self-administered questionnaire was used to collect information on the variables under study. The study subjects were asked about time spent sitting during typical 24-hour periods over the past 12months. Subjects were divided into four groups according to self-reported sitting time: 1) <5hours, 2) 5-7hours, 3) 7-9hours, and 4) ≥9hours. ED was defined as present when a subject had a Sexual Health Inventory for Men score <8. Adjustment was made for age, body mass index, duration of type 2 diabetes, current smoking, current drinking, hypertension, coronary artery disease, stroke, glycated hemoglobin, walking habit, and diabetic neuropathy. The prevalence values of moderate to severe ED and severe ED were 36.1% and 49.8%. At least 9hours sitting was independently positively associated with severe ED but not moderate to severe ED; the adjusted OR was 1.84 (95% CI: 1.06-3.33). In the multivariate model, there was a statistically significant inverse exposure-response relationship between the self-reported sitting time and severe ED (p for trend=0.029). Self-reported sitting time may be positively associated with ED in Japanese patients with type 2 diabetes mellitus. Copyright © 2017 Elsevier Inc. All rights reserved.

Nocturia and Prevalence of Depressive Symptoms in Japanese Adult Patients With Type 2 Diabetes Mellitus: The Dogo Study.

PubMed

Furukawa, Shinya; Sakai, Takenori; Niiya, Tetsuji; Miyaoka, Hiroaki; Miyake, Teruki; Yamamoto, Shin; Kanzaki, Sayaka; Maruyama, Koutatsu; Tanaka, Keiko; Ueda, Teruhisa; Senba, Hidenori; Torisu, Masamoto; Minami, Hisaka; Tanigawa, Takeshi; Matsuura, Bunzo; Hiasa, Yoichi; Miyake, Yoshihiro

2018-02-01

No studies have investigated the association between nocturia and depressive symptoms in patients with type 2 diabetes mellitus. Because nocturia and depressive symptoms are common in patients with type 2 diabetes, we examined this association in Japanese patients with type 2 diabetes. We studied 762 Japanese patients with type 2 diabetes. A self-administered questionnaire was used to collect information about the variables under study. The subjects were divided into 3 groups according to their nocturnal micturition: 1) no nocturia; 2) mild nocturia (1 void per night) and 3) moderate to severe nocturia (2 or more voids per night). Depressive symptoms were defined as being present when a subject had a Self-Rating Depression Scale score higher than 49. The prevalence values of mild nocturia, moderate to severe nocturia and depressive symptoms were 39.5%, 41.9% and 16.8%, respectively. Both mild nocturia and moderate to severe nocturia were independently positively associated with depressive symptoms in all patients; the adjusted ORs were 1.96 (95% CI 1.06 to 3.77) and 2.58 (95% CI 1.38 to 5.04). In female patients, both mild nocturia and moderate to severe nocturia were independently associated with depressive symptoms; the adjusted ORs were 5.26 (95% CI 1.73 to 20.61) and 6.91 (95% CI 2.15 to 28.54), respectively. In male patients, neither mild nocturia nor moderate to severe nocturia was significantly related to depressive symptoms. In Japanese female patients with type 2 diabetes, nocturia may be positively associated with depressive symptoms. Copyright © 2017 Diabetes Canada. Published by Elsevier Inc. All rights reserved.

Types of Cancer Clinical Trials

Cancer.gov

Information about the several types of cancer clinical trials, including treatment trials, prevention trials, screening trials, supportive and palliative care trials. Each type of trial is designed to answer different research questions.

Associations between recent severe hypoglycemia, retinal vessel diameters, and cognition in adults with type 1 diabetes.

PubMed

Ryan, Christopher M; Klein, Barbara E K; Lee, Kristine E; Cruickshanks, Karen J; Klein, Ronald

Mild cognitive dysfunction has been identified in children and adults with type 1 diabetes, but most studies have failed to find a relationship between severe hypoglycemia and cognition, despite reports of such associations in older adults with type 2 diabetes. Focusing on older adults with type 1 diabetes, we examined the associations between cognitive performance and recent episodes of severe hypoglycemia, retinal vessel diameters and the presence of micro- and macrovascular complications. Cognitive functioning was assessed in 244 participants enrolled in the Wisconsin Epidemiologic Study of Diabetic Retinopathy. The mean (SD; range) age at assessment in 2012-14 was 55.2 (8.3; 37-82) years and the mean (SD) duration of diabetes was 41.1 (5.6) years. Three cognitive domains were assessed in this cross-sectional study: mental efficiency and executive function, nonverbal memory, and verbal memory. Multivariate modeling demonstrated that although age and/or education are most strongly associated with performance on measures of mental efficiency, three diabetes-related variables were also associated with poorer test scores: an episode of severe hypoglycemia in the past year (β=-0.360 [95% CI, -0.672, -0.047]), retinal arteriolar and venular diameters (β=0.140 [95% CI, 0.062, 0.219]; β=-0.127 [95% CI -0.207, -0.047]), and carotid artery plaque (β=-0.372 [95% CI -0.741, -0.003]). In addition, recent severe hypoglycemia was associated with poorer nonverbal memory (β=-0.522 [95% CI, -0.849, -0.194]). For middle-aged and older adults with long-duration type 1 diabetes, poorer cognition was associated with a recent episode of severe hypoglycemia as well as with the presence of micro- and/or macrovascular conditions. Given the increasing numbers of aging adults with type 1 diabetes, future longitudinal studies are needed to identify causality and to determine whether diabetes management techniques that reduce the onset or severity of vascular complications and hypoglycemia can also reduce the risk of cognitive dysfunction in this population. Copyright © 2016 Elsevier Inc. All rights reserved.

A prospective randomised cross-over study of the effect of insulin analogues and human insulin on the frequency of severe hypoglycaemia in patients with type 1 diabetes and recurrent hypoglycaemia (the HypoAna trial): study rationale and design

PubMed Central

2012-01-01

Background Severe hypoglycaemia still represents a significant problem in insulin-treated diabetes. Most patients do not experience severe hypoglycaemia often. However, 20% of patients with type 1 diabetes experience recurrent severe hypoglycaemia corresponding to at least two episodes per year. The effect of insulin analogues on glycaemic control has been documented in large trials, while their effect on the frequency of severe hypoglycaemia is less clear, especially in patients with recurrent severe hypoglycaemia. The HypoAna Trial is designed to investigate whether short-acting and long-acting insulin analogues in comparison with human insulin are superior in reducing the occurrence of severe hypoglycaemic episodes in patients with recurrent hypoglycaemia. This paper reports the study design of the HypoAna Trial. Methods/design The study is a Danish two-year investigator-initiated, prospective, randomised, open, blinded endpoint (PROBE), multicentre, cross-over trial investigating the effect of insulin analogues versus human insulin on the frequency of severe hypoglycaemia in subjects with type 1 diabetes. Patients are randomised to treatment with basal-bolus therapy with insulin detemir / insulin aspart or human NPH insulin / human regular insulin in random order. The major inclusion criterion is history of two or more episodes of severe hypoglycaemia in the preceding year. Discussion In contrast to almost all other studies in this field the HypoAna Trial includes only patients with major problems with hypoglycaemia. The HypoAna Trial will elucidate whether basal-bolus regimen with short-acting and long-acting insulin analogues in comparison with human insulin are superior in reducing occurrence of severe hypoglycaemic episodes in hypoglycaemia prone patients with type 1 diabetes. http://www.clinicaltrials.gov: NCT00346996. PMID:22727048

A retrospective observational study of people with Type 1 diabetes with self-reported severe hypoglycaemia reveals high level of ambulance attendance but low levels of therapy change and specialist intervention.

PubMed

Field, B C T; Nayar, R; Kilvert, A; Baxter, M; Hickey, J; Cummings, M; Bain, S C

2018-05-15

To evaluate the impact of severe hypoglycaemia on NHS resources and overall glycaemic control in adults with Type 1 diabetes. An observational, retrospective study of adults (aged ≥ 18 years) with Type 1 diabetes reporting one or more episodes of severe hypoglycaemia during the preceding 24 months in 10 NHS hospital diabetes centres in England and Wales. The primary outcome was healthcare resource utilization associated with severe hypoglycaemia. Secondary outcomes included demographic and clinical characteristics, diabetes control and pathway of care. Some 140 episodes of severe hypoglycaemia were reported by 85 people during the 2-year observation period. Ambulances were called in 99 of 140 (71%) episodes and Accident and Emergency attendance occurred in 26 of 140 (19%) episodes, whereas 29 of 140 (21%) episode required no immediate help from healthcare providers. Participants attended a median of 5 (range 0-58) diabetes clinic consultations during the observation period; 13% (70 of 552) of all consultations were severe hypoglycaemia-related. Of the HbA 1c measurements recorded closest prior to severe hypoglycaemia (n = 119), only 7 of 119 measurements were < 48 mmol/mol (< 6.5%) and mean HbA 1c was 70 (sd 19) mmol/mol (8.5%, sd 1.7%). Some 119 changes to diabetes treatment were recorded during the observation period (median/person 0;, range 0-11), of which 52 of 119 changes (44%) followed severe hypoglycaemic events. We observed a high level of ambulance service intervention but surprisingly low levels of hypoglycaemia follow-up, therapy change and specialist intervention in people self-reporting severe hypoglycaemia. These results suggest there may be important gaps in care pathways for people with Type 1 diabetes self-reporting severe hypoglycaemia. © 2018 Diabetes UK.

Severity of clinical presentation in youth with type 1 diabetes is associated with differences in brain structure.

PubMed

Siller, Alejandro F; Lugar, Heather; Rutlin, Jerrel; Koller, Jonathan M; Semenkovich, Katherine; White, Neil H; Arbelaez, Ana Maria; Shimony, Joshua; Hershey, Tamara

2017-12-01

Differences in cognition and brain structure have been found in youth with type 1 diabetes compared with controls, even after relatively short disease duration. To determine whether severity of clinical presentation contributes to these differences, we obtained structural magnetic resonance imaging (MRI) scans in youth ages 7-17 who were either newly diagnosed with type 1 diabetes (<3.5 months from diagnosis, n  = 46) or a sibling without diabetes (n = 28). Severity of presentation was measured by the presence of diabetic ketoacidosis (DKA) and degree of hyperglycemia exposure [hemoglobin A1c (HbA1c)] at diagnosis. MRI were obtained using T1-weighted, T2-weighted, and diffusion-weighted sequences. Within the group with type 1 diabetes, 12 subjects presented in DKA and 34 did not. After controlling for age, sex, and multiple comparisons, the type 1 diabetes group had lower volume in the left temporal-parietal-occipital cortex compared with controls. Within the type 1 diabetes group, DKA at presentation was associated with lower radial, axial, and mean diffusivity (MD) throughout major white matter tracts and higher HbA1c was associated with lower hippocampal, thalamic, and cerebellar white matter volumes, lower right posterior parietal cortical thickness, and greater right occipital cortical thickness. These data suggest that severity of clinical presentation is an important factor in predicting brain structural differences in youth with type 1 diabetes approximately 3 months after diagnosis. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

The impact of fibromyalgia on health status according to the types, demographic background and pain index.

PubMed

Ghavidel-Parsa, Banafsheh; Bidari, Ali; Maafi, Alireza A; Hassankhani, Amir; Hajiabbasi, Asghar; Montazeri, Ali; Sanaei, Omid; Ghalehbaghi, Babak

2016-01-01

To compare fibromyalgia (FM) core symptoms, FM impact severity and health status between the recently defined type A and type B of fibromyalgia. To compare disease impact and health status between FM patients and non-FM chronic pain control group. Finally, to compare health related quality of life and disease symptom severity by demographic background and widespread pain index (WPI). A total of 284 consecutive FM patients and 96 non-FM control patients were enrolled. The information of four questionnaires including the Fibromyalgia Survey Questionnaire (FSQ), the Fibromyalgia Impact Questionnaire (FIQ), the 12-item Short Form Health Survey (SF-12) and questionnaires regarding demographic features were collected from a local FM registry. Of all FM patients, 102 (94%) and 7 (6%) were type A and B, respectively. We found statistically significant differences in symptomatology, the FIQ scores and the SF-12 subscales across two type and control groups (p<0.001). However, when we compared these scores pairwise, except WPI there were no significant differences in other scores between type A and B. Also, there were no significant differences in FIQ and SF-12 scores across different age or educational status groups. Interestingly, patients with higher WPI had significantly higher FIQ (overall, symptom, and total) scores, worse PCS-12 and MCS-12 scores, and vice versa. Type B constitutes a minor but important component of FM that probably has a marked impact on the patient's perceived illness severity and quality of life. Further, WPI probably is the most important single indicator of disease severity and quality of life in FM.

Recurrent respiratory papillomatosis: a longitudinal study comparing severity associated with human papilloma viral types 6 and 11 and other risk factors in a large pediatric population.

PubMed

Wiatrak, Brian J; Wiatrak, Deborah W; Broker, Thomas R; Lewis, Linda

2004-11-01

A database was developed for prospective, longitudinal study of recurrent respiratory papillomatosis (RRP) in a large population of pediatric patients. Data recorded for each patient included epidemiological factors, human papilloma virus (HPV) type, clinical course, staged severity of disease at each surgical intervention, and frequency of surgical intervention. The study hypothesizes that patients with HPV type 11 (HPV-11) and patients younger than 3 years of age at diagnosis are at risk for more aggressive and extensive disease. The 10-year prospective epidemiological study used disease staging for each patient with an original scoring system. Severity scores were updated at each surgical procedure. Parents of children with RRP referred to the authors' hospital completed a detailed epidemiological questionnaire at the initial visit or at the first return visit after the study began. At the first endoscopic debridement after study enrollment, tissue was obtained and submitted for HPV typing using polymerase chain reaction techniques and in situ hybridization. Staging of disease severity was performed in real time at each endoscopic procedure using an RRP scoring system developed by one of the authors (B.J.W.). The frequency of endoscopic operative debridement was recorded for each patient. Information in the database was analyzed to identify statistically significant relationships between extent of disease and/or HPV type, patient age at diagnosis, and selected epidemiological factors. The study may represent the first longitudinal prospective analysis of a large pediatric RRP population. Fifty-eight of the 73 patients in the study underwent HPV typing. Patients infected with HPV-11 were significantly more likely to have higher severity scores, require more frequent surgical intervention, and require adjuvant therapy to control disease progression. In addition, patients with HPV-11 RRP were significantly more likely to develop tracheal disease, to require tracheotomy, and to develop pulmonary disease. Patients receiving a diagnosis of RRP before 3 years of age had significantly higher severity scores, higher frequencies of surgical intervention, and greater likelihood of requiring adjuvant medical therapy. Patients with Medicaid insurance had significantly higher severity scores and required more frequent surgical debridement. Birth by cesarean section appeared to be a significant risk factor for more severe disease and necessity of more frequent surgical intervention. Statistical analysis of the relationships among epidemiological factors, HPV type, and clinical course revealed that patients with HPV-11 and patients younger than 3 years of age at RRP diagnosis are prone to develop more aggressive disease as represented by higher severity scores at endoscopic debridement, more frequent operative debridement procedures per year, a greater requirement for adjuvant therapy, and greater likelihood of tracheal disease with tracheotomy.

Status of NASA full-scale engine aeroelasticity research

NASA Technical Reports Server (NTRS)

Lubomski, J. F.

1980-01-01

Data relevant to several types of aeroelastic instabilities were obtained using several types of turbojet and turbofan engines. In particular, data relative to separated flow (stall) flutter, choke flutter, and system mode instabilities are presented. The unique characteristics of these instabilities are discussed, and a number of correlations are presented that help identify the nature of the phenomena.

Extravasation injuries.

PubMed

Chiu, Kenneth; Tindholdt, Tyge Tind; Tønseth, Kim Alexander

2016-02-09

It is common for an intravascular catheter to be inserted to administer various types of therapy. Extravasation occurs frequently, and in the most severe cases plastic surgeons are often summoned to assess the extent of the injury and the possibility for reconstruction. The Department of Plastic and Reconstructive Surgery at Oslo University Hospital assesses approximately 15 severe cases of this type each year.

Fires following bark beetles: Factors controlling severity and disturbance interactions in ponderosa pine

Treesearch

Carolyn H. Sieg; Rodman R. Linn; Francois Pimont; Chad M. Hoffman; Joel D. McMillin; Judith Winterkamp; L. Scott Baggett

2017-01-01

Previous studies have suggested that bark beetles and fires can be interacting disturbances, whereby bark beetle-caused tree mortality can alter the risk and severity of subsequent wildland fires. However, there remains considerable uncertainty around the type and magnitude of the interaction between fires following bark beetle attacks, especially in drier forest types...

Alveolar macrophage–derived type I interferons orchestrate innate immunity to RSV through recruitment of antiviral monocytes

PubMed Central

Goritzka, Michelle; Makris, Spyridon; Kausar, Fahima; Durant, Lydia R.; Pereira, Catherine; Kumagai, Yutaro; Culley, Fiona J.; Mack, Matthias; Akira, Shizuo

2015-01-01

Type I interferons (IFNs) are important for host defense from viral infections, acting to restrict viral production in infected cells and to promote antiviral immune responses. However, the type I IFN system has also been associated with severe lung inflammatory disease in response to respiratory syncytial virus (RSV). Which cells produce type I IFNs upon RSV infection and how this directs immune responses to the virus, and potentially results in pathological inflammation, is unclear. Here, we show that alveolar macrophages (AMs) are the major source of type I IFNs upon RSV infection in mice. AMs detect RSV via mitochondrial antiviral signaling protein (MAVS)–coupled retinoic acid–inducible gene 1 (RIG-I)–like receptors (RLRs), and loss of MAVS greatly compromises innate immune restriction of RSV. This is largely attributable to loss of type I IFN–dependent induction of monocyte chemoattractants and subsequent reduced recruitment of inflammatory monocytes (infMo) to the lungs. Notably, the latter have potent antiviral activity and are essential to control infection and lessen disease severity. Thus, infMo recruitment constitutes an important and hitherto underappreciated, cell-extrinsic mechanism of type I IFN–mediated antiviral activity. Dysregulation of this system of host antiviral defense may underlie the development of RSV-induced severe lung inflammation. PMID:25897172

Recent achievements on polyanion-type compounds for sodium-ion batteries: Syntheses, crystal chemistry and electrochemical performance

NASA Astrophysics Data System (ADS)

Guo, Sheng-Ping; Li, Jia-Chuang; Xu, Qian-Ting; Ma, Ze; Xue, Huai-Guo

2017-09-01

In the past several years, many efforts have been made to develop polyanion-type cathode materials for sodium ion batteries by chemists and material scientists. These materials are one of the main types of promising cathodes though the studies are still in their infancy. This paper reviews almost all the important advances of polyanion-type cathodes on their syntheses, crystal structures, morphologies, electrochemical performance and Na redox mechanisms. It specifically focuses on their crystal chemistry and electrochemical behaviors. The contents are divided into several categories according to their chemical compositions. After introduction of the synthetic methods, phosphates (ortho-, pyro- and fluoro-), silicates, sulfates, and mixed anions type cathodes are summarized and discussed successively.

Severe hypoglycaemia and late-life cognitive ability in older people with Type 2 diabetes: the Edinburgh Type 2 Diabetes Study.

PubMed

Aung, P P; Strachan, M W J; Frier, B M; Butcher, I; Deary, I J; Price, J F

2012-03-01

To determine the association between lifetime severe hypoglycaemia and late-life cognitive ability in older people with Type 2 diabetes. Cross-sectional, population-based study of 1066 men and women aged 60-75 years, with Type 2 diabetes. Frequency of severe hypoglycaemia over a person's lifetime and in the year prior to cognitive testing was assessed using a previously validated self-completion questionnaire. Results of age-sensitive neuropsychological tests were combined to derive a late-life general cognitive ability factor, 'g'. Vocabulary test scores, which are stable during ageing, were used to estimate early life (prior) cognitive ability. After age- and sex- adjustment, 'g' was lower in subjects reporting at least one prior severe hypoglycaemia episode (n = 113), compared with those who did not report severe hypoglycaemia (mean 'g'-0.34 vs. 0.05, P < 0.001). Mean vocabulary test scores did not differ significantly between the two groups (30.2 vs. 31.0, P = 0.13). After adjustment for vocabulary, difference in 'g' between the groups persisted (means -0.25 vs. 0.04, P < 0.001), with the group with severe hypoglycaemia demonstrating poorer performance on tests of Verbal Fluency (34.5 vs. 37.3, P = 0.02), Digit Symbol Testing (45.9 vs. 49.9, P = 0.002), Letter-Number Sequencing (9.1 vs. 9.8, P = 0.005) and Trail Making (P < 0.001). These associations persisted after adjustment for duration of diabetes, vascular disease and other potential confounders. Self-reported history of severe hypoglycaemia was associated with poorer late-life cognitive ability in people with Type 2 diabetes. Persistence of this association after adjustment for estimated prior cognitive ability suggests that the association may be attributable, at least in part, to an effect of hypoglycaemia on age-related cognitive decline. © 2011 The Authors. Diabetic Medicine © 2011 Diabetes UK.

Application of RF-MEMS-Based Split Ring Resonators (SRRs) to the Implementation of Reconfigurable Stopband Filters: A Review

PubMed Central

Martín, Ferran; Bonache, Jordi

2014-01-01

In this review paper, several strategies for the implementation of reconfigurable split ring resonators (SRRs) based on RF-MEMS switches are presented. Essentially three types of RF-MEMS combined with split rings are considered: (i) bridge-type RF-MEMS on top of complementary split ring resonators CSRRs; (ii) cantilever-type RF-MEMS on top of SRRs; and (iii) cantilever-type RF-MEMS integrated with SRRs (or RF-MEMS SRRs). Advantages and limitations of these different configurations from the point of view of their potential applications for reconfigurable stopband filter design are discussed, and several prototype devices are presented. PMID:25474378

Sexual harassment of nurses and nursing students.

PubMed

Bronner, Gila; Peretz, Chava; Ehrenfeld, Mally

2003-06-01

Nursing has dealt with sexual harassment long before the term was coined during the 1970s. The current study investigated sexual harassment of nurses and nursing students in Israel following new legislation against sexual harassment in the workplace. A self-report questionnaire was administered to 281 nurses and 206 nursing students (80% women) from five medical centres in Israel. Seven types of sexual harassment behaviour patterns were evaluated. Frequency of sexual harassment decreased as the behaviour became more intimate and offensive. Ninety percent of subjects reported experiencing at least one type of sexual harassment and 30% described at least four types. A significant difference was found between nurses and nursing students. Furthermore, "severe" types of behaviour were experienced by 33% of nurses, in comparison with 23% of nursing students. Women were significantly more exposed than men to "mild" and "moderate" types of sexual harassment, while 35% of men vs. 26% of women were exposed to "severe" types of harassment. However, women responded significantly more assertively than men to "severe" sexual harassment. Particular attention is needed when sexual harassment occurs to male students and nurses because they may be subjected to the more offensive sexual conducts and at the same time may lack the ability to respond assertively.

A novel TRPS1 mutation in a Moroccan family with Tricho-rhino-phalangeal syndrome type III: case report.

PubMed

Smaili, W; Elalaoui, S Chafai; Meier, S; Zerkaoui, M; Sefiani, A; Heinimann, K

2017-05-03

Tricho-rhino-phalangeal syndrome (TRPS) is an autosomal dominant disorder characterized by craniofacial and skeletal malformations including short stature, thin scalp hair, sparse lateral eyebrows, pear-shaped nose and cone shaped epiphyses. This condition is caused by haploinsufficiency of the TRPS1 gene. Previous genotype-phenotype studies have correlated exon 6 missense mutations with TRPS type III, a severe form of type I with pronounced, facial characteristics, short stature and brachydactyly and differing from type II by the absence of exostoses and mental retardation. We report the first case of a Moroccan family, a father and his three children, in which the diagnosis of type III TRPS was suspected based on severe clinical and radiological features. Molecular analysis of the TRPS1 gene revealed a novel missense mutation in exon 6, (p.Ala932Ser), located in the GATA-type DNA-binding zinc finger domain. Our observations in this kindred support the previous genotype-phenotype results suggesting that patients with more pronounced facial characteristics and more severe shortening of hands and feet are more likely to have mutation in exon 6 of TRPS1.

Diabetic ketoacidosis characteristics and differences In type 1 versus type 2 diabetes patients.

PubMed

Rashid, Muhammad Owais; Sheikh, Aisha; Salam, Abdus; Farooq, Saad; Kiran, Zareen; Islam, Najmul

2017-01-01

Diabetes is undoubtedly one of the most challenging health problems of the 21st century. It is well known that diabetes once develop can lead to several complications. Diabetic ketoacidosis (DKA) is one of the life-threatening complications of diabetes. This study was designed to determine the frequency of DKA in diabetes patients and find out the clinical and biochemical determinants of DKA. This descriptive study was conducted at Aga Khan University Hospital (AKUH) Karachi, Pakistan from January 2010 to February 2016. All known or newly diagnosed diabetic patients of >16 years of age irrespective of gender and type of diabetes were included. Information regarding patient's demographics, presenting symptoms, precipitating causes of DKA, biochemical profiles and outcome at the time of discharge was collected. Majority (54.7%) had moderate and 12.4% had severe DKA at presentation. Previous history of DKA was found higher in type 1 diabetes patients (T1DM) (14%) as compare to (4%) type 2 diabetes patients (T2DM) (p<0.05). DKA severity was observed more (12%) in newly diagnosed (T1DM) (p<0.05). Comorbidities were found more (81%) in (T2DM) (p<0.05) Mortality was also observed higher in Type 2 diabetes patients (p<0.05). Majority of the diabetics had moderate to severe DKA at presentation. Mortality and morbidity related with DKA was found considerably higher among patients with T2DM while infection, myocardial infarction and stroke found as triggering factors in these patients.

Maltreatment type, exposure characteristics, and mental health outcomes among clinic referred trauma-exposed youth.

PubMed

Hodgdon, Hilary B; Spinazzola, Joseph; Briggs, Ernestine C; Liang, Li-Jung; Steinberg, Alan M; Layne, Christopher M

2018-05-28

Building upon prior research documenting differential effects of psychological maltreatment, physical, and sexual abuse on youth mental health outcomes (Spinazzola et al., 2014), the present study sought to clarify the relative predictive contributions of type of maltreatment compared to salient exposure characteristics. The sample included 5058 clinic-referred youth from the Core Dataset (CDS) of the National Child Traumatic Stress Network (NCTSN) with lifetime histories of exposure to one or more of three specific types of maltreatment: psychological maltreatment (PM), physical abuse (PA), and sexual abuse (SA). First, we examined variations in salient trauma characteristics (age of onset, duration of exposure, number of co-occurring trauma types, and perpetrator type and number) by maltreatment group. Second, we examined whether type of maltreatment remained associated with mental health measures after adjusting for demographic variables and trauma characteristics. Profiles for youth with PM were more severe than youth who experienced either PA or SA only. Co-occurring PM and PA was associated with the most severe trauma exposure profile and with severity of PTSD symptoms, even after adjusting for demographic and trauma characteristics. Youth exposed to SA only had a distinct trauma profile and greater PTSD symptom severity after adjusting for demographic and trauma characteristic variables. Study findings hold important implications for trauma screening, assessment, and intervention, as well as for traumatic stress research methods that extend beyond abuse-specific or cumulative-risk approaches. Copyright © 2018 Elsevier Ltd. All rights reserved.

Severe Hypertriglyceridemia Possibly Masked Acute Pancreatitis and Led to a Difficult Diagnosis in an Obese Patient with Ketoacidosis-onset Type 2 Diabetes.

PubMed

Fujishiro, Midori; Horita, Akiko; Nakagawara, Hiroshi; Mawatari, Takayuki; Kishigami, Yoshifusa; Tominaga, Yoshiteru; Moriyama, Mitsuhiko; Ishihara, Hisamitsu

2017-10-01

A young obese man with ketoacidosis-onset type 2 diabetes mellitus, associated with severe hypertriglyceridemia, was admitted to a local hospital complaining of abdominal pain. Although the abdominal pain worsened, his serum amylase level remained normal with persistent severe hypertriglyceridemia until the second day of hospitalization. The next day, computed tomography showed severe acute pancreatitis (AP) with serum amylase elevation, while the patient's triglyceride level decreased to 558 mg/dL. He was transferred to our hospital and recovered after intensive care. AP accompanied by diabetic ketoacidosis is not rare but an early diagnosis can be difficult to make due to normal amylase levels in the presence of severe hypertriglyceridemia.

Exploring motorcyclist injury severity resulting from various crash configurations at T-junctions in the United Kingdom--an application of the ordered probit models.

PubMed

Pai, Chih-Wei; Saleh, Wafaa

2007-03-01

The fact that motorcycle users tend to be more vulnerable to injuries than those using other motorized vehicles may act synergistically with the complexity of conflicting movements between vehicles and motorcycles to increase injury severity in a junction-type accident. A junction-type collision tends to be more severe than a non-junction case due to the fact that some of the injurious crashes such as angle-collision commonly occur. Existing studies have applied several statistical modeling techniques to examine influential factors on the occurrences of different crashes among motorized vehicles but surprisingly very little has empirically explored whether a particular crash type, resulting from a junction-type accident, is more injurious to motorcyclists. This article attempts to investigate whether a particular collision is more deadly to motorcyclists conditioned on crash occurrence at T-junctions in the U.K., while controlling for environment, vehicle, and demographic factors. The statistical modeling technique employed is the ordered probit models using the data extracted from the STATS19 accident injury database (1999-2004). The modeling found determinants of injury severity among motorcyclists at T-junctions in the U.K. For example, an approach-turn/head-on collision is much more injurious to motorcyclists; and, those riding in early morning (i.e., 0000-0659) are more likely to be severely injured. This study offers a guideline for future research, as well as insight into potential prevention strategies that might help moderate motorcyclist injuries.

Prevention of severe hypoglycaemia in type I diabetes: a randomised controlled population study

PubMed Central

Nordfeldt, S; Johansson, C; Carlsson, E; Hammersjo, J

2003-01-01

Aims: To investigate use of targeted self study material in type I diabetes patient education regarding dissemination, perceived patient benefit, and prevention of severe hypoglycaemia. Methods: In a randomised 1:1:1 controlled study, 332 patients with type I diabetes (aged 2.6–18.9 years) were studied; 313 completed clinical follow up, 261 completed endpoint questionnaire. The intervention group received videotapes and a brochure designed to review skills for self control and treatment, aimed at preventing severe hypoglycaemia. Two control groups received a videotape and brochure with general diabetes information, or traditional treatment only, respectively. Results: Yearly incidence of severe hypoglycaemia decreased from 42% to 27% in the intervention group, but not in controls. HbA1c remained unchanged. Levels of use ranged from 1 to 20 times (median 2); 40–49% had shown the materials to friends, relatives, school staff, sports coaches, etc (there was little difference between intervention and control groups). Higher benefit and learning levels resulted from the intervention material, especially in patients with severe hypoglycaemia. Conclusions: Mass distributed pedagogical devices such as high quality video programmes and brochures may contribute to the prevention of severe hypoglycaemia. Such self study materials can reach high dissemination levels and constitute a cost effective complement to regular visits to a diabetes team and to other types of education. The findings may have implications for other topics, other ages, and other diagnosis groups. PMID:12598392

Risk factors and management of severe life-threatening anaphylaxis in patients with clonal mast cell disorders.

PubMed

Valent, P

2014-07-01

Several different risk factors and conditions may predispose to severe life-threatening anaphylaxis. Systemic mastocytosis (SM) is one such condition. Although many SM patients are suffering from mild or even no mediator-related symptoms, others have recurrent episodes of severe anaphylaxis, with clear signs of a mast cell activation syndrome (MCAS) despite prophylactic therapy with anti-mediator-type drugs. In several of these patients, an IgE-dependent allergy is diagnosed. The severity and frequency of MCAS reactions neither correlate with the burden of neoplastic mast cells nor with the levels of specific IgE or the basal tryptase level. However, there is a relationship between severe anaphylaxis in SM and the type of allergen. Notably, many of these patients suffer from hymenoptera venom allergy. Currently recommended therapies include the prophylactic use of anti-mediator-type drugs, long-term immunotherapy for hymenoptera venom allergic patients, and epinephrine-self-injector treatment for emergency situations. In patients who present with an excess burden of mast cells, such as smouldering SM, cytoreductive therapy with cladribine (2CdA) may reduce the frequency of severe events. For the future, additional treatment options, such as IgE-depletion or the use of tyrosine kinase inhibitors blocking IgE-dependent mediator secretion as well as KIT activation, may be useful alternatives. © 2014 John Wiley & Sons Ltd.

Correlation between clinical severity and type and degree of pectus excavatum in twelve brachycephalic dogs.

PubMed

Hassan, Elham A; Hassan, Marwa H; Torad, Faisal A

2018-05-18

The aim of the study was to correlate the clinical severity of pectus excavatum with its type and degree based on objective radiographic evaluation. Twelve brachycephalic dogs were included. Grading of the clinical severity was done based on a 6-point grading score. Thoracic radiographs were used to calculate the frontosagittal and vertebral indices at the tenth thoracic vertebra and the vertebra overlying the excavatum. Correlation between the clinical severity score and frontosagittal and vertebral indices was evaluated using Pearson's correlation coefficient. Typical pectus excavatum was recorded in the caudal sternum in seven dogs, with a mean clinical severity score of 1.7 ± 1.4, whereas in five dogs, atypical mid-sternal deviation was recorded with a mean clinical severity score of 3.8 ± 0.7. A strong correlation (r=0.7) was recorded between the clinical severity score and vertebral index in the atypical form, whereas a weak correlation (r=0.02) was recorded in the typical form (P<0.05). The clinical severity and degree of pectus excavatum was poorly correlated (r=0.3) in the typical form of pectus excavatum, whereas it was strongly correlated (r=0.9) in the atypical form. Pectus excavatum in dogs is associated with compressive cardiopulmonary dysfunction, which depends mainly on the site/type of deviation rather than the degree of deviation.

Impact of roadway geometric features on crash severity on rural two-lane highways.

PubMed

Haghighi, Nima; Liu, Xiaoyue Cathy; Zhang, Guohui; Porter, Richard J

2018-02-01

This study examines the impact of a wide range of roadway geometric features on the severity outcomes of crashes occurred on rural two-lane highways. We argue that crash data have a hierarchical structure which needs to be addressed in modeling procedure. Moreover, most of previous studies ignored the impact of geometric features on crash types when developing crash severity models. We hypothesis that geometric features are more likely to determine crash type, and crash type together with other occupant, environmental and vehicle characteristics determine crash severity outcome. This paper presents an application of multilevel models to successfully capture both hierarchical structure of crash data and indirect impact of geometric features on crash severity. Using data collected in Illinois from 2007 to 2009, multilevel ordered logit model is developed to quantify the impact of geometric features and environmental conditions on crash severity outcome. Analysis results revealed that there is a significant variation in severity outcomes of crashes occurred across segments which verifies the presence of hierarchical structure. Lower risk of severe crashes is found to be associated with the presence of 10-ft lane and/or narrow shoulders, lower roadside hazard rate, higher driveway density, longer barrier length, and shorter barrier offset. The developed multilevel model offers greater consistency with data generating mechanism and can be utilized to evaluate safety effects of geometric design improvement projects. Published by Elsevier Ltd.

Patients' experiences of continuity in the care of type 2 diabetes: a focus group study in primary care

PubMed Central

Alazri, Mohammed H; Neal, Richard D; Heywood, Phil; Leese, Brenda

2006-01-01

Background Continuity of care is fundamental to general practice and type 2 diabetes is a common chronic disease with major health and social impacts. Nevertheless continuity, as experienced by patients with type 2 diabetes, remains a neglected area. Aim To explore perceptions and experiences of continuity of care in general practice from the perspectives of patients with type 2 diabetes, focusing on the advantages and disadvantages of different types of continuity. Design of study Focus groups with patients. Setting Seven practices with different organisational structures in Leeds, UK. Method Seventy-nine patients with type 2 diabetes were recruited. Focus group interviews were conducted with 79 patients with type 2 diabetes from seven practices in Leeds, UK. Results Patients experienced three different types of continuity: relational (or longitudinal) continuity, cross-boundary (or team) continuity, and continuity of information. Patients' perceptions of continuity were influenced by several factors including a personal relationship between themselves and their healthcare professional, their own beliefs and behaviours, presence of diabetes, and the systems and structures of general practices. Patients identified the advantages and disadvantages of two types of continuity. Relational or longitudinal continuity was important in providing psychosocial care, but with a risk of misdiagnosis. The advantages of cross-boundary or team continuity were to provide physical care, whereas the main disadvantages were the absence of personal care and patient confusion. Conclusion Perceptions of continuity by patients with type 2 diabetes were influenced by several factors; they perceived several advantages and disadvantages associated with different types of continuity. Patients might expect certain healthcare benefits by following certain types of continuity. PMID:16834874

Disease severity is associated with the use of complementary medicine to treat or manage type-2 diabetes: data from the 2002 and 2007 National Health Interview Survey.

PubMed

Nahin, Richard L; Byrd-Clark, Danita; Stussman, Barbara J; Kalyanaraman, Nilesh

2012-10-22

The overall prevalence of complementary medicine (CM) use among adults in the United States with diabetes has been examined both in representative national samples and in more restricted populations. However, none of these earlier studies attempted to identify predictors of CM use to treat diabetes among the populations sampled, nor looked for a relationship between CM use and diabetes severity. Combining data from the 2002 and 2007 National Health Interview Survey (NHIS), we constructed a nationally representative sample of 3,978 U.S. adults aged ≥18 years with self-reported diabetes. Both the 2002 and 2007 NHIS contained extensive questions on the use of CM. We used logistic regression to examine the association between diabetes severity and overall CM use, as well as the use of specific categories of CM. In adults with type-2 diabetes, 30.9% used CM for any reason, but only 3.4% used CM to treat or manage their type-2 diabetes versus 7.1% of those with type-1 diabetes. Among those using CM to treat/manage their type-2 diabetes, 77% used both CM and conventional prescription medicine for their diabetes. The most prevalent types of CM therapies used were diet-based interventions (35.19%, S.E. 5.11) and non-vitamin/non-mineral dietary supplements (33.74%, S.E. 5.07). After controlling for sociodemographic factors, we found that, based on a count of measures of diabetes severity, persons with the most severe diabetes had nearly twice the odds of using CM as those with less severe disease (OR=1.9, 95%CI 1.2-3.01). Persons who had diabetes 10 years or more (OR=1.66, 95%CI 1.04-3.66) and those that had a functional limitation resulting from their diabetes (OR=1.74, 95%CI 1.09-2.8) had greater odds of using CM than those not reporting these measures. No significant associations were observed between overall CM use and other individual measures of diabetes severity: use of diabetic medications, weak or failing kidneys, coronary heart disease, or severe vision problems. Our results demonstrate that individuals with more severe diabetes are more likely to use CM independent of sociodemographic factors. Further studies are essential to determine if CM therapies actually improve clinical outcomes when used to treat/manage diabetes.

Disease severity is associated with the use of complementary medicine to treat or manage type-2 diabetes: data from the 2002 and 2007 National Health Interview Survey

PubMed Central

2012-01-01

Background The overall prevalence of complementary medicine (CM) use among adults in the United States with diabetes has been examined both in representative national samples and in more restricted populations. However, none of these earlier studies attempted to identify predictors of CM use to treat diabetes among the populations sampled, nor looked for a relationship between CM use and diabetes severity. Methods Combining data from the 2002 and 2007 National Health Interview Survey (NHIS), we constructed a nationally representative sample of 3,978 U.S. adults aged ≥18 years with self-reported diabetes. Both the 2002 and 2007 NHIS contained extensive questions on the use of CM. We used logistic regression to examine the association between diabetes severity and overall CM use, as well as the use of specific categories of CM. Results In adults with type-2 diabetes, 30.9% used CM for any reason, but only 3.4% used CM to treat or manage their type-2 diabetes versus 7.1% of those with type-1 diabetes. Among those using CM to treat/manage their type-2 diabetes, 77% used both CM and conventional prescription medicine for their diabetes. The most prevalent types of CM therapies used were diet-based interventions (35.19%, S.E. 5.11) and non-vitamin/non-mineral dietary supplements (33.74%, S.E. 5.07). After controlling for sociodemographic factors, we found that, based on a count of measures of diabetes severity, persons with the most severe diabetes had nearly twice the odds of using CM as those with less severe disease (OR=1.9, 95%CI 1.2-3.01). Persons who had diabetes 10 years or more (OR=1.66, 95%CI 1.04-3.66) and those that had a functional limitation resulting from their diabetes (OR=1.74, 95%CI 1.09-2.8) had greater odds of using CM than those not reporting these measures. No significant associations were observed between overall CM use and other individual measures of diabetes severity: use of diabetic medications, weak or failing kidneys, coronary heart disease, or severe vision problems. Conclusions Our results demonstrate that individuals with more severe diabetes are more likely to use CM independent of sociodemographic factors. Further studies are essential to determine if CM therapies actually improve clinical outcomes when used to treat/manage diabetes. PMID:23088705

Personal and interpersonal correlates of bullying behaviors among Korean middle school students.

PubMed

Lee, Chang-Hun

2010-01-01

This study simultaneously investigates personal and interpersonal traits that were found to be important factors of bullying behavior using data collected from 1,238 randomly selected Korean middle school students. Using a modified and expanded definition of bullying based on a more culturally sensitive approach to bullying, this study categorizes bullies into three groups: Type I (minor-covert-nonchronic bullying), Type II (moderate-covert-chronic or severe-overt-nonchronic bullying), and Type III (severe-overt-chronic bullying). In addition, this study empirically tests several factors for the first time. Those factors are fun-seeking tendency, teachers' attitude toward bullying, teachers' effectiveness of intervention, teachers' moral authority, power dynamic, and pseudofriendship. The comparison across three groups provided unique findings that different factors were differently related to different groups of bullies. Specifically, teachers have influence on bullying only for the moderate group (Type II), and parents have influence on bullying only for the minor group (Type I). The most important and constant factors across all different groups were prior bullying victimization experience and fun-seeking tendency.

NEGATIVE EMOTIONS IN CANCER CARE: DO ONCOLOGISTS’ RESPONSES DEPEND ON SEVERITY AND TYPE OF EMOTION?

PubMed Central

Kennifer, Sarah L.; Alexander, Stewart C.; Pollak, Kathryn I.; Jeffreys, Amy S.; Olsen, Maren K.; Rodriguez, Keri L.; Arnold, Robert M.; Tulsky, James A.

2009-01-01

Objective To examine how type and severity of patients’ negative emotions influence oncologists’ responses and subsequent conversations. Methods We analyzed 264 audio-recorded conversations between advanced cancer patients and their oncologists. Conversations were coded for patients’ expressions of negative emotion, which were categorized by type of emotion and severity. Oncologists’ responses were coded as using either empathic language or blocking and distancing approaches. Results Patients presented fear more often than anger or sadness; severity of disclosures was most often moderate. Oncologists responded to 35% of these negative emotional disclosures with empathic language. They were most empathic when patients presented intense emotions. Responding empathically to patients’ emotional disclosures lengthened discussions by an average of only 21 seconds. Conclusion Greater response rates to severe emotions suggest oncologists may recognize negative emotions better when patients express them more intensely. Oncologists were least responsive to patient fear and responded with greatest empathy to sadness. Practice Implications Oncologists may benefit from additional training to recognize negative emotions, even when displayed without intensity. Teaching cancer patients to better articulate their emotional concerns may also enhance patient-oncologist communication. PMID:19041211

A case of severe type of cerebro-costo-mandibular syndrome.

PubMed

Matić, Aleksandra; Velisavljev-Filipović, Gordana; Lovrenski, Jovan; Gajdobranski, Djordje

2016-01-01

Cerebro-costo-mandibular syndrome (CCMS) is a rare disorder, with only 75 cases described in the literature to date. CCMS is characterized by association of micrognathia and specific multiple rib defects. It is accompanied by mental deficiency in considerable number of cases. Sometimes, there are associated anomalies and problems, such as spine deformities, brain, heart, kidney or ear anomalies, feeding difficulties, delayed psychomotor development, and growth impairment. Depending on severity of deformities and consecutive respiratory insufficiency, in about 35–50% of CCMS cases, death occurs during the first year of life. These cases are referred to as severe types of CCMS. In this paper we present a female infant with severe type of CCMS. Diagnosis was established in the first day of life, based on micrognathia and findings of posterior rib-gap defects on the chest X-ray, accompanied by dyspnea. Progressive severe respiratory insufficiency caused by chest and air-way deformities and exacerbated by episodes of pneumonia, led to respiratory failure and death at the age of 7.5 months. CCMS should be considered in every infant with micrognathia and rib-gap defects on chest X-ray.

Evaluation of thunderstorm indices from ECMWF analyses, lightning data and severe storm reports

NASA Astrophysics Data System (ADS)

Kaltenböck, Rudolf; Diendorfer, Gerhard; Dotzek, Nikolai

This study describes the environmental atmospheric characteristics in the vicinity of different types of severe convective storms in Europe during the warm seasons in 2006 and 2007. 3406 severe weather events from the European Severe Weather Database ESWD were investigated to get information about different types of severe local storms, such as significant or weak tornadoes, large hail, damaging winds, and heavy precipitation. These data were combined with EUCLID (European Cooperation for Lightning Detection) lightning data to distinguish and classify thunderstorm activity on a European scale into seven categories: none, weak and 5 types of severe thunderstorms. Sounding parameters in close proximity to reported events were derived from daily high-resolution T799 ECMWF (European Centre for Medium-range Weather Forecasts) analyses. We found from the sounding-derived parameters in Europe: 1) Instability indices and CAPE have considerable skill to predict the occurrence of thunderstorms and the probability of severe events. 2) Low level moisture can be used as a predictor to distinguish between significant tornadoes or non-severe convection. 3) Most of the events associated with wind gusts during strong synoptic flow situations reveal the downward transport of momentum as a very important factor. 4) While deep-layer shear discriminates well between severe and non-severe events, the storm-relative helicity in the 0-1 km and especially in the 0-3 km layer adjacent to the ground has more skill in distinguishing between environments favouring significant tornadoes and wind gusts versus other severe events. Additionally, composite parameters that combine measurements of buoyancy, vertical shear and low level moisture have been tested to discriminate between severe events.

[Decreased consciousness of hypoglycaemia and the incidence of severe hypoglycaemia in children and adolescents with diabetes type 1].

PubMed

Peczyńska, Jadwiga; Urban, Mirosława; Głowińska, Barbara; Florys, Bozena

2002-01-01

Maintaining good metabolic control is connected with an increasing risk of hypoglycaemia, which is the most frequent and most dangerous side effect of intensive insulin therapy. The results of the DCCT trial revealed that the intensification in insulin therapy increases three-fold the risk of severe hypoglycaemia. Severe hypoglycaemia was defined by loose of consciousness, coma and/or convulsions. Feeling the state of hypoglycaemia is the basic defensive mechanism in patients with diabetes type 1, making possible to start the self treatment. The decreased consciousness of hypoglycaemia makes limitations to the intensive insulin- therapy, the main aim of which is to stop later complications. The aim of the study was to evaluate the incidence of severe hypoglycaemia during a 5 yrs period, the attempt to find the reason and correlations between severe hypoglycaemia and decreased consciousness of feeling this state in children and adolescents with diabetes type 1. The study was carried out on 280 patients aged x=13.1 yrs (2.2-18.6), suffering from diabetes, mean duration 7 yrs (2.0-13.9). The study was retrospective, taking into consideration the period from 1.01.1995 to 31.12.2000. During the analysed period we noticed 48 cases of severe hypoglycaemia in 31 patients (21 boys and 10 girls), mean age 13.8 yrs, with diabetes duration about 7 yrs. Every tenth patient had severe hypoglycaemia. Mean level of HbA1c was little lower in children with episode of severe hypoglycaemia (7.2%) than in patients without it (7.9%). The frequency of episodes of severe hypoglycaemia increased with the duration of the disease. The dose of insulin per day did not differ between groups. In patients with severe hypoglicaemias only 5 were treated with use of Humalog. In 38 (81%), severe hypoglycaemias occurred between 1-3 o'clock a.m., 4 (1.9%) in the early morning and 6 (2.88%) in late evening hours. Only in 9 cases the reason for severe hypoglycaemia was found. 11 patients had at least twice incidents of severe hypoglycaemia and 7 of them (63%) did not feel the signs of the decreasing glycaemia level. The lack of consciousness of hypoglycaemia is connected with the increased frequency of severe hypoglycaemia in children and adolescents with diabetes type 1.

Rational GARCH model: An empirical test for stock returns

NASA Astrophysics Data System (ADS)

Takaishi, Tetsuya

2017-05-01

We propose a new ARCH-type model that uses a rational function to capture the asymmetric response of volatility to returns, known as the "leverage effect". Using 10 individual stocks on the Tokyo Stock Exchange and two stock indices, we compare the new model with several other asymmetric ARCH-type models. We find that according to the deviance information criterion, the new model ranks first for several stocks. Results show that the proposed new model can be used as an alternative asymmetric ARCH-type model in empirical applications.

The Social Context of Anger among Violent Forensic Patients: An Analysis via Experience Sampling Method.

ERIC Educational Resources Information Center

Hillbrand, Marc; Waite, Bradley M.

1992-01-01

Used Experience Sampling Method to investigate experiences of anger in 10 patients at maximum security forensic institute who had histories of severe, violent behavior. Found severity of anger influenced by type of activity in which subject was engaged and by emotional valence of preceding events but not by time of day nor by type of interpersonal…

Evaluation of the Mangled Extremity Severity Score in Combat-Related Type III Tibia Fracture

DTIC Science & Technology

2014-09-01

Return to duty rates of amputee soldiers in the current conflicts in Afghanistan and Iraq. J Trauma. 2010; 68:1476–1479. 5. Johansen K, Daines M, Howey T...severity score (MESS) in combat related type III tibia fracture. J Orthop Trauma. 2013. 4. Johansen K, Daines M, Howey T, et al. Objective criteria

Severe acute bovine viral diarrhea in Ontario, 1993-1995.

PubMed

Carman, S; van Dreumel, T; Ridpath, J; Hazlett, M; Alves, D; Dubovi, E; Tremblay, R; Bolin, S; Godkin, A; Anderson, N

1998-01-01

In 1993, noncytopathic bovine viral diarrhea virus (BVDV) strains with enhanced virulence caused unprecedented outbreaks of severe acute bovine viral diarrhea (BVD) in dairy, beef, and veal herds in Ontario (Canada). Fever, pneumonia, diarrhea, and sudden death occurred in all age groups of cattle. Abortions often occurred in pregnant animals. Gross lesions in the alimentary tract were similar to those associated with mucosal disease, especially in animals >6 months of age. Cattle of all age groups had microscopic lesions in the alimentary tract similar to those seen with mucosal disease. The epidemic peaked in the summer of 1993, with 15% of all bovine accessions from diseased cattle presented to the diagnostic laboratory being associated with BVDV. The virus strains involved in the outbreak were analyzed using monoclonal and polyclonal antibodies and the polymerase chain reaction. The virus isolates from these outbreaks of severe disease were determined to be type 2 BVDV. Type 2 BVDV has been present in Ontario at least since 1981 without causing widespread outbreaks of severe acute BVD, which suggests that type 2 designation in itself does not imply enhanced virulence. Cattle properly vaccinated with type 1 BVDV vaccines appear to be protected from clinical disease.

Strain hypothesis of Toxoplasma gondii infection on the outcome of human diseases

PubMed Central

Xiao, Jianchun; Yolken, Robert H.

2015-01-01

The intracellular protozoan Toxoplasma gondii is an exceptionally successful food- and waterborne parasite that infects approximately 1 billion people worldwide. Genotyping of T. gondii isolates from all continents revealed a complex population structure. Recent research supports the notion that T. gondii genotype may be associated with disease severity. Here, we (1) discuss molecular and serological approaches for designation of T. gondii strain type, (2) overview the literatures on the association of T. gondii strain type and the outcome of human disease, and (3) explore possible mechanisms underlying these strain specific pathology and severity of human toxoplasmosis. Although no final conclusions can be drawn, it is clear that virulent strains (e. g. strains containing type I or atypical alleles) are significantly more often associated with increased frequency and severity of human toxoplasmosis. The significance of highly virulent strains can cause severe diseases in immunocompetent patients and might implicated in brain disorders such as schizophrenia should led to reconsideration of toxoplasmosis. Further studies that combine parasite strain typing and human factor analysis (e.g. immune status and genetic background) are required for better understanding of human susceptibility or resistance to toxoplasmosis. PMID:25600911

Gender differences in depression severity and symptoms across depressive sub-types.

PubMed

Parker, Gordon; Fletcher, Kathryn; Paterson, Amelia; Anderson, Josephine; Hong, Michael

2014-01-01

Lifetime rates of depression are distinctly higher in women reflecting both real and artefactual influences. Most prevalence studies quantifying a female preponderance have examined severity-based diagnostic groups such as major depression or dysthymia. We examined gender differences across three depressive sub-type conditions using four differing measures to determine whether any gender differences emerge more from severity or symptom prevalence, reflect nuances of the particular measure, or whether depressive sub-type is influential. A large clinical sample was recruited. Patients completed two severity-weighted depression measures: the Depression in the Medically Ill 10 (DMI-10) and Quick Inventory of Depressive Symptoms-Self-Report (QIDS-SR) and two measures weighting symptoms and illness correlates of melancholic and non-melancholic depressive disorders - the Severity of Depressive Symptoms (SDS) and Sydney Melancholia Prototype Index (SMPI). Analyses were undertaken of three diagnostic groups comprising those with unipolar melancholic, unipolar non-melancholic and bipolar depressive conditions. Women in the two unipolar groups scored only marginally (and non-significantly) higher than men on the depression severity measures. Women in the bipolar depression group, did however, score significantly higher than men on depression severity. On measures weighted to assessing melancholic and non-melancholic symptoms, there were relatively few gender differences identified in the melancholic and non-melancholic sub-sets, while more gender differences were quantified in the bipolar sub-set. The symptoms most commonly and consistently differentiating by gender were those assessing appetite/weight change and psychomotor disturbance. Our analyses of several measures and the minimal differentiation of depressive symptoms and symptom severity argues against any female preponderance in unipolar depression being contributed to distinctly by these depression rating measures. Our analyses indicated that gender had minimal if any impact on depression severity estimates. Gender differences in depressive symptoms and severity were more distinctive in bipolar patients, a finding seemingly not previously identified or reported. The study had considerable power reflecting large sample sizes and thus risks assigning significant differences where none truly exist, although we repeated analyses after controlling for the type I error rate. Copyright © 2014 Elsevier B.V. All rights reserved.

Differential Muscle Hypertrophy Is Associated with Satellite Cell Numbers and Akt Pathway Activation Following Activin Type IIB Receptor Inhibition in Mtm1 p.R69C Mice

PubMed Central

Lawlor, Michael W.; Viola, Marissa G.; Meng, Hui; Edelstein, Rachel V.; Liu, Fujun; Yan, Ke; Luna, Elizabeth J.; Lerch-Gaggl, Alexandra; Hoffmann, Raymond G.; Pierson, Christopher R.; Buj-Bello, Anna; Lachey, Jennifer L.; Pearsall, Scott; Yang, Lin; Hillard, Cecilia J.; Beggs, Alan H.

2015-01-01

X-linked myotubular myopathy is a congenital myopathy caused by deficiency of myotubularin. Patients often present with severe perinatal weakness, requiring mechanical ventilation to prevent death from respiratory failure. We recently reported that an activin receptor type IIB inhibitor produced hypertrophy of type 2b myofibers and modest increases of strength and life span in the severely myopathic Mtm1δ4 mouse model of X-linked myotubular myopathy. We have now performed a similar study in the less severely symptomatic Mtm1 p.R69C mouse in hopes of finding greater treatment efficacy. Activin receptor type IIB inhibitor treatment of Mtm1 p.R69C animals produced behavioral and histological evidence of hypertrophy in gastrocnemius muscles but not in quadriceps or triceps. The ability of the muscles to respond to activin receptor type IIB inhibitor treatment correlated with treatment-induced increases in satellite cell number and several muscle-specific abnormalities of hypertrophic signaling. Treatment-responsive Mtm1 p.R69C gastrocnemius muscles displayed lower levels of phosphorylated ribosomal protein S6 and higher levels of phosphorylated eukaryotic elongation factor 2 kinase than were observed in Mtm1 p.R69C quadriceps muscle or in muscles from wild-type littermates. Hypertrophy in the Mtm1 p.R69C gastrocnemius muscle was associated with increased levels of phosphorylated ribosomal protein S6. Our findings indicate that muscle-, fiber type-, and mutation-specific factors affect the response to hypertrophic therapies that will be important to assess in future therapeutic trials. PMID:24726641

Differential muscle hypertrophy is associated with satellite cell numbers and Akt pathway activation following activin type IIB receptor inhibition in Mtm1 p.R69C mice.

PubMed

Lawlor, Michael W; Viola, Marissa G; Meng, Hui; Edelstein, Rachel V; Liu, Fujun; Yan, Ke; Luna, Elizabeth J; Lerch-Gaggl, Alexandra; Hoffmann, Raymond G; Pierson, Christopher R; Buj-Bello, Anna; Lachey, Jennifer L; Pearsall, Scott; Yang, Lin; Hillard, Cecilia J; Beggs, Alan H

2014-06-01

X-linked myotubular myopathy is a congenital myopathy caused by deficiency of myotubularin. Patients often present with severe perinatal weakness, requiring mechanical ventilation to prevent death from respiratory failure. We recently reported that an activin receptor type IIB inhibitor produced hypertrophy of type 2b myofibers and modest increases of strength and life span in the severely myopathic Mtm1δ4 mouse model of X-linked myotubular myopathy. We have now performed a similar study in the less severely symptomatic Mtm1 p.R69C mouse in hopes of finding greater treatment efficacy. Activin receptor type IIB inhibitor treatment of Mtm1 p.R69C animals produced behavioral and histological evidence of hypertrophy in gastrocnemius muscles but not in quadriceps or triceps. The ability of the muscles to respond to activin receptor type IIB inhibitor treatment correlated with treatment-induced increases in satellite cell number and several muscle-specific abnormalities of hypertrophic signaling. Treatment-responsive Mtm1 p.R69C gastrocnemius muscles displayed lower levels of phosphorylated ribosomal protein S6 and higher levels of phosphorylated eukaryotic elongation factor 2 kinase than were observed in Mtm1 p.R69C quadriceps muscle or in muscles from wild-type littermates. Hypertrophy in the Mtm1 p.R69C gastrocnemius muscle was associated with increased levels of phosphorylated ribosomal protein S6. Our findings indicate that muscle-, fiber type-, and mutation-specific factors affect the response to hypertrophic therapies that will be important to assess in future therapeutic trials. Copyright © 2014 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

The profound impact of combined severe acidosis and malperfusion on operative mortality in the surgical treatment of type A aortic dissection.

PubMed

Lawton, Jennifer S; Moon, Marc R; Liu, Jingxia; Koerner, Danielle J; Kulshrestha, Kevin; Damiano, Ralph J; Maniar, Hersh; Itoh, Akinobu; Balsara, Keki R; Masood, Faraz M; Melby, Spencer J; Pasque, Michael K

2018-03-01

Surgery for type A aortic dissection is associated with a high operative mortality, and a variety of predictive risk factors have been reported. We hypothesized that a combination of risk factors associated with organ malperfusion and severe acidosis that are not currently documented in databases would be associated with a level of extreme operative risk that would warrant the consideration of treatment paradigms other than immediate ascending aortic surgery. Charts of patients undergoing repair of acute type A aortic dissection between January 1, 1996, and May 1, 2016, were queried for preoperative malperfusion, preoperative base deficit, pH, bicarbonate, cardiopulmonary resuscitation, severe aortic insufficiency, redo status, and preoperative intubation. Multivariable logistic analyses were considered to evaluate interested variables and operative mortality. Between January 1, 1996, and May 1, 2016, 282 patients underwent surgical repair of type A aortic dissection. A total of 66 patients had a calculated base deficit -5 or greater. Eleven of 12 patients (92%) with severe acidosis (base deficit ≥-10) with malperfusion had operative mortality. No patient with severe acidosis with abdominal malperfusion survived. Multivariable analyses identified base deficit, intubation, congestive heart failure, dyslipidemia/statin use, and renal failure as predictors of operative death. The most significant predictor was base deficit -10 or greater (odds ratio, 9.602; 95% confidence interval, 2.649-34.799). The combination of severe acidosis (base deficit ≥-10) with abdominal malperfusion was uniformly fatal. Further research is needed to determine whether the identification of extreme risk warrants consideration of alternate treatment options to address the cause of severe acidosis before ascending aortic procedures. Copyright © 2017 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.

The number of microvascular complications is associated with an increased risk for severity of periodontitis in type 2 diabetes patients: Results of a multicenter hospital-based cross-sectional study.

PubMed

Nitta, Hiroshi; Katagiri, Sayaka; Nagasawa, Toshiyuki; Izumi, Yuichi; Ishikawa, Isao; Izumiyama, Hajime; Uchimura, Isao; Kanazawa, Masao; Chiba, Hiroshige; Matsuo, Akira; Utsunomiya, Kazunori; Tanabe, Haruyasu; Takei, Izumi; Asanami, Soichiro; Kajio, Hiroshi; Ono, Toaki; Hayashi, Yoichi; Ueki, Kiichi; Tsuji, Masatomi; Kurachi, Yoichi; Yamanouchi, Toshikazu; Ichinokawa, Yoshimi; Inokuchi, Toshiki; Fukui, Akiko; Miyazaki, Shigeru; Miyauchi, Takashi; Kawahara, Reiko; Ogiuchi, Hideki; Yoshioka, Narihito; Negishi, Jun; Mori, Masatomo; Mogi, Kenji; Saito, Yasushi; Tanzawa, Hideki; Nishikawa, Tetsuo; Takada, Norihiko; Nanjo, Kishio; Morita, Nobuo; Nakamura, Naoto; Kanamura, Narisato; Makino, Hirofumi; Nishimura, Fusanori; Kobayashi, Kunihisa; Higuchi, Yoshinori; Sakata, Toshiie; Yanagisawa, Shigetaka; Tei, Chuwa; Ando, Yuichi; Hanada, Nobuhiro; Inoue, Shuji

2017-09-01

To explore the relationships between periodontitis and microvascular complications as well as glycemic control in type 2 diabetes patients. This multicenter, hospital-based, cross-sectional study included 620 patients with type 2 diabetes. We compared the prevalence and severity of periodontitis between patients with ≥1 microvascular complication and those without microvascular complications. We also compared the prevalence and severity of periodontitis among patients with different degrees of glycemic control. After adjusting for confounding factors, multiple logistic regression analysis showed that the severity of periodontitis was significantly associated with the number of microvascular complications (odds ratio 1.3, 95% confidence interval 1.1-1.6), glycated hemoglobin ≥8.0% (64 mmol/mol; odds ratio 1.6; 95% confidence interval 1.1-2.3), and older age (≥50 years; odds ratio 1.7; 95% confidence interval 1.1-2.6). However, the prevalence of periodontitis was not significantly associated with the number of microvascular complications, but was associated with male sex, high glycated hemoglobin (≥8.0% [64 mmol/mol]), older age (≥40 years), longer duration of diabetes (≥15 years) and fewer teeth (≤25). Furthermore, propensity score matching for age, sex, diabetes duration and glycated hemoglobin showed that the incidence of severe periodontitis was significantly higher among patients with microvascular complications than among those without microvascular complications (P < 0.05). The number of microvascular complications is a risk factor for more severe periodontitis in patients with type 2 diabetes, whereas poor glycemic control is a risk factor for increased prevalence and severity of periodontitis. © 2017 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.

Twelve-Month Clinical and Quality-of-Life Outcomes in the Interventional Management of Stroke III Trial.

PubMed

Palesch, Yuko Y; Yeatts, Sharon D; Tomsick, Thomas A; Foster, Lydia D; Demchuk, Andrew M; Khatri, Pooja; Hill, Michael D; Jauch, Edward C; Jovin, Tudor G; Yan, Bernard; von Kummer, Rüdiger; Molina, Carlos A; Goyal, Mayank; Schonewille, Wouter J; Mazighi, Mikael; Engelter, Stefan T; Anderson, Craig; Spilker, Judith; Carrozzella, Janice; Ryckborst, Karla J; Janis, L Scott; Simpson, Annie; Simpson, Kit N; Broderick, Joseph P

2015-05-01

Randomized trials have indicated a benefit for endovascular therapy in appropriately selected stroke patients at 3 months, but data regarding outcomes at 12 months are currently lacking. We compared functional and quality-of-life outcomes at 12 months overall and by stroke severity in stroke patients treated with intravenous tissue-type plasminogen activator followed by endovascular treatment as compared with intravenous tissue-type plasminogen activator alone in the Interventional Management of Stroke III Trial. The key outcome measures were a modified Rankin Scale score ≤2 (functional independence) and the Euro-QoL EQ-5D, a health-related quality-of-life measure. 656 subjects with moderate-to-severe stroke (National Institutes of Health Stroke Scale ≥8) were enrolled at 58 centers in the United States (41 sites), Canada (7), Australia (4), and Europe (6). There was an interaction between treatment group and stroke severity in the repeated measures analysis of modified Rankin Scale ≤2 outcome (P=0.039). In the 204 participants with severe stroke (National Institutes of Health Stroke Scale ≥20), a greater proportion of the endovascular group had a modified Rankin Scale ≤2 (32.5%) at 12 months as compared with the intravenous tissue-type plasminogen activator group (18.6%, P=0.037); no difference was seen for the 452 participants with moderately severe strokes (55.6% versus 57.7%). In participants with severe stroke, the endovascular group had 35.2 (95% confidence interval: 2.1, 73.3) more quality-adjusted-days over 12 months as compared with intravenous tissue-type plasminogen activator alone. Endovascular therapy improves functional outcome and health-related quality-of-life at 12 months after severe ischemic stroke. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00359424. © 2015 American Heart Association, Inc.

Validation of WINROP for detecting retinopathy of prematurity in a North American cohort of preterm infants.

PubMed

Jung, Jennifer L; Wagner, Brandie D; McCourt, Emily A; Palestine, Alan G; Cerda, Ashlee; Cao, Jennifer H; Enzenauer, Robert W; Singh, Jasleen K; Braverman, Rebecca S; Wymore, Erica; Lynch, Anne M

2017-06-01

WINROP (weight, insulin-like growth factor 1, neonatal, retinopathy of prematurity) is a web-based retinopathy of prematurity (ROP) risk algorithm that uses postnatal weight gain as a surrogate of insulin-like growth factor-1 (IGF-1) to predict the risk of severe ROP in premature infants. The purpose of this study was to validate the web-based algorithm WINROP in detecting severe (type 1 or type 2) ROP in a North American cohort of infants. The records of consecutive infants who underwent ROP examinations between 2008 and 2011 were reviewed retrospectively. Infants were classified into categories of "alarm" (at risk for developing severe ROP) and "no alarm" (minimal risk for severe ROP). A total of 483 were included. Alarm occurred in 241 neonates (50%), with the median time from birth to alarm of 2 weeks. WINROP had a sensitivity of 81.8% (95% CI, 67.3%-91.8%) and specificity of 53.3% (95% CI, 48.5%-58.0%) for identifying infants with severe ROP. Eight of the 44 infants with severe ROP were not detected (5 with type 1 and 3 with type 2). Of these 8 infants, 7 (88%) had birth weight in excess of the 70 th pecentile. With additional weight data entry, sensitivity of WINROP rose to 88.6%. Very preterm infants (gestational age of ≤27 weeks) with relatively high birth weight for gestational age may not be detected by WINROP as high risk for developing severe ROP. Copyright © 2017 American Association for Pediatric Ophthalmology and Strabismus. Published by Elsevier Inc. All rights reserved.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Johnson, C.; Burnett, M.; Goodman, C.

A survey of currency flaw severity was carried out using 300 banknotes and 37 judges. Each judge assigned each note to one of five flaw severity categories. These categories correspond to severity grades of 1 to 5 with 1 equivalent to ''always accepted'' and 5 ''never accepted.'' An average flaw severity grade for each note was obtained by taking the mean of the severity grades assigned to that note by the 37 judges. Thus, each note has a single numerical real-number flaw grade between 1 and 5. Mathematical modeling of the currency flaw survey results is continuing with some verymore » promising initial results. Our present model handles common excess ink and missing ink flaw types quite well. We plan to extend the model to ink level, mash, setoff and blanket impression flaw types.« less

Seasonal variations of severe hypoglycemia in patients with type 1 diabetes mellitus, type 2 diabetes mellitus, and non-diabetes mellitus: clinical analysis of 578 hypoglycemia cases.

PubMed

Tsujimoto, Tetsuro; Yamamoto-Honda, Ritsuko; Kajio, Hiroshi; Kishimoto, Miyako; Noto, Hiroshi; Hachiya, Remi; Kimura, Akio; Kakei, Masafumi; Noda, Mitsuhiko

2014-11-01

Blood glucose control in patients with diabetes mellitus (DM) is reportedly influenced by the seasons, with hemoglobin A1c (HbA1c) levels decreasing in the summer or warm season and increasing in the winter or cold season. In addition, several studies have shown that sepsis is also associated with the seasons. Although both blood glucose control and sepsis can strongly affect the occurrence of severe hypoglycemia, few studies have examined the seasonal variation of severe hypoglycemia. The aim of the present study is to examine the association between severe hypoglycemia and the seasons in patients with type 1 diabetes mellitus (T1DM), type 2 diabetes mellitus (T2DM), and non-diabetes mellitus (non-DM). We retrospectively reviewed all the patients with severe hypoglycemia at a national center in Japan between April 1, 2006 and March 31, 2012. A total of 57,132 consecutive cases that had visited the emergency room by ambulance were screened, and 578 eligible cases of severe hypoglycemia were enrolled in this study. The primary outcome was to assess the seasonality of severe hypoglycemia. In the T1DM group (n  =  88), severe hypoglycemia occurred significantly more often in the summer than in the winter (35.2% in summer vs 18.2% in winter, P  =  0.01), and the HbA1c levels were highest in the winter and lowest in the summer (9.1% [7.6%-10.1%] in winter vs 7.7% [7.1%-8.3%] in summer, P  =  0.13). In the non-DM group (n  =  173), severe hypoglycemia occurred significantly more often in the winter than in the summer (30.6% in winter vs 19.6% in summer, P  =  0.01), and sepsis as a complication occurred significantly more often in winter than in summer (24.5% in winter vs 5.9% in summer, P  =  0.02). In the T2DM group (n  =  317), the occurrence of severe hypoglycemia and the HbA1c levels did not differ significantly among the seasons. The occurrence of severe hypoglycemia might be seasonal and might fluctuate with temperature changes. Patients should be treated more carefully during the season in which severe hypoglycemia is more common.

Severe Weather

ERIC Educational Resources Information Center

Forde, Evan B.

2004-01-01

Educating the public about safety issues related to severe weather is part of the National Oceanic and Atmospheric Administration's (NOAA) mission. This month's insert, Severe Weather, has been created by NOAA to help educate the public about hazardous weather conditions. The four types of severe weather highlighted in this poster are hurricanes,…

Severe Weather

ERIC Educational Resources Information Center

Forde, Evan B.

2004-01-01

Educating the public about safety issues related to severe weather is part of the National Oceanic and Atmospheric Administration's (NOAA) mission. This article deals with a poster entitled, "Severe Weather," that has been created by NOAA to help educate the public about hazardous weather conditions. The four types of severe weather highlighted in…

Predicting The Type Of Pregnancy Using Flexible Discriminate Analysis And Artificial Neural Networks: A Comparison Study

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hooman, A.; Mohammadzadeh, M

Some medical and epidemiological surveys have been designed to predict a nominal response variable with several levels. With regard to the type of pregnancy there are four possible states: wanted, unwanted by wife, unwanted by husband and unwanted by couple. In this paper, we have predicted the type of pregnancy, as well as the factors influencing it using three different models and comparing them. Regarding the type of pregnancy with several levels, we developed a multinomial logistic regression, a neural network and a flexible discrimination based on the data and compared their results using tow statistical indices: Surface under curvemore » (ROC) and kappa coefficient. Based on these tow indices, flexible discrimination proved to be a better fit for prediction on data in comparison to other methods. When the relations among variables are complex, one can use flexible discrimination instead of multinomial logistic regression and neural network to predict the nominal response variables with several levels in order to gain more accurate predictions.« less

Hayabusa2 Sampler: Collection of Asteroidal Surface Material

NASA Astrophysics Data System (ADS)

Sawada, Hirotaka; Okazaki, Ryuji; Tachibana, Shogo; Sakamoto, Kanako; Takano, Yoshinori; Okamoto, Chisato; Yano, Hajime; Miura, Yayoi; Abe, Masanao; Hasegawa, Sunao; Noguchi, Takaaki

2017-07-01

Japan Aerospace Exploration Agency (JAXA) launched the asteroid exploration probe "Hayabusa2" in December 3rd, 2014, following the 1st Hayabusa mission. With technological and scientific improvements from the Hayabusa probe, we plan to visit the C-type asteroid 162137 Ryugu (1999 JU3), and to sample surface materials of the C-type asteroid that is likely to be different from the S-type asteroid Itokawa and contain more pristine materials, including organic matter and/or hydrated minerals, than S-type asteroids. We developed the Hayabusa2 sampler to collect a minimum of 100 mg of surface samples including several mm-sized particles at three surface locations without any severe terrestrial contamination. The basic configuration of the sampler design is mainly as same as the 1st Hayabusa (Yano et al. in Science, 312(5778):1350-1353, 2006), with several minor but important modifications based on lessons learned from the Hayabusa to fulfill the scientific requirements and to raise the scientific value of the returned samples.

[Severe depression : psychoanalysis].

PubMed

Bouvet de la Maisonneuve, O

2009-12-01

The indication for psychoanalysis in severe depression is not clear. And yet, demands for this type of intervention are increasing, despite the absence of any form of consensus on the subject. Freud considered depression as a failure of analytical efforts and, based on this observation, revised his theory, in particular to include the notions of narcissism and the death drive. Many analysts have been reluctant to follow his teachings on this last point and provide depressed patients with analytical-type therapies aimed at restoring narcissism. Melanie Klein pushed Freud's ideas about depression even further and brought such therapies back to the heart of analytical practice. Jacques Lacan took the debate to another level by proposing an overhaul of the principles on which analysis has been based. Today, while following certain precautionary rules, true psychoanalyses can be proposed to patients with severe depression, whether of the bipolar, recurring or even neurotic type that can reach this level of severity. Copyright 2009 L'Encéphale. Published by Elsevier Masson SAS.. All rights reserved.

Lipoprotein lipase gene-deficient mice with hypertriglyceridaemia associated with acute pancreatitis.

PubMed

Tang, Maochun; Zong, Pengfei; Zhang, Ting; Wang, Dongyan; Wang, Yuhui; Zhao, Yan

2016-10-01

To investigate the severity of pancreatitis in lipoprotein lipase (LPL)-deficient hypertriglyceridaemic (HTG) heterozygous mice and to establish an experimental animal model for HTG pancreatitis study. LPL-deficient HTG heterozygous mice were rescued by somatic gene transfer and mated with wild-type mice. The plasma amylase, triglyceride, and pathologic changes in the pancreas of the LPL-deficient HTG heterozygous mice were compared with those of wild-type mice to assess the severity of pancreatitis. In addition, acute pancreatitis (AP) was induced by caerulein (50 µg/kg) for further assessment. The levels of plasma amylase and triglyceride were significantly higher in the LPL-deficient HTG heterozygous mice. According to the pancreatic histopathologic scores, the LPL-deficient HTG heterozygous mice showed more severe pathologic damage than the wild-type mice. Lipoprotein lipase deficient heterozygous mice developed severe caerulein-induced pancreatitis. In addition, their high triglyceride levels were stable. Therefore, LPL-deficient HTG heterozygous mice are a useful experimental model for studying HTG pancreatitis.

Gene mapping of the Usher syndromes.

PubMed

Kimberling, W; Smith, R J

1992-10-01

USH is an autosomal recessive group of diseases characterized by auditory impairment and visual loss owing to RP. Two common types of USH are known, types I and II. USH type I is characterized by a congenital severe to profound hearing impairment, absent vestibular function, and a progressive pigmentary retinopathy. Persons with type I do not find hearing aids useful, have delayed motor development, and experience progressive night blindness and peripheral visual loss, which usually begins in their second decade. USH type II is characterized by a congenital moderate to severe hearing loss with a down-sloping audiogram, normal vestibular function, and a progressive pigmentary retinopathy. Persons with USH2 find hearing aids beneficial, have normal psychomotor development, and experience progressive night blindness and peripheral visual loss, which usually begins in their third decade. Vestibular dysfunction is the best distinguishing hallmark to differentiate USH type I from type II. One USH type II gene (called USH2) has been assigned to chromosome 1q. One USH type I gene has been tentatively assigned to chromosome 14q. There are other USH genes that have not yet been localized.

Dynamic apical surface rings in superficial layer cells of koi Cyprinus carpio scale epidermis.

PubMed

DePasquale, J A

2016-09-01

This study examined the novel ring-shaped structures found in the apical surface of individual cells of the scale epidermis of koi Cyprinus carpio. These apical rings are highly dynamic structures with lifetimes ranging from a few to several minutes. While several ring forms were observed, the predominant ring morphology is circular or oval. Two distinct ring forms were identified and designated type I and type II. Type I rings have a well-defined outer border that encircles the surface microridges. Type II rings are smooth-surfaced, dinner-plate-like structures with membranous folds or compressed microridges in the centre. Type II rings appear less frequently than type I rings. Type I rings form spontaneously, arising from swollen or physically interrupted microridges but without initially perturbing the encircled microridges. After persisting for up to several minutes the ring closes in a centripetal movement to form a circular or irregular-shaped structure, the terminal disc. The terminal disc eventually disappears, leaving behind a submembranous vesicle-like structure, the terminal body. Type I rings can undergo multiple cycles of formation and closing. Recycling epidermal apical rings form through centrifugal expansion from the terminal disc followed by apparent contraction back to the disc structure, whereupon the cycle may repeat or cease. The findings demonstrate a novel skin surface structure in fishes and are discussed with respect to communication with the external aqueous environment. © 2016 The Fisheries Society of the British Isles.

The effect of exercise on skeletal muscle fibre type distribution in obesity: From cellular levels to clinical application.

PubMed

Pattanakuhar, Sintip; Pongchaidecha, Anchalee; Chattipakorn, Nipon; Chattipakorn, Siriporn C

Skeletal muscles play important roles in metabolism, energy expenditure, physical strength, and locomotive activity. Skeletal muscle fibre types in the body are heterogeneous. They can be classified as oxidative types and glycolytic types with oxidative-type are fatigue-resistant and use oxidative metabolism, while fibres with glycolytic-type are fatigue-sensitive and prefer glycolytic metabolism. Several studies demonstrated that an obese condition with abnormal metabolic parameters has been negatively correlated with the distribution of oxidative-type skeletal muscle fibres, but positively associated with that of glycolytic-type muscle fibres. However, some studies demonstrated otherwise. In addition, several studies demonstrated that an exercise training programme caused the redistribution of oxidative-type skeletal muscle fibres in obesity. In contrast, some studies showed inconsistent findings. Therefore, the present review comprehensively summarizes and discusses those consistent and inconsistent findings from clinical studies, regarding the association among the distribution of skeletal muscle fibre types, obese condition, and exercise training programmes. Furthermore, the possible underlying mechanisms and clinical application of the alterations in muscle fibre type following obesity are presented and discussed. Copyright © 2016 Asia Oceania Association for the Study of Obesity. Published by Elsevier Ltd. All rights reserved.

Child and Adult Pedestrian Impact: The Influence of Vehicle Type on Injury Severity

PubMed Central

Henary, Basem Y.; Crandall, Jeff; Bhalla, Kavi; Mock, Charles N.; Roudsari, Bahman S.

2003-01-01

In the United States, the vehicle fleet is shifting from predominantly passenger cars (automobiles) to SUVs, light trucks, and vans (LTV). This study investigates how pedestrian severe injury and mortality are associated with vehicle type and pedestrian age. The Pedestrian Crash Data Study (PCDS) database for years 1994–1998 was used for a cross-sectional study design. Outcome measures were Injury Severity Score, Maximum Abbreviated Injury Score, Abbreviated Injury Scale, Pedestrian Mortality, Functional Capacity Index and Life Years Lost to Injury. Compared to children, adult pedestrians were more likely to sustain severe injury (OR = 2.81; 95% CI: 1.56–5.06) or mortality (OR = 2.91; 95% CI: 1.10–7.74) when examining all vehicle types. However, after adjusting for vehicle type and impact speed, this association was not statistically significant at p < 0.05. Compared to passenger cars, pedestrians struck by LTV were more likely to have severe injuries (OR = 1.31; 95% CI: 0.88–1.94) or mortality (OR = 1.40; 95% CI: 0.84–2.34) for all pedestrians. Adjusting for pedestrian age, this association was more obvious and significant at lower impact speeds (≤ 30 km/h); odds ratios of severe injury and mortality were 3.34 (p< 0.01) and 1.87 (p= 0.07), respectively. Adults hit by LTV had the highest risk of injury and mortality. These findings indicate that pedestrian age, vehicle engineering design and impact speed are highly contributing to risks of pedestrian injury and mortality. PMID:12941221

Genomic Loads and Genotypes of Respiratory Syncytial Virus: Viral Factors during Lower Respiratory Tract Infection in Chilean Hospitalized Infants

PubMed Central

Espinosa, Yazmín; San Martín, Camila; Torres, Alejandro A.; Farfán, Mauricio J.; Torres, Juan P.; Avadhanula, Vasanthi; Piedra, Pedro A.; Tapia, Lorena I.

2017-01-01

The clinical impact of viral factors (types and viral loads) during respiratory syncytial virus (RSV) infection is still controversial, especially regarding newly described genotypes. In this study, infants with RSV bronchiolitis were recruited to describe the association of these viral factors with severity of infection. RSV antigenic types, genotypes, and viral loads were determined from hospitalized patients at Hospital Roberto del Río, Santiago, Chile. Cases were characterized by demographic and clinical information, including days of lower respiratory symptoms and severity. A total of 86 patients were included: 49 moderate and 37 severe cases. During 2013, RSV-A was dominant (86%). RSV-B predominated in 2014 (92%). Phylogenetic analyses revealed circulation of GA2, Buenos Aires (BA), and Ontario (ON) genotypes. No association was observed between severity of infection and RSV group (p = 0.69) or genotype (p = 0.87). After a clinical categorization of duration of illness, higher RSV genomic loads were detected in infants evaluated earlier in their disease (p < 0.001) and also in infants evaluated later, but coursing a more severe infection (p = 0.04). Although types and genotypes did not associate with severity in our children, higher RSV genomic loads and delayed viral clearance in severe patients define a group that might benefit from new antiviral therapies. PMID:28335547

PTSD's factor structure and measurement invariance across subgroups with differing count of trauma types.

PubMed

Contractor, Ateka A; Caldas, Stephanie V; Dolan, Megan; Lagdon, Susan; Armour, Chérie

2018-06-01

To investigate the effect of the count of traumatizing event (TE) types on post-trauma mental health, several studies have compared posttraumatic stress disorder (PTSD) severity between individuals experiencing one versus multiple TE types. However, the validity of these studies depends on the establishment of measurement invariance of the construct(s) of interest. The current study examined the stability of the most optimal PTSD Model symptom cluster constructs (assessed by the PTSD Checklist for DSM-5 [PCL-5]) across subgroups experiencing one versus multiple TE types. The sample included university students (n = 556) endorsing at least one TE (Stressful Life Events Screening Questionnaire). Using data from the entire sample, results suggest that the PCL-5-assessed Hybrid Model provided a significantly better fit compared to other models. Results also indicated invariance of factor loadings (metric), and intercepts (scalar) for the PCL-5-assessed Hybrid Model factors across subgroups endorsing one (n = 191) versus multiple TE types (n = 365). Our findings thus support the stability, applicability, and meaningful comparison of the PCL-assessed Hybrid Model factor structure (including subscale severity scores) across subgroups experiencing one versus multiple TE types. Copyright © 2018 Elsevier B.V. All rights reserved.

Identification of airway mucosal type 2 inflammation by using clinical biomarkers in asthmatic patients.

PubMed

Silkoff, Philip E; Laviolette, Michel; Singh, Dave; FitzGerald, J Mark; Kelsen, Steven; Backer, Vibeke; Porsbjerg, Celeste M; Girodet, Pierre-Olivier; Berger, Patrick; Kline, Joel N; Chupp, Geoffrey; Susulic, Vedrana S; Barnathan, Elliot S; Baribaud, Frédéric; Loza, Matthew J

2017-09-01

The Airways Disease Endotyping for Personalized Therapeutics (ADEPT) study profiled patients with mild, moderate, and severe asthma and nonatopic healthy control subjects. We explored this data set to define type 2 inflammation based on airway mucosal IL-13-driven gene expression and how this related to clinically accessible biomarkers. IL-13-driven gene expression was evaluated in several human cell lines. We then defined type 2 status in 25 healthy subjects, 28 patients with mild asthma, 29 patients with moderate asthma, and 26 patients with severe asthma based on airway mucosal expression of (1) CCL26 (the most differentially expressed gene), (2) periostin, or (3) a multigene IL-13 in vitro signature (IVS). Clinically accessible biomarkers included fraction of exhaled nitric oxide (Feno) values, blood eosinophil (bEOS) counts, serum CCL26 expression, and serum CCL17 expression. Expression of airway mucosal CCL26, periostin, and IL-13-IVS all facilitated segregation of subjects into type 2-high and type 2-low asthmatic groups, but in the ADEPT study population CCL26 expression was optimal. All subjects with high airway mucosal CCL26 expression and moderate-to-severe asthma had Feno values (≥35 ppb) and/or high bEOS counts (≥300 cells/mm 3 ) compared with a minority (36%) of subjects with low airway mucosal CCL26 expression. A combination of Feno values, bEOS counts, and serum CCL17 and CCL26 expression had 100% positive predictive value and 87% negative predictive value for airway mucosal CCL26-high status. Clinical variables did not differ between subjects with type 2-high and type 2-low status. Eosinophilic inflammation was associated with but not limited to airway mucosal type 2 gene expression. A panel of clinical biomarkers accurately classified type 2 status based on airway mucosal CCL26, periostin, or IL-13-IVS gene expression. Use of Feno values, bEOS counts, and serum marker levels (eg, CCL26 and CCL17) in combination might allow patient selection for novel type 2 therapeutics. Copyright © 2017 American Academy of Allergy, Asthma & Immunology. All rights reserved.

Effects of Test Level Discrimination and Difficulty on Answer-Copying Indices

ERIC Educational Resources Information Center

Sunbul, Onder; Yormaz, Seha

2018-01-01

In this study Type I Error and the power rates of omega (?) and GBT (generalized binomial test) indices were investigated for several nominal alpha levels and for 40 and 80-item test lengths with 10,000-examinee sample size under several test level restrictions. As a result, Type I error rates of both indices were found to be below the acceptable…

Severe hypoglycemia and diabetic ketoacidosis among youth with type 1 diabetes in the T1D Exchange clinic registry

USDA-ARS?s Scientific Manuscript database

Severe hypoglycemia (SH) and diabetic ketoacidosis (DKA) are common serious acute complications of type 1 diabetes (T1D). The aim of this study was to determine the frequency of SH and DKA and identify factors related to their occurrence in the T1D Exchange pediatric and young adult cohort. The anal...

Reducing fatalities and severe injuries on Florida's high-speed multi-lane arterial corridors : part I, preliminary severity analysis of driver crash involvements, final report, April 2009

DOT National Transportation Integrated Search

2009-04-28

Severe injury involvements on arterial roads account for a quarter of the total severe injuries reported statewide. Crash severity analysis was conducted and consisted of six road entity models and twenty crash type models. The data preparation and s...

Popcorn calcification in osteogenesis imperfecta: incidence, progression, and molecular correlation.

PubMed

Obafemi, Abimbola A; Bulas, Dorothy I; Troendle, James; Marini, Joan C

2008-11-01

Osteogenesis imperfecta (OI) is a heritable disorder characterized by osteoporosis and increased susceptibility to fracture. All children with severe OI have extreme short stature and some have "popcorn" calcifications, areas of disorganized hyperdense lines in the metaphysis and epiphysis around the growth plate on lower limb radiographs. Popcorn calcifications were noted on radiographs of two children with non-lethal type VIII OI, a recessive form caused by P3H1 deficiency. To determine the incidence, progression, and molecular correlations of popcorn calcifications, we retrospectively examined serial lower limb radiographs of 45 children with type III or IV OI and known dominant mutations in type I collagen. Popcorn calcifications were present in 13 of 25 type III (52%), but only 2 of 20 type IV (10%), OI children. The mean age of onset was 7.0 years, with a range of 4-14 years. All children with popcorn calcifications had this finding in their distal femora, and most also had calcifications in proximal tibiae. While unilateral popcorn calcification contributes to femoral growth deficiency and leg length discrepancy, severe linear growth deficiency, and metaphyseal flare do not differ significantly between type III OI patients with and without popcorn calcifications. The type I collagen mutations associated with popcorn calcifications occur equally in both COL1A1 and COL1A2, and have no preferential location along the chains. These data demonstrate that popcorn calcifications are a frequent feature of severe OI, but do not distinguish cases with defects in collagen structure (primarily dominant type III OI) or modification (recessive type VIII OI). Copyright 2008 Wiley-Liss, Inc.

Spotter's Guide for Identifying and Reporting Severe Local Storms.

ERIC Educational Resources Information Center

National Oceanic and Atmospheric Administration (DOC), Rockville, MD.

This guide is designed to assist personnel working in the National Weather Service's Severe Local Storm Spotter Networks in identifying and reporting severe local storms. Provided are pictures of cloud types for severe storms including tornadoes, hail, thunder, lightning, heavy rains, and waterspouts. Instructions for key indications to watch for…

A Study on the Correlation of Pertrochanteric Osteoporotic Fracture Severity with the Severity of Osteoporosis.

PubMed

Hayer, Prabhnoor Singh; Deane, Anit Kumar Samuel; Agrawal, Atul; Maheshwari, Rajesh; Juyal, Anil

2016-04-01

Osteoporosis is a metabolic bone disease caused by progressive bone loss. It is characterized by low Bone Mineral Density (BMD) and structural deterioration of bone tissue leading to bone fragility and increased risk of fractures. When classifying a fracture, high reliability and validity are crucial for successful treatment. Furthermore, a classification system should include severity, method of treatment, and prognosis for any given fracture. Since it is known that treatment significantly influences prognosis, a classification system claiming to include both would be desirable. Since there is no such classification system, which includes both the fracture type and the osteoporosis severity, we tried to find a correlation between fracture severity and osteoporosis severity. The aim of the study was to evaluate whether the AO/ASIF fracture classification system, which indicates the severity of fractures, has any relationship with the bone mineral status in patients with primary osteoporosis. We hypothesized that fracture severity and severity of osteoporosis should show some correlation. An observational analytical study was conducted over a period of one year during which 49 patients were included in the study at HIMS, SRH University, Dehradun. The osteoporosis status of all the included patients with a pertrochanteric fracture was documented using a DEXA scan and T-Score (BMD) was calculated. All patients had a trivial trauma. All the fractures were classified as per AO/ASIF classification. Pearson Correlation between BMD and fracture type was calculated. Data was entered on Microsoft Office Excel version 2007 and Interpretation and analysis of obtained data was done using summary statistics. Pearson Correlation between BMD and fracture type was calculated using the SPSS software version 22.0. The average age of the patients included in the study was 71.2 years and the average bone mineral density was -4.9. The correlation between BMD and fracture type was calculated and the r-values obtained was 0.180, which showed low a correlation and p-value was 0.215, which was insignificant. Statistically the pertrochanteric fracture configuration as per AO Classification does not correlate with the osteoporosis severity of the patient.

Landscape-scale effects of fire severity on mixed-conifer and red fir forest structure in Yosemite National Park

USGS Publications Warehouse

Kane, Van R.; Lutz, James A.; Roberts, Susan L.; Smith, Douglas F.; McGaughey, Robert J.; Povak, Nicholas A.; Brooks, Matthew L.

2013-01-01

While fire shapes the structure of forests and acts as a keystone process, the details of how fire modifies forest structure have been difficult to evaluate because of the complexity of interactions between fires and forests. We studied this relationship across 69.2 km2 of Yosemite National Park, USA, that was subject to 32 fires ⩾40 ha between 1984 and 2010. Forests types included ponderosa pine (Pinus ponderosa), white fir-sugar pine (Abies concolor/Pinus lambertiana), and red fir (Abies magnifica). We estimated and stratified burned area by fire severity using the Landsat-derived Relativized differenced Normalized Burn Ratio (RdNBR). Airborne LiDAR data, acquired in July 2010, measured the vertical and horizontal structure of canopy material and landscape patterning of canopy patches and gaps. Increasing fire severity changed structure at the scale of fire severity patches, the arrangement of canopy patches and gaps within fire severity patches, and vertically within tree clumps. Each forest type showed an individual trajectory of structural change with increasing fire severity. As a result, the relationship between estimates of fire severity such as RdNBR and actual changes appears to vary among forest types. We found three arrangements of canopy patches and gaps associated with different fire severities: canopy-gap arrangements in which gaps were enclosed in otherwise continuous canopy (typically unburned and low fire severities); patch-gap arrangements in which tree clumps and gaps alternated and neither dominated (typically moderate fire severity); and open-patch arrangements in which trees were scattered across open areas (typically high fire severity). Compared to stands outside fire perimeters, increasing fire severity generally resulted first in loss of canopy cover in lower height strata and increased number and size of gaps, then in loss of canopy cover in higher height strata, and eventually the transition to open areas with few or no trees. However, the estimated fire severities at which these transitions occurred differed for each forest type. Our work suggests that low severity fire in red fir forests and moderate severity fire in ponderosa pine and white fir-sugar pine forests would restore vertical and horizontal canopy structures believed to have been common prior to the start of widespread fire suppression in the early 1900s. The fusion of LiDAR and Landsat data identified post-fire structural conditions that would not be identified by Landsat alone, suggesting a broad applicability of combining Landsat and LiDAR data for landscape-scale structural analysis for fire management.

Exploring the effects of roadway characteristics on the frequency and severity of head-on crashes: case studies from Malaysian federal roads.

PubMed

Hosseinpour, Mehdi; Yahaya, Ahmad Shukri; Sadullah, Ahmad Farhan

2014-01-01

Head-on crashes are among the most severe collision types and of great concern to road safety authorities. Therefore, it justifies more efforts to reduce both the frequency and severity of this collision type. To this end, it is necessary to first identify factors associating with the crash occurrence. This can be done by developing crash prediction models that relate crash outcomes to a set of contributing factors. This study intends to identify the factors affecting both the frequency and severity of head-on crashes that occurred on 448 segments of five federal roads in Malaysia. Data on road characteristics and crash history were collected on the study segments during a 4-year period between 2007 and 2010. The frequency of head-on crashes were fitted by developing and comparing seven count-data models including Poisson, standard negative binomial (NB), random-effect negative binomial, hurdle Poisson, hurdle negative binomial, zero-inflated Poisson, and zero-inflated negative binomial models. To model crash severity, a random-effect generalized ordered probit model (REGOPM) was used given a head-on crash had occurred. With respect to the crash frequency, the random-effect negative binomial (RENB) model was found to outperform the other models according to goodness of fit measures. Based on the results of the model, the variables horizontal curvature, terrain type, heavy-vehicle traffic, and access points were found to be positively related to the frequency of head-on crashes, while posted speed limit and shoulder width decreased the crash frequency. With regard to the crash severity, the results of REGOPM showed that horizontal curvature, paved shoulder width, terrain type, and side friction were associated with more severe crashes, whereas land use, access points, and presence of median reduced the probability of severe crashes. Based on the results of this study, some potential countermeasures were proposed to minimize the risk of head-on crashes. Copyright © 2013 Elsevier Ltd. All rights reserved.

'Change means sacrificing a good life': perceptions about severity of type 2 diabetes and preventive lifestyles among people afflicted or at high risk of type 2 diabetes in Iganga Uganda.

PubMed

Mayega, Roy W; Etajak, Samuel; Rutebemberwa, Elizeus; Tomson, Goran; Kiguli, Juliet

2014-08-21

Interventions for prevention of type 2 diabetes ought to be acceptable to target communities. We assessed perceptions about type 2 diabetes and lifestyle change among people afflicted or at high risk of this disease in a low income setting in Iganga Uganda. Twelve focus group discussions (FGDs) of eight participants each were conducted, balancing rural and peri-urban (near the Municipality) residence and gender. The FGDs involved people with suspected type 2 diabetes (based on fasting plasma glucose (FPG), people with suspected pre-diabetes and obese people with normal FPG. Content analysis was conducted. Diabetes was perceived to be a very severe disease. Its severity was attributed to its incurability and its numerous health effects. Men were also concerned about reduced sexual performance. However, participants' strong concerns about the severity of diabetes were not reflected in their perceptions about the risk factors and lifestyles associated with it. While people with diabetes perceive obesity as 'sickness', those without diabetes perceive it as a sign of 'success'. Although participants are willing to change their diet, they mention numerous barriers including poverty, family size, and access to some foods. Because of their good taste, reduction of high risk foods like sugar and fried food is perceived as 'sacrificing a good life'. Increments in physical activity were said to be feasible, but only in familiar forms like domestic work. An over-arching theme emerged that 'lifestyle changes are viewed as sacrificing a good life'. Health promotion should target both community norms and individual awareness regarding obesity, physical activity and diet, and should address the notion that obesity and unhealthy foods represent a good life. Health educators should plan with clients on how to overcome barriers and misconceptions to lifestyle change, leveraging the pervasive perception of type 2 diabetes as a severe disease to motivate change.

Broken and guilty since it happened: A population study of trauma-related shame and guilt after violence and sexual abuse.

PubMed

Aakvaag, Helene Flood; Thoresen, Siri; Wentzel-Larsen, Tore; Dyb, Grete; Røysamb, Espen; Olff, Miranda

2016-11-01

There is increasing interest in trauma-related shame and guilt. However, much remains unknown in terms of how these emotions relate to the type of event, gender and mental health. We investigated shame and guilt in men and women following various types of severe violence and their relation to mental health. Telephone interviews were conducted with a Norwegian general population sample (n=4529; age=18-75; response rate=42.9%). Measures included child sexual abuse, child and adult rape, severe physical violence from/between parents, severe violence from a partner and non-partners, less severe violence and non-violent trauma, the new Shame and Guilt After Trauma Scale, and the Hopkins Symptom Checklist. Analyses included t-tests and linear regressions. All types of severe violence were significantly associated with trauma-related shame and guilt (coefficients from 0.11 to 0.38, p-values <0.001). The number of violence types showed a graded relationship with both emotions. Women had significantly more shame and guilt than men did (p-values <0.001 for both emotions), which was partially explained by violence exposure. Both emotions were independently associated with mental health problems (p-values <0.001). The study is cross-sectional. The shame and guilt measure requires further validation. The more types of violence that were reported, the higher levels of shame and guilt were. Clinicians should be aware of shame and guilt after a variety of violent events, including non-sexual violence, in both men and women and should particularly be aware of whether individuals have multiple violent experiences. Copyright © 2016. Published by Elsevier B.V.

[A cross-sectional study of moderate or severe visual impairment and blindness in residents with type 2 diabetes living in Xinjing Town, Shanghai].

PubMed

Bai, X L; Xu, X; Lu, M; He, J N; Xu, X; Du, X; Zhang, B; He, X G; Lu, L N; Zhu, J F; Zou, H D; Zhao, J L

2016-11-11

Objective: To investigate the prevalence, underlying causes and risk factors of moderate or severe visual impairment and blindness in a population with type 2 diabetes in Xinjing Town, Shanghai, China. Methods: A cross-sectional survey among local Han adult residents, who were previously diagnosed as type 2 diabetes, was conducted between October 2014 and January 2015. The survey was preceded by a pilot study; operational methods were refined and quality assurance evaluation was carried out. The best corrected visual acuity was recorded and classified following the modified World Health Organization grading system. Assigned ophthalmic doctors assured the leading causes of every blind or visually impaired eye. Binary logistic regression analysis was used to determine the related factors of blindness and moderate or severe visual impairment. Results: A total of 2 216 type 2 diabetic residents were enrolled, and 166 eyes (3.7%, 166/4 432) were blind. Cataract was the leading cause of blindness (39.8%); macular degeneration (18.0%) and eyeball atrophy (11.4%) were the second and third leading causes of blindness, respectively. Moderate or severe visual impairment was found in 376 eyes (8.5%, 376/4 432), and the most frequent cause was cataract (65.7%), followed by diabetic retinopathy (9.8%) and macular degeneration (9.4% ). Older age, female gender, earlier onset diabetes and a lower spherical equivalent in the better eye were associated with best corrected visual acuity<20/63 in the better eye. Conclusion: The prevalences of moderate or severe visual impairment and blindness in our population with type 2 diabetes were high. (Chin J Ophthalmol, 2016, 52: 825-830) .

A comparison of freeway median crash frequency, severity, and barrier strike outcomes by median barrier type.

PubMed

Russo, Brendan J; Savolainen, Peter T

2018-08-01

Median-crossover crashes are among the most hazardous events that can occur on freeways, often resulting in severe or fatal injuries. The primary countermeasure to reduce the occurrence of such crashes is the installation of a median barrier. When installation of a median barrier is warranted, transportation agencies are faced with the decision among various alternatives including concrete barriers, beam guardrail, or high-tension cable barriers. Each barrier type differs in terms of its deflection characteristics upon impact, the required installation and maintenance costs, and the roadway characteristics (e.g., median width) where installation would be feasible. This study involved an investigation of barrier performance through an in-depth analysis of crash frequency and severity data from freeway segments where high-tension cable, thrie-beam, and concrete median barriers were installed. A comprehensive manual review of crash reports was conducted to identify crashes in which a vehicle left the roadway and encroached into the median. This review also involved an examination of crash outcomes when a barrier strike occurred, which included vehicle containment, penetration, or re-direction onto the travel lanes. The manual review of crash reports provided critical supplementary information through narratives and diagrams not normally available through standard fields on police crash report forms. Statistical models were estimated to identify factors that affect the frequency, severity, and outcomes of median-related crashes, with particular emphases on differences between segments with varying median barrier types. Several roadway-, traffic-, and environmental-related characteristics were found to affect these metrics, with results varying across the different barrier types. The results of this study provide transportation agencies with important guidance as to the in-service performance of various types of median barrier. Copyright © 2018 Elsevier Ltd. All rights reserved.

Hypoglycaemia, chronic kidney disease and death in type 2 diabetes: the Hong Kong diabetes registry

PubMed Central

2014-01-01

Background In patients with type 2 diabetes, chronic kidney disease (CKD) is associated with increased risk of hypoglycaemia and death. Yet, it remains uncertain whether hypoglycaemia-associated mortality is modified by CKD. Methods Type 2 diabetic patients, with or without CKD at enrolment were observed between 1995 and 2007, and followed up till 2009 at hospital medical clinics. We used additive interaction, estimated by relative excess risk due to interaction (RERI) and attributable proportion due to interaction (AP) to examine possible synergistic effects between CKD and severe hypoglycaemia (defined as hospitalisations due to hypoglycaemia in the 12 months prior to enrolment) on the risk of death. Results In this cohort of 8,767 type 2 diabetic patients [median age: 58 (interquartile range: 48 to 68) years; disease duration: 5 (1 to 11) years, men: 47.0%], 1,070 (12.2%) had died during a median follow-up period of 6.66 years (3.42-10.36) with 60,379 person-years.Upon enrolment, 209 patients had severe hypoglycaemia and 194 developed severe hypoglycaemia during follow-up (15 patients had both). In multivariable analysis and using patients without severe hypoglycaemia nor CKD as the referent group (683 deaths in 7,598 patients), severe hypoglycaemia alone (61 deaths in 272 patients) or CKD alone (267 death in 781 patients) were associated with increased risk of death [Hazard ratio, HR: 1.81(95%CI: 1.38 to 2.37) and 1.63 (1.38 to 1.93) respectively]. Having both risk factors (59 deaths in 116 patients) greatly enhanced the HR of death to 3.91 (2.93 to 5.21) with significant interaction (RERI: 1.46 and AP: 0.37, both p-values < 0.05). Conclusions Severe hypoglycaemia and CKD interact to increase risk of death in type 2 diabetes patients. PMID:24927961

An update on the genetics of usher syndrome.

PubMed

Millán, José M; Aller, Elena; Jaijo, Teresa; Blanco-Kelly, Fiona; Gimenez-Pardo, Ascensión; Ayuso, Carmen

2011-01-01

Usher syndrome (USH) is an autosomal recessive disease characterized by hearing loss, retinitis pigmentosa (RP), and, in some cases, vestibular dysfunction. It is clinically and genetically heterogeneous and is the most common cause underlying deafness and blindness of genetic origin. Clinically, USH is divided into three types. Usher type I (USH1) is the most severe form and is characterized by severe to profound congenital deafness, vestibular areflexia, and prepubertal onset of progressive RP. Type II (USH2) displays moderate to severe hearing loss, absence of vestibular dysfunction, and later onset of retinal degeneration. Type III (USH3) shows progressive postlingual hearing loss, variable onset of RP, and variable vestibular response. To date, five USH1 genes have been identified: MYO7A (USH1B), CDH23 (USH1D), PCDH15 (USH1F), USH1C(USH1C), and USH1G(USH1G). Three genes are involved in USH2, namely, USH2A (USH2A), GPR98 (USH2C), and DFNB31 (USH2D). USH3 is rare except in certain populations, and the gene responsible for this type is USH3A.

An Update on the Genetics of Usher Syndrome

PubMed Central

Millán, José M.; Aller, Elena; Jaijo, Teresa; Blanco-Kelly, Fiona; Gimenez-Pardo, Ascensión; Ayuso, Carmen

2011-01-01

Usher syndrome (USH) is an autosomal recessive disease characterized by hearing loss, retinitis pigmentosa (RP), and, in some cases, vestibular dysfunction. It is clinically and genetically heterogeneous and is the most common cause underlying deafness and blindness of genetic origin. Clinically, USH is divided into three types. Usher type I (USH1) is the most severe form and is characterized by severe to profound congenital deafness, vestibular areflexia, and prepubertal onset of progressive RP. Type II (USH2) displays moderate to severe hearing loss, absence of vestibular dysfunction, and later onset of retinal degeneration. Type III (USH3) shows progressive postlingual hearing loss, variable onset of RP, and variable vestibular response. To date, five USH1 genes have been identified: MYO7A (USH1B), CDH23 (USH1D), PCDH15 (USH1F), USH1C(USH1C), and USH1G(USH1G). Three genes are involved in USH2, namely, USH2A (USH2A), GPR98 (USH2C), and DFNB31 (USH2D). USH3 is rare except in certain populations, and the gene responsible for this type is USH3A. PMID:21234346

The prognostic value of ABO blood group in cancer patients

PubMed Central

Franchini, Massimo; Liumbruno, Giancarlo M.; Lippi, Giuseppe

2016-01-01

The antigens of the ABO system are expressed on red blood cell membranes as well as on the surface of several other normal and pathological cells and tissues. Following the first clinical observations more than 60 years ago, the role of ABO blood group in cancer biology has been intensely studied by several investigators, and it is now widely recognised that ABO antigens are associated with the risk of developing several types of tumours, namely pancreatic and gastric cancers. However, whether this association also affects the clinical outcome of cancer patients is less certain. In this narrative review, based on literature data, we discuss the role of ABO blood types as prognostic biomarkers in different types of cancers. The current knowledge of the underlying pathogenic mechanisms of the association is also analysed. PMID:26674825

Severe Clinical Course in a Patient with Congenital Amegakaryocytic Thrombocytopenia Due to a Missense Mutation of the c-MPL Gene.

PubMed

Ok Bozkaya, İkbal; Yaralı, Neşe; Işık, Pamir; Ünsal Saç, Rukiye; Tavil, Betül; Tunç, Bahattin

2015-06-01

Congenital amegakaryocytic thrombocytopenia (CAMT) generally begins at birth with severe thrombocytopenia and progresses to pancytopenia. It is caused by mutations in the thrombopoietin receptor gene, the myeloproliferative leukemia virus oncogene (c-MPL). The association between CAMT and c-MPL mutation type has been reported in the literature. Patients with CAMT have been categorized according to their clinical symptoms caused by different mutations. Missense mutations of c-MPL have been classified as type II and these patients have delayed onset of bone marrow failure compared to type I patients. Here we present a girl with severe clinical course of CAMT II having a missense mutation in exon 4 of the c-MPL gene who was admitted to our hospital with intracranial hemorrhage during the newborn period.

Fingerprints: A simple method for Screening Hemophilic Patients.

PubMed

Jamalian, M; Mesri, M; Vishteh, H R K; Solhi, H; Salehpour, R

2014-08-01

The present study aims to compare hemophilic patients' fingerprint types with the normal people to help diagnose the disease, particularly new occurrences of the disease. This case-control study was conducted in 2012. Sixty two patients with hemophilia type A and 62 normal healthy people were selected. The type of fingerprint was determined by a forensic specialist who was kept unaware of the participants' group. Using advanced Henry method, the main types of fingerprints were classified as arch, loop, whorl, as well as other types. In the control group, loop type (65%) and in the case group the whorl type (34%) were the most frequent fingerprint type (p < 0.001) and there was a significant difference of fingerprint in each finger between two groups. In addition, the average number of whorl type in the patients with mild disease was significantly higher and the average number of arch and other types of fingerprints was significantly lower than patients with moderate or severe disease. The findings of the present study indicated that not only are the fingerprints of normal and hemophilic people different, but also a difference was observed between hemophilic patients with the mild factor level and patients with moderate or severe one.

Avoiding or coping with severe hypoglycemia in patients with type 2 diabetes

PubMed Central

Yun, Jae-Seung

2015-01-01

Hypoglycemia is a major barrier to achieving the glycemic goal in patients with type 2 diabetes. In particular, severe hypoglycemia, which is defined as an event that requires the assistance of another person to actively administer carbohydrates, glucagon, or take other corrective actions, is a serious clinical concern in patients with diabetes. If severe hypoglycemia is not managed promptly, it can be life threatening. Hypoglycemia-associated autonomic failure (HAAF) is the main pathogenic mechanism behind severe hypoglycemia. Defective glucose counter-regulation (altered insulin secretion, glucagon secretion, and an attenuated increase in epinephrine during hypoglycemia) and a lack of awareness regarding hypoglycemia (attenuated sympathoadrenal activity) are common components of HAAF in patients with diabetes. There is considerable evidence that hypoglycemia is an independent risk factor for cardiovascular disease. In addition, hypoglycemia has a significant influence on the quality of life of patients with diabetes. To prevent hypoglycemic events, the setting of glycemic goals should be individualized, particularly in elderly individuals or patients with complicated or advanced type 2 diabetes. Patients at high-risk for the future development of severe hypoglycemia should be selected carefully, and intensive education with reinforcement should be implemented. PMID:25589828

Diagnosis of Morquio Syndrome in Dried Blood Spots Based on a New MRM-MS Assay.

PubMed

Cozma, Claudia; Eichler, Sabrina; Wittmann, Gyula; Flores Bonet, Alba; Kramp, Guido Johannes; Giese, Anne-Katrin; Rolfs, Arndt

2015-01-01

Mucopolysaccharidosis IVA (MPS IVA; Morquio A disease) is an autosomal recessive disease caused and characterized by a decreased activity of N-acetylgalactosamine-6-sulfate sulfatase (GALNS), resulting in accumulation of keratan sulfate and chondroitin-6-sulfate in tissues and secondary organ damage. Recently approved enzyme replacement therapy renders the easy and early identification of MPS IVA of out-most importance. We propose a completely new assay for the stable and reproducible detection of GALNS deficiency in dry blood spots (DBS). For the validation blood samples were taken from 59 healthy individuals and 24 randomly selected genetically confirmed MPS IVA patients. The material extracted from DBS was incubated with a 4-methylumbelliferyl-β-D-galactopyranoside-6-sulfate as a specific substrate. Final enzymatic product, 4-methylumbelliferone, obtained after adding exogenous beta-galactosidase, was quantified by LC/MRM-MS (liquid-chromatography/multiple-reaction-monitoring mass-spectrometry). 4-propyl-5-hydroxy-7-methyl-2h-chromen-2-one was used as internal standard, a compound with a similar molecular structure and fragmentation pattern in negative ion mode as 4-methylumbelliferone. The enzymatic assay yielded a positive and negative predictive value of 1.0 for genetically confirmed MPS IVA patients (GALNS activity of 0.35 ± 0.21 μmol/L/h) and for controls with normal GALNS activity (23.1 ± 5.3 μmol/L /h). With present enzymatic conditions, the reaction yield in dried blood spots is at least 20 fold higher than any previously reported data with other assays. The present LC/MRM-MS based assay for MPS IVA diagnosis provides an easy, highly-standardized, accurate and innovative quantification of the enzymatic product in vitro and distinguishes perfectly between MPS IVA affected patients and normal controls. This technique will significantly simplify the early detection of MPS IVA patients.

A biochemical and physicochemical comparison of two recombinant enzymes used for enzyme replacement therapies of hunter syndrome.

PubMed

Chung, Yo Kyung; Sohn, Young Bae; Sohn, Jong Mun; Lee, Jieun; Chang, Mi Sun; Kwun, Younghee; Kim, Chi Hwa; Lee, Jin Young; Yook, Yeon Joo; Ko, Ah-Ra; Jin, Dong-Kyu

2014-05-01

Mucopolysaccharidosis II (MPS II, Hunter syndrome; OMIM 309900) is an X-linked lysosomal storage disease caused by a deficiency in the enzyme iduronate-2-sulfatase (IDS), leading to accumulation of glycosaminoglycans (GAGs). For enzyme replacement therapy (ERT) of Hunter syndrome, two recombinant enzymes, idursulfase (Elaprase(®), Shire Human Genetic Therapies, Lexington, MA) and idursulfase beta (Hunterase(®), Green Cross Corporation, Yongin, Korea), are currently available in Korea. To compare the biochemical and physicochemical differences between idursulfase and idursulfase beta, we examined the formylglycine (FGly) content, specific enzyme activity, mannose-6-phosphate (M6P) content, sialic acid content, and in vitro cell uptake activity of normal human fibroblasts of these two enzymes.The FGly content, which determines the enzyme activity, of idursulfase beta was significantly higher than that of idursulfase (79.4 ± 0.9 vs. 68.1 ± 2.2 %, P < 0.001). In accordance with the FGly content, the specific enzyme activity of idursulfase beta was significantly higher than that of idursulfase (42.6 ± 1.1 vs. 27.8 ± 0.9 nmol/min/μg protein, P < 0.001). The levels of M6P and sialic acid were not significantly different (2.4 ± 0.1 vs 2.4 ± 0.3 mol/mol protein for M6P and 12.3 ± 0.7 vs. 12.4 ± 0.4 mol/mol protein for sialic acid). However, the cellular uptake activity of the normal human fibroblasts in vitro showed a significant difference (Kuptake, 5.09 ± 0.96 vs. 6.50 ± 1.28 nM protein, P = 0.017).In conclusion, idursulfase beta exhibited significantly higher specific enzyme activity than idursulfase, resulting from higher FGly content. These biochemical differences may be partly attributed to clinical efficacy. However, long-term clinical evaluations of Hunter syndrome patients treated with these two enzymes will be needed to demonstrate the clinical implications of significant difference of the enzyme activity and the FGly content.

Aircraft measurements and analysis of severe storms: 1976 field experiment

NASA Technical Reports Server (NTRS)

Sinclair, P. C.

1982-01-01

Severe storm aircraft measurements are documented, as well as the instrumentation and operational features of aircraft mobility capabilities. The measurements and data analyses indicate that the concept of a highly mobile research aircraft capability for obtaining detailed measurements of wind, temperature, moisture, spherics, etc., near and within severe storm systems, forecast 48 hours in advance in a 1000 nm operating radius, is feasible, and was successfully demonstrated. The measurements and analyses reveal several severe storm features and insights with respect to storm air flow circulations and inflow-outflow orientation. Precipitation downdraft air is recirculated back into the updraft core below the scud cloud in both back and front feeder type storms. In a back feeder type storm, the downdraft outflow air ahead of the storm is also recirculated back into the updraft region near cloud base.

Types of Data Systems

ERIC Educational Resources Information Center

Gould, Tate; Nicholas, Amy; Ruggiero, Tony; Blandford, William; Thayer, Sara; Bull, Bruce

2015-01-01

There are several types of data systems that support data from Part C/619 programs. Although the system types have similarities, each has its own unique characteristics and purposes. The attributes that make one type of data system a particularly good fit for one data-related need or function can be less desirable for another need or function. In…

Error-Free Text Typing Performance of an Inductive Intra-Oral Tongue Computer Interface for Severely Disabled Individuals.

PubMed

Andreasen Struijk, Lotte N S; Bentsen, Bo; Gaihede, Michael; Lontis, Eugen R

2017-11-01

For severely paralyzed individuals, alternative computer interfaces are becoming increasingly essential for everyday life as social and vocational activities are facilitated by information technology and as the environment becomes more automatic and remotely controllable. Tongue computer interfaces have proven to be desirable by the users partly due to their high degree of aesthetic acceptability, but so far the mature systems have shown a relatively low error-free text typing efficiency. This paper evaluated the intra-oral inductive tongue computer interface (ITCI) in its intended use: Error-free text typing in a generally available text editing system, Word. Individuals with tetraplegia and able bodied individuals used the ITCI for typing using a MATLAB interface and for Word typing for 4 to 5 experimental days, and the results showed an average error-free text typing rate in Word of 11.6 correct characters/min across all participants and of 15.5 correct characters/min for participants familiar with tongue piercings. Improvements in typing rates between the sessions suggest that typing ratescan be improved further through long-term use of the ITCI.

The ecology of mixed severity fire regimes in Washington, Oregon, and Northern California

Treesearch

David Perry; Paul Hessburg; Carl Skinner; Thomas Spies; Scott Stephens; Alan Henry Taylor; Jerry Franklin; Brenda McComb; Greg Riegel

2011-01-01

Forests characterized by mixed-severity fires occupy a broad moisture gradient between lower elevation forests typified by low-severity fires and higher elevation forests in which high-severity, stand replacing fires are the norm. Mixed-severity forest types are poorly documented and little understood but likely occupy significant areas in the western United States. By...

Proteomic Approach for Diagnostic Applications in Head and Neck Cancer — EDRN Public Portal

Cancer.gov

To evaluate the test characteristics of a panel of biomarkers for identifying patients with early stage head and neck squamous cell carcinoma (HNSCC). The primary endpoints are sensitivity, specificity and accuracy of the marker panel. This study of the test characteristics of a modeling strategy for diagnosing HNSCC uses a case-control design, with several types of cases and several types of controls.

Space vehicle concepts

NASA Technical Reports Server (NTRS)

Tucker, Michael; Meredith, Oliver; Brothers, Bobby

1986-01-01

Several concepts of chemical-propulsion Space Vehicles (SVs) for manned Mars landing missions are presented. For vehicle sizing purposes, several specific missions were chosen from opportunities in the late 1990's and early 2000's, and a vehicle system concept is then described which is applicable to the full range of missions and opportunities available. In general, missions utilizing planetary opposition alignments can be done with smaller vehicles than those utilizing planetary opposition alignments. The conjunction missions have a total mission time of about 3 years, including a required stay-time of about 60 days. Both types of missions might be desirable during a Mars program, the opposition type for early low-risk missions and/or for later unmanned cargo missions, and the conjunction type for more extensive science/exploration missions and/or for Mars base activities. Since the opposition missions appeared to drive the SV size more severely, there were probably more cases examined for them. Some of the concepts presented utilize all-propulsive braking, some utilize and all aerobraking approach, and some are hybrids. Weight statements are provided for various cases. Most of the work was done on 0-g vehicle concepts, but partial-g and 1-g concepts are also provided and discussed. Several options for habitable elements are shown, such as large-diameter modules and space station (SS) types of modules.

Measuring adolescents’ exposure to victimization: The Environmental Risk (E-Risk) Longitudinal Twin Study

PubMed Central

Fisher, Helen L.; Caspi, Avshalom; Moffitt, Terrie E.; Wertz, Jasmin; Gray, Rebecca; Newbury, Joanne; Ambler, Antony; Zavos, Helena; Danese, Andrea; Mill, Jonathan; Odgers, Candice L.; Pariante, Carmine; Wong, Chloe C.; Arseneault, Louise

2016-01-01

This paper presents mutlilevel findings on adolescents’ victimization exposure from a large longitudinal cohort of twins. Data were obtained from the Environmental Risk (E-Risk) Longitudinal Twin Study, an epidemiological study of 2,232 children (1,116 twin pairs) followed to 18 years of age (with 93% retention). To assess adolescent victimization we combined best practices in survey research on victimization with optimal approaches to measuring life stress and traumatic experiences, and introduce a reliable system for coding severe victimization. One in three children experienced at least one type of severe victimization during adolescence (crime victimization, peer/sibling victimization, internet/mobile phone victimization, sexual victimization, family violence, maltreatment, or neglect), and most types of victimization were more prevalent amongst children from low socioeconomic backgrounds. Exposure to multiple victimization types was common, as was re-victimization; over half of those physically maltreated in childhood were also exposed to severe physical violence in adolescence. Biometric twin analyses revealed that environmental factors had the greatest influence on most types of victimization, while severe physical maltreatment from caregivers during adolescence was predominantly influenced by heritable factors. The findings from this study showcase how distinct levels of victimization measurement can be harmonized in large-scale studies of health and development. PMID:26535933

Safety and efficacy of repaglinide in type 2 diabetic patients with and without impaired renal function.

PubMed

Hasslacher, Christoph

2003-03-01

To evaluate the influence of renal impairment on the safety and efficacy of repaglinide in type 2 diabetic patients. This multinational, open-label study comprised a 6-week run-in period, continuing prestudy antidiabetic medication, followed by a titration period (1-4 weeks) and a 3-month maintenance period. Patients with normal renal function (n = 151) and various degrees of renal impairment (n = 130) were treated with repaglinide (maximal dose of 4 mg, three times daily). Safety and efficacy assessments were performed at baseline (end of run-in) and at the end of study treatment. The type and severity of adverse events during repaglinide treatment were similar to the run-in period. The number of patients with adverse events was not significantly related to renal function during run-in or repaglinide treatment. Percentage of patients with hypoglycemic episodes increased significantly (P = 0.007) with increasing severity of renal impairment during run-in but not during repaglinide treatment (P = 0.074). Metabolic control (HbA(1c) and fasting blood glucose) with repaglinide was unchanged from that on previous antidiabetic medication. Final repaglinide dose tended to be lower for patients with severe and extreme renal impairment than for patients with less severe renal impairment or normal renal function (P = 0.032). Repaglinide has a good safety and efficacy profile in type 2 diabetic patients complicated by renal impairment and is an appropriate treatment choice, even for individuals with more severe degrees of renal impairment.

The Effect of ABO Blood Groups, Hemoglobinopathy, and Heme Oxygenase-1 Polymorphisms on Malaria Susceptibility and Severity.

PubMed

Kuesap, Jiraporn; Na-Bangchang, Kesara

2018-04-01

Malaria is one of the most important public health problems in tropical areas on the globe. Several factors are associated with susceptibility to malaria and disease severity, including innate immunity such as blood group, hemoglobinopathy, and heme oxygenase-1 (HO-1) polymorphisms. This study was carried out to investigate association among ABO blood group, thalassemia types and HO-1 polymorphisms in malaria. The malarial blood samples were collected from patients along the Thai-Myanmar border. Determination of ABO blood group, thalassemia variants, and HO-1 polymorphisms were performed using agglutination test, low pressure liquid chromatography and polymerase chain reaction, respectively. Plasmodium vivax was the major infected malaria species in the study samples. Distribution of ABO blood type in the malaria-infected samples was similar to that in healthy subjects, of which blood type O being most prevalent. Association between blood group A and decreased risk of severe malaria was significant. Six thalassemia types (30%) were detected, i.e. , hemoglobin E (HbE), β-thalassemia, α-thalassemia 1, α-thalassemia 2, HbE with α-thalassemia 2, and β-thalassemia with α-thalassemia 2. Malaria infected samples without thalassemia showed significantly higher risk to severe malaria. The prevalence of HO-1 polymorphisms, S/S, S/L and L/L were 25, 62, and 13%, respectively. Further study with larger sample size is required to confirm the impact of these 3 host genetic factors in malaria patients.

Botulinum toxin type a injections to salivary glands: combination with single event multilevel chemoneurolysis in 2 children with severe spastic quadriplegic cerebral palsy.

PubMed

Kim, Heakyung; Lee, Yung; Weiner, Daniel; Kaye, Robin; Cahill, Anne Marie; Yudkoff, Marc

2006-01-01

We describe 2 children with severe spastic quadriplegic cerebral palsy (CP) who have significant drooling and frequent aspiration pneumonia. They underwent simultaneous botulinum toxin type A (BTX-A) injections to salivary glands for drooling and prevention of aspiration pneumonia along with single-event multilevel chemoneurolysis (SEMLC) with BTX-A and 5% phenol for severe diffuse spasticity. There was significant improvement in drooling, frequency of aspiration pneumonia, and spasticity without adverse effect. BTX-A injections into the salivary glands, in addition to SEMLC, for these 2 children with medically complicated severe spastic quadriplegic CP, were safe and highly successful procedures, which improved their health-related quality of life.

Use of the disease severity index for null hypothesis testing

USDA-ARS?s Scientific Manuscript database

A disease severity index (DSI) is a single number for summarizing a large amount of disease severity information. It is used to indicate relative resistance of cultivars, to relate disease severity to yield loss, or to compare treatments. The DSI has most often been based on a special type of ordina...

Screening for obstructive sleep apnea syndrome in patients with type 2 diabetes mellitus: a prospective study on sensitivity of Berlin and STOP-Bang questionnaires.

PubMed

Westlake, Katerina; Plihalova, Andrea; Pretl, Martin; Lattova, Zuzana; Polak, Jan

2016-10-01

Obstructive sleep apnea (OSA) is highly prevalent in patients with Type 2 diabetes mellitus representing an additional risk factor for already increased cardiovascular mortality. As cardiovascular diseases are the main cause of death in this population, there is a need to identify patients with moderate to severe OSA indicated for treatment. We aimed to evaluate the performance of the Berlin, STOP, and STOP-Bang screening questionnaires in a population of patients with Type 2 diabetes mellitus. 294 consecutive patients with Type 2 diabetes mellitus filled in the questionnaires and underwent overnight home sleep monitoring using a type IV sleep monitor. Severe, moderate, and mild OSA was found in 31 (10%), 61 (21%), and 121 (41%) patients, respectively. The questionnaires showed a similar sensitivity and specificity for AHI ≥ 15: 0.69 and 0.50 for Berlin, 0.65 and 0.49 for STOP, and 0.59 and 0.68 for STOP-Bang. However, the performance of the STOP-Bang questionnaire was different in men vs. women, sensitivity being 0.74 vs. 0.29 (p < 0.05) and specificity 0.56 vs. 0.82 (p < 0.05). Even the best-performing Berlin questionnaire failed to identify 31% of patients with moderate to severe OSA as being at high risk of OSA, thus preventing them from receiving a correct diagnosis and treatment. Considering that patients with Type 2 diabetes mellitus are at high risk of cardiovascular mortality and also have a high prevalence of moderate to severe OSA, we find screening based on the questionnaires suboptimal and suggest that OSA screening should be performed using home sleep monitoring devices. Copyright © 2016 Elsevier B.V. All rights reserved.

Use of Ganga Hospital Open Injury Severity Scoring for determination of salvage versus amputation in open type IIIB injuries of lower limbs in children-An analysis of 52 type IIIB open fractures.

PubMed

Venkatadass, K; Grandhi, Tarani Sai Prasanth; Rajasekaran, S

2017-11-01

Open injuries in children are rare compared to adults. In children with major open injuries, there is no specific scoring system to guide when to amputate or salvage the limb. The use of available adult scoring systems may lead to errors in management. The role of Ganga Hospital Open Injury Severity Scoring (GHOISS) for open injuries in adults is well established and its applicability for pediatric open injuries has not been studied. This study was done to analyse the usefulness of GHOISS in pediatric open injuries and to compare it with MESS(Mangled Extremity Severity Score). All children (0-18 years) who were admitted with Open type IIIB injuries of lower limbs between January 2008 and March 2015 were included. MESS and GHOISS were calculated for all the patients. There were 50 children with 52 type IIIB Open injuries of which 39 had open tibial fractures and 13 had open femur fractures. Out of 52 type IIIB open injuries, 48 were salvaged and 4 were amputated. A MESS score of 7 and above had sensitivity of 25% for amputation while GHOISS of 17 and above was found to be more accurate for determining amputation with sensitivity of 75% and specificity of 93.75%. GHOISS is a reliable predictor of injury severity in type IIIB open fractures in children and can be used as a guide for decision-making. The use of MESS score in children has a lower predictive value compared to GHOISS in deciding amputation versus salvage. A GHOISS of 17 or more has the highest sensitivity and specificity to predict amputation. Copyright © 2017 Elsevier Ltd. All rights reserved.

Return to play after nonoperative management for a severe type III acromioclavicular separation in the throwing shoulder of a collegiate pitcher.

PubMed

Watson, Scott T; Wyland, Douglas J

2015-02-01

Treatment of type III acromioclavicular (AC) separations is controversial, especially in the dominant shoulder of a high-level throwing athlete. This case report describes the return to play after nonoperative management of a collegiate baseball pitcher with a severe type III AC separation in his throwing shoulder. Case report of return to play with nonoperative management of a type III AC separation in the throwing shoulder of a collegiate pitcher. A case report of a single patient. Prospective data were recorded in the case of a collegiate pitcher who suffered an acute injury to the dominant shoulder, resulting in a severe type III AC separation. He was initially treated with a figure-of-8 brace and a sling. Postinjury, strengthening of the wrist, hand, and elbow began at 3½ weeks, and shoulder range of motion (ROM) and a periscapular strengthening program began at 6 weeks. At 2 months postinjury, a deformity was still present, but the athlete was pain free, with full shoulder ROM and strength without tenderness at the AC joint. Formal physical therapy was initiated to include an accelerated interval throwing program. At 12 weeks postinjury, the athlete was pitching asymptomatically, and gradually returned to regular play. At 6 months and now through 24 months postinjury, the athlete reported full strength, full ROM, and return to his previous level of throwing and velocity without complication. He volunteered that he was 100% satisfied with the result, and feels he is the same pitcher as, if not stronger than, prior to this injury. This case demonstrates a collegiate baseball pitcher who returned to his preinjury level of pitching with nonoperative treatment of a severe type III AC separation.

The association between uric acid levels and different clinical manifestations of coronary artery disease.

PubMed

Larsen, Trine R; Gerke, Oke; Diederichsen, Axel C P; Lambrechtsen, Jess; Steffensen, Flemming H; Sand, Niels P; Saaby, Lotte; Antonsen, Steen; Mickley, Hans

2018-05-01

Uric acid (UA) has been associated with the presence and severity of coronary artery disease. To further assess the role of UA role in coronary artery disease, we investigated UA levels in both healthy asymptomatic middle-aged individuals and in different subgroups of hospitalized patients with suspected or definite myocardial infarction (MI). The severity of coronary artery calcification (CAC) was examined in asymptomatic individuals (n=1039) using a noncontrast computed tomography scan. Hospitalized patients with suspected acute MI (n=772) were grouped according to troponin I (TnI) concentrations: (i) elevated TnI concentrations (>0.03 µg/l) with subdivision according to the type of MI and other clinical conditions associated with myocardial injury, or (ii) nonelevated TnI concentrations (≤0.03 µg/l). UA was not associated with the severity of CAC in asymptomatic individuals when adjusting for relevant risk factors. Patients with type 2 MI and patients with myocardial injury associated with conditions of myocardial ischemia showed significantly higher UA levels (0.390 mmol/l, P=0.002 and 0.400 mmol/l, P=0.001, respectively) than patients with type 1 MI (0.329 mmol/l), after adjusting for other risk factors. UA was not correlated with the severity of CAC in asymptomatic middle-aged individuals, and patients with type 2 MI or ischemic myocardial injury were shown to have higher UA levels than type 1 MI patients. This observation is concordant with the hypothesis that UA might be involved in the pathophysiological mechanisms leading to an imbalance in the oxygen supply/demand ratio in type 2 MI and ischemic myocardial injury.

Severe fatigue in type 1 diabetes: Exploring its course, predictors and relationship with HbA1c in a prospective study.

PubMed

Menting, Juliane; Nikolaus, Stephanie; van der Veld, William M; Goedendorp, Martine M; Tack, Cees J; Knoop, Hans

2016-11-01

To prospectively identify the course of severe fatigue, its predictors and the relationship with HbA 1c in patients with type 1 diabetes. 214 adult patients completed questionnaires on fatigue severity and fatigue-related factors at baseline. HbA 1c was retrieved from medical records. After 43months, fatigue severity and HbA 1c were reassessed in 194 patients. A logistic regression analysis was used to determine predictors of severe fatigue at follow-up with various cognitive-behavioral and clinical factors as potential predictors. The relationship between fatigue and HbA 1c was investigated in a sub-analysis by differentiating between patients with suboptimal glucose control [HbA 1c >7% (53mmol/mol)] and optimal glucose control [HbA 1c ⩽7% (53mmol/mol)]. The prevalence of severe fatigue was 40% at baseline and 42% at follow-up. In three out of four severely fatigued patients at baseline (76%), severe fatigue persisted over time. More depressive symptoms, more pain, sleep disturbances, lower self-efficacy concerning fatigue, less confidence in diabetes self-care, more fatigue severity at baseline and more diabetes complications predicted severe fatigue at follow-up. Over time, HbA 1c at baseline was positively associated with fatigue severity at follow-up in both groups (suboptimal glucose control: r=.18, p<.05; optimal glucose control: r=.09, p<.05). About three quarters of fatigued[corrected] patients with type 1 diabetes suffer from persistent fatigue. Aside from the number of diabetes complications, no clinical factors explained the persistence of fatigue. HbA 1c and fatigue were weakly associated in a sub-analysis. Since the strongest predictors of severe fatigue were cognitive-behavioral factors, behavioral interventions might be effective in decreasing fatigue. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Predictive value of the fibrosis scores in patients with chronic hepatitis C associated with liver fibrosis and metabolic syndrome.

PubMed

Miyaaki, Hisamitsu; Ichikawa, Tatsuki; Taura, Naota; Miuma, Satoshi; Shibata, Hidetaka; Isomoto, Hajime; Takeshima, Fuminao; Nakao, Kazuhiko

2011-01-01

We evaluated patients with chronic hepatitis C (CHC) and compared the clinical and pathological features of steatosis and metabolic syndrome to identify the risk factors for CHC with severe fibrosis. One hundred seventy-one patients with biopsy-confirmed CHC were included in the study: 90 males and 81 females, age 56.2 ± 12.8 years; 46 with obesity (BMI≥25 kg/m(2)); 51 with hypertension; 36 with type 2 diabetes mellitus; and 20 with hypertriglyceridemia. Steatosis was detected in 79 patients (46%); 92 patients (54%) showed no steatosis. Seventy-four patients (43%) showed mild fibrosis and 97 patients (56%) showed severe fibrosis. The variables that were significantly associated with steatosis were obesity [odds ratio 2.160 (1.010-4.727), p=0.046] and type 2 diabetes [odds ratio 3.667 (1.559-8.430), p=0.027]. The variables that were significantly associated with severe fibrosis were older age [odds ratio 2.675 (1.309-5.464), p=0.007], obesity [odds ratio 2.156 (1.006-4.619), p=0.048] and type 2 diabetes [odds ratio 8.739 (2.845-26.846), p=0.0002]. Nagasaki (N) score (the total number of specific risk factors, namely an older age, obesity, and type 2 diabetes) was higher in the severe fibrosis group than in the mild fibrosis group (mild fibrosis: severe fibrosis=1.48 ± 1.14 vs.2.66 ± 94, p<0.001). Metabolic syndrome factors, including obesity and diabetes, play a critical role in the pathogenesis of fibrosis in CHC. The N score was therefore found to be a significant predictor of severe fibrosis in CHC.

Self-reported comorbid pains in severe headaches or migraines in a US national sample.

PubMed

Plesh, Octavia; Adams, Sally H; Gansky, Stuart A

2012-06-01

To compare prevalence of self-reported comorbid temporomandibular joint muscle disorder-type, neck, back, and joint pains in people with severe headache or migraine; and analyze these self-reported pains in the 2000-2005 US National Health Interview Survey by gender and age for non-Hispanic whites, Hispanics, and non-Hispanic blacks (African Americans). National Health Interview Survey data included information on gender, age, race, ethnicity, health status, and common pain types: severe headache or migraine, temporomandibular joint muscle disorder-type, neck, and low back in the last 3 months, as well as prior-month joint pains. Analyses included survey prevalence estimation and survey logistic regression to obtain odds ratios and 95% confidence intervals. The study included 189,967 adults: 48% males, 52% females; 73% white, 12% Hispanic, and 11% black. Of the entire sample, 29,712 (15%) reported severe headache or migraine, and 19,228 (64%) had severe headache or migraine with at least 1 comorbid pain. Two or more comorbid pains were reported in 10,200 (33%), with no gender difference, and with Hispanics (n = 1847 or 32%) and blacks (n = 1301 or 30%) less likely to report 2 or more comorbid pains than whites (n = 6747 or 34%) (odds ratio = 0.91, P = .032; OR = 0.82, P < .001, respectively). This group also reported significantly lower ratings of self-rated health (P < .001). Differences in type of comorbid pain by age patterns were found. Severe headache or migraine is often associated with other common pains, seldom existing alone. Two or more comorbid pains are common, similarly affecting gender and racial/ethnic groups. © 2012 American Headache Society.

Self- Reported Comorbid Pains in Severe Headaches or Migraines in a US National Sample

PubMed Central

Plesh, Octavia; Adams, Sally H; Gansky, Stuart A

2012-01-01

Aims To compare prevalence of self-reported comorbid temporomandibular joint muscle disorder (TMJMD)-type, neck, back and joint pains in people with severe headache or migraine; analyze these self-reported pains in the 2000–2005 US National Health Interview Survey (NHIS) by gender and age for Non-Hispanic Whites, Hispanics and Non-Hispanic Blacks (African Americans). Methods NHIS data included information on gender, age, race, ethnicity, health status, and common pain types: severe headache or migraine, TMJMD-type, neck, and low back in the last 3 months, as well as prior month joint pains. Analyses included survey prevalence estimation and survey logistic regression to obtain odds ratios and 95% confidence intervals. Results 189,967 adults, 48% males, 52% females; 73% White, 12% Hispanic, and 11% Black were included. 29,712 (15%) of the entire sample reported severe headache or migraine, 19,228 (64%) had severe headache or migraine with at least one comorbid pain. 10,200 (33%) reported 2 or more comorbid pains, with no gender difference, and with Hispanics (n=1,847 or 32%) and Blacks (n=1,301 or 30%) less likely to report 2 or more comorbid pains than Whites (n=6,747 or 34%) (OR=0.91, p=0.032; OR=0.82, p<0.001, respectively). This group also reported significantly lower ratings of self-rated health (p<0.001). Differences in type of comorbid pain by age patterns were found. Conclusions Severe headache or migraine is often associated with other common pains, seldom existing alone. Two or more comorbid pains are common, similarly affecting gender and racial/ethnic groups. PMID:22553936

MLST typing of antimicrobial-resistant Propionibacterium acnes isolates from patients with moderate to severe acne vulgaris.

PubMed

Giannopoulos, Lambros; Papaparaskevas, Joseph; Refene, Eirini; Daikos, Georgios; Stavrianeas, Nikolaos; Tsakris, Athanassios

2015-02-01

Molecular typing data on antimicrobial-resistant Propionibacterium strains are limited in the literature. We examined antimicrobial resistance profiles and the underlying resistance mechanisms in Propionibacterium spp. isolates recovered from patients with moderate to severe acne vulgaris in Greece. The clonallity of the resistant Propionibacterium acnes isolates was also investigated. Propionibacterium spp. isolates were detected using Tryptone-Yeast Extract-Glucose (TYG) agar plates supplemented with 4% furazolidone. Erythromycin, clindamycin, vancomycin, penicillin, co-trimoxazole, doxycycline, minocycline and ciprofloxacin MICs were determined using the gradient strip method. Erythromycin, clindamycin and tetracycline mechanisms of resistance were determined using PCR and sequencing of the domain V of 23S rRNA and 16S rRNA, as well as the presence of the ermX gene. Typing was performed using the multi locus sequence typing (MLST) methodology. Seventy nine isolates from 76 patients were collected. Twenty-three isolates (29.1%) exhibited resistance to erythromycin and clindamycin, while two additional isolates (2.5%) were resistant only to erythromycin. Resistance to tetracycline was not detected. The underlying molecular mechanisms were point mutations A2059G and A2058G. MLST typing of the P. acnes resistant isolates revealed that lineage type IA1 (ST-1, 3 and 52) prevailed (12/18; 66.7%), whilst lineage type IA2 (ST-2 and 22) accounted for five more isolates (27.8%). Susceptible isolates were more evenly distributed between ST types. Propionibacterium spp. from moderate to severe acne vulgaris in Greece are frequently resistant to erythromycin/clindamycin but not to tetracyclines, mainly due to the point mutations A2059G and A2058G. P. acnes resistant isolates were more clonally related than susceptible ones and belonged to a limited number of MLST types. Copyright © 2014 Elsevier Ltd. All rights reserved.

Molecular characterization of infants with type 2 Gaucher disease

DOE Office of Scientific and Technical Information (OSTI.GOV)

Stubblefield, B.; Martin, B.M.; Ginns, E.I.

1994-09-01

Type 2 (acute neuronopathic) Gaucher disease was previously thought to be stereotypic in presentation with neurologic deterioration and death by age 2-3 years. However, the generation of a null allele knock-out Gaucher mouse led to the recognition of a subset of type 2 patients who die as neonates. To better understand this subgroup we studied DNA, RNA and residual enzyme activity in fibroblasts from neonatal type 2 Gaucher patients, {open_quotes}classic{close_quotes} type 2 patients, type 1 and type 3 patients and normal individuals. Mutational analysis revealed genotypic heterogeneity in each group. One patient with severe neonatal Gaucher disease and hydrops fetalismore » was homoallelic for a complex allele including mutations L44P, A456P and V460V, while others had different or unknown alleles. Northern blots demonstrated that transcription was intact even in the neonatal lethal patients. However, the more severe type 2 patients had virtually no protein on Western, indicating that the transcript is either not appropriately translated or results in an unstable protein. Thus type 2 Gaucher disease exhibits more phenotypic, genotypic and biochemical heterogeneity than previously appreciated.« less

Canine parvovirus--a review of epidemiological and diagnostic aspects, with emphasis on type 2c.

PubMed

Decaro, Nicola; Buonavoglia, Canio

2012-02-24

Canine parvovirus type 2 (CPV-2) emerged in late 1970s causing severe epizootics in kennels and dog shelters worldwide. Soon after its emergence, CPV-2 underwent genetic evolution giving rise consecutively to two antigenic variants, CPV-2a and CPV-2b that replaced progressively the original type. In 2000, a new antigenic variant, CPV-2c, was detected in Italy and rapidly spread to several countries. In comparison to the original type CPV-2, the antigenic variants display increased pathogenicity in dogs and extended host range, being able to infect and cause disease in cats. Epidemiological survey indicate that the newest type CPV-2c is becoming prevalent in different geographic regions and is often associated to severe disease in adult dogs and also in dogs that have completed the vaccination protocols. However, the primary cause of failure of CPV vaccination is interference by maternally derived immunity. Diagnosis of CPV infection by traditional methods has been shown to be poorly sensitive, especially in the late stages of infections. New diagnostic approaches based on molecular methods have been developed for sensitive detection of CPV in clinical samples and rapid characterisation of the viral type. Continuous surveillance will help assess whether there is a real need to update currently available vaccines and diagnostic tests. Copyright © 2011 Elsevier B.V. All rights reserved.

Expression of cancer-associated simple mucin-type O-glycosylated antigens in parasites.

PubMed

Osinaga, Eduardo

2007-01-01

Simple mucin-type O-glycan structures, such as Tn, TF, sialyl-Tn and Tk antigens, are among of the most specific human cancer-associated structures. These antigens are involved in several types of receptor-ligand interactions, and they are potential targets for immunotherapy. In the last few years several simple mucin-type O-glycan antigens were identified in different species belonging to the main two helminth parasite phyla, and sialyl-Tn bearing glycoproteins were detected in Trypanosoma cruzi. These results are of interest to understand new aspects in parasite glycoimmunology and may help identify new biological characteristics of parasites as well of the host-parasite relationship. Considering that different groups reported a negative correlation between certain parasite infections and cancer development, we could hypothesize that simple mucin-type O-glycosylated antigens obtained from parasites could be good potential targets for cancer immunotherapy.

Towards an entirely endovascular aortic world: an update of techniques and outcomes for endovascular and open treatment of type I, II, and III endoleaks.

PubMed

Mangialardi, Nicola; Orrico, Matteo; Ronchey, Sonia; Praquin, Barbara; Alberti, Vittorio; Setacci, Carlo

2016-10-01

Endovascular aneurysm repair (EVAR) is largely the most adopted strategy for aneurysmal disease of the aorta. Nevertheless, the high incidence of reintervention makes it difficult to identify EVAR as a definitive solution; in particular, the most frequent indication of reintervention is endoleak, which is defined as persistent flow into the aneurysmal sac from different sources. Several treatment strategies are described. A contemporary literature search was performed with the intent of describing techniques and outcomes of endovascular and open strategies to type I, II, and III endoleak. Described techniques and outcomes were organized by indication (type I, II, and III endoleak) and by type of approach (endovascular, open, and laparoscopic) to give an overview of the current status of the treatment for the three most frequent types of endoleak. Several endovascular means are described in the literature for the treatment of endoleak.

Design and test of the Stirling-type pulse tube cryocooler

NASA Astrophysics Data System (ADS)

Hong, Yong-Ju; Ko, Junseok; Kim, Hyo-Bong; Yeom, Han-Kil; In, Sehwan; Park, Seong-Je

2017-12-01

Stirling type pulse tube cryocoolers are very attractive for cooling of diverse application because it has it has several inherent advantages such as no moving part in the cold end, low manufacturing cost and long operation life. To develop the Stirling-type pulse tube cryocooler, we need to design a linear compressor to drive the pulse tube cryocooler. A moving magnet type linear motor of dual piston configuration is designed and fabricated, and this compressor could be operated with the electric power of 100 W and the frequency up to 60 Hz. A single stage coaxial type pulse tube cold finger aiming at over 1.5 W at 80K is built and tested with the linear compressor. Experimental investigations have been conducted to evaluate their performance characteristics with respect to several parameters such as the phase shifter, the charging pressure and the operating frequency of the linear compressor.

Running Batch Jobs on Peregrine | High-Performance Computing | NREL

Science.gov Websites

Using Resource Feature to Request Different Node Types Peregrine has several types of compute nodes incompatibility and get the job running. More information about requesting different node types in Peregrine is available. Queues In order to meet the needs of different types of jobs, nodes on Peregrine are available

Comparison of diabetic ketoacidosis in patients with type-1 and type-2 diabetes mellitus.

PubMed

Barski, Leonid; Nevzorov, Roman; Harman-Boehm, Ilana; Jotkowitz, Alan; Rabaev, Elena; Zektser, Miri; Zeller, Lior; Shleyfer, Elena; Almog, Yaniv

2013-04-01

Diabetic ketoacidosis (DKA) occurs most often in patients with type 1 diabetes, however patients with type 2 diabetes are also susceptible to DKA under stressful conditions. The aims of our study were to evaluate and compare the clinical and biochemical characteristics and outcomes of type 1 versus type 2 diabetes mellitus (DM) patients with DKA. A retrospective cohort study of adult patients hospitalized with DKA between January 1, 2003, and January 1, 2010. The clinical and biochemical characteristics of DKA patients with type-1 DM were compared with those of patients with type-2 DM. The primary outcome was in-hospital all-cause mortality. The study cohort included 201 consecutive patients for whom the admission diagnosis was DKA: 166 patients (82.6%) with type-1 DM and 35 patients (17.4%) with type-2 DM. The patients with DKA and type-2 DM were significantly older than patients with type-1 DM (64.3 versus 37.3, P < 0.001). Significantly more patients with severe forms of DKA were seen in the group with type-2 DM (25.7% versus 9.0%, P = 0.018). The total in-hospital mortality rate of patients with DKA was 4.5%. The primary outcome was significantly worse in the group of patients with type-2 DM. DKA in patients with type-2 DM is a more severe disease with worse outcomes compared with type-1 DM. Advanced age, mechanical ventilation and bed-ridden state were independent predictors of 30-day mortality.

Strategies for Individualizing Typing Instruction

ERIC Educational Resources Information Center

Quible, Zane K.

1978-01-01

Strategies to individualize instruction in typewriting classes discussed in the article are the multimedia approach, mechanical pacing devices, computer-assisted instruction, learning activity packages, and several project-type devices. (MF)

Stomach cancer

MedlinePlus

Cancer - stomach; Gastric cancer; Gastric carcinoma; Adenocarcinoma of the stomach ... Several types of cancer can occur in the stomach. The most common type is called adenocarcinoma. It starts from one of the cell ...

Decipher the Molecular Response of Plant Single Cell Types to Environmental Stresses

DOE PAGES

Nourbakhsh-Rey, Mehrnoush; Libault, Marc

2016-01-01

The analysis of the molecular response of entire plants or organs to environmental stresses suffers from the cellular complexity of the samples used. Specifically, this cellular complexity masks cell-specific responses to environmental stresses and logically leads to the dilution of the molecular changes occurring in each cell type composing the tissue/organ/plant in response to the stress. Therefore, to generate a more accurate picture of these responses, scientists are focusing on plant single cell type approaches. Several cell types are now considered as models such as the pollen, the trichomes, the cotton fiber, various root cell types including the root hairmore » cell, and the guard cell of stomata. Among them, several have been used to characterize plant response to abiotic and biotic stresses. Lastly, in this review, we are describing the various -omic studies performed on these different plant single cell type models to better understand plant cell response to biotic and abiotic stresses.« less

Decipher the Molecular Response of Plant Single Cell Types to Environmental Stresses

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nourbakhsh-Rey, Mehrnoush; Libault, Marc

The analysis of the molecular response of entire plants or organs to environmental stresses suffers from the cellular complexity of the samples used. Specifically, this cellular complexity masks cell-specific responses to environmental stresses and logically leads to the dilution of the molecular changes occurring in each cell type composing the tissue/organ/plant in response to the stress. Therefore, to generate a more accurate picture of these responses, scientists are focusing on plant single cell type approaches. Several cell types are now considered as models such as the pollen, the trichomes, the cotton fiber, various root cell types including the root hairmore » cell, and the guard cell of stomata. Among them, several have been used to characterize plant response to abiotic and biotic stresses. Lastly, in this review, we are describing the various -omic studies performed on these different plant single cell type models to better understand plant cell response to biotic and abiotic stresses.« less

A collection of edge-based elements

NASA Technical Reports Server (NTRS)

Kempel, Leo C.; Volakis, John L.

1992-01-01

Edge-based elements have proved useful in solving electromagnetic problems since they are nondivergent. Previous authors have presented several two and three dimensional elements. Herein, we present four types of elements which are suitable for modeling several types of three dimensional geometries. Distorted brick and triangular prism elements are given in cartesian coordinates as well as the specialized cylindrical shell and pie-shaped prism elements which are suitable for problems best described in polar cylindrical coordinates.

Feasibility Investigation into Strengthening of Timber Bridge Stringers

DTIC Science & Technology

2007-05-01

life . They exhibit several types of damage, which occurs in their structural elements such as timber stringers. The most commonly encountered damage...United States are nearing, or at the end of their service life , which means they exhibit several types of damage. This occurs mostly on structural... life of a timber bridge is approximately 30–40 years, the majority of timber bridges in the United States are nearing the end of their service life

Analysis of Alaskan burn severity patterns using remotely sensed data

USGS Publications Warehouse

Duffy, P.A.; Epting, J.; Graham, J.M.; Rupp, T.S.; McGuire, A.D.

2007-01-01

Wildland fire is the dominant large-scale disturbance mechanism in the Alaskan boreal forest, and it strongly influences forest structure and function. In this research, patterns of burn severity in the Alaskan boreal forest are characterised using 24 fires. First, the relationship between burn severity and area burned is quantified using a linear regression. Second, the spatial correlation of burn severity as a function of topography is modelled using a variogram analysis. Finally, the relationship between vegetation type and spatial patterns of burn severity is quantified using linear models where variograms account for spatial correlation. These results show that: 1) average burn severity increases with the natural logarithm of the area of the wildfire, 2) burn severity is more variable in topographically complex landscapes than in flat landscapes, and 3) there is a significant relationship between burn severity and vegetation type in flat landscapes but not in topographically complex landscapes. These results strengthen the argument that differential flammability of vegetation exists in some boreal landscapes of Alaska. Additionally, these results suggest that through feedbacks between vegetation and burn severity, the distribution of forest vegetation through time is likely more stable in flat terrain than it is in areas with more complex topography. ?? IAWF 2007.

Use of Oxycodone in Pain Management

PubMed Central

Moradi, Mohammad; Esmaeili, Sara; Shoar, Saeed; Safari, Saeid

2012-01-01

Oxycodone is widely used to alleviate moderate-to severe acute pain, It is an effective analgesic for many types of pain, and is especially useful for paroxysmal spontaneous pain, steady pain, allodynia associated with postherpetic neuralgia, and it is also increasingly used in the management of cancer-related and chronic pain, oxycodone has been found to improve the quality of life of patients with many types of pain. In 2011, following chemical and physical manipulation, an extended-release form of oxycodone was developed in order to maintain its rate-controlling mechanism. This new formulation significantly improved analgesia among patients with moderate-to-severe chronic osteoarthritis pain with an adverse event profile similar to that of other opioids. The long-term safety and efficacy of extended-release form of oxycodone in relieving moderate-to-severe chronic pain has been demonstrated. In this study we discussed about different aspects of this drug in managing of various types of pain. PMID:24904812

A chondrodysplasia family produced by mutations in the diastrophic dysplasia sulfate transporter gene: Genotype/phenotype correlations

DOE Office of Scientific and Technical Information (OSTI.GOV)

Superti-Furga, A.; Steinmann, B.; Gitzelmann, R.

1996-05-03

Achondrogenesis type 1B (ACG-1B), atelosteogenesis type 2 (AO-2), and diastrophic dysplasia (DTD) are recessively inherited chondrodysplasia of decreasing severity caused by mutations in the diastrophic dysplasia sulfate transporter (DTDST) gene on chromosome 5. In these conditions, sulfate transport across the cell membrane is impaired which results in insufficient sulfation of cartilage proteoglycans and thus in an abnormally low sulfate content of cartilage. The severity of the phenotype correlates well with the predicted effect of the underlying DTDST mutations: homozygosity or compound heterozygosity for stop codons or transmembrane domain substitutions mostly result in achondrogenesis type 1B, while other structural or regulatorymore » mutations usually result in one of the less severe phenotypes. The chondrodysplasia arising at the DTDST locus constitute a bone dysplasia family with recessive inheritance. 28 refs., 2 tabs.« less

Stanford Type A Acute Aortic Dissection with Intimal Intussusception.

PubMed

Yanase, Yohsuke; Ohkawa, Akihito; Inoue, Satomi; Niida, Yukihiro

2018-03-17

In case of complete circumferential dissection of the ascending aorta, the dissected flap has the potential to fold backwards, causing several complications. We report two cases of Stanford type A acute aortic dissection (AAD) whose intimal flaps intussuscepted into the left ventricular outflow tract.Case 1: A 41-year-old man with AAD in whom transthoracic echocardiography (TTE) showed the dissected flap as folded back into the left ventricular outflow tract, causing severe aortic regurgitation (AR) with rapidly progressing acute pulmonary edema. Despite performing salvage surgery, the patient could not be rescued.Case 2: An 81-year-old man with annuloaortic ectasia developed Stanford type A AAD. TTE showed an extremely mobile intimal flap intussuscepting into the left ventricular outflow tract. However, AR was not severe as it was prevented by the flap itself. The patient was rescued by performance of the modified Bentall procedure.

Atelosteogenesis type II is caused by mutations in the diastrophic dysplasia sulfate-transporter gene (DTDST): Evidence for a phenotypic series involving three chondrodysplasias

DOE Office of Scientific and Technical Information (OSTI.GOV)

Haestbacka, J.; Lander, E.S.; Superti-Furga, A.

1996-02-01

Atelosteogenesis type II (AO II) is a neonatally lethal chondrodysplasia whose clinical and histological characteristics resemble those of another chondrodysplasia, the much less severe diastrophic dysplasia (DTD). The similarity suggests a shared pathogenesis involving lesions in the same biochemical pathway and perhaps the same gene. DTD is caused by mutations in the recently identified diastrophic dysplasia sulfate-transporter gene (DTDST). Here, we report that AOII patients also have DTDST mutations, which lead to defective uptake of inorganic sulfate and insufficient sulfation of macromolecules by patient mesenchymal cells in vitro. Together with our recent observation that a third even more severe chondrodysplasia,more » achondrogenesis type IB, is also caused by mutations in DTDST, these results demonstrate a phenotypic series of three chondrodysplasias of increasing severity caused by lesions in a single sulfate-transporter gene. The severity of the phenotype appears to be correlated with the predicted effect of the mutations on the residual activity of the DTDST protein. 24 refs., 6 figs., 1 tab.« less

[Management of hyperglycemic crises and severe hypoglycemia in the emergency department].

PubMed

Miyake, Yasufumi

2014-02-01

The morbidity of hyperglycemic crises and acute hypoglycemic attacks in patients with diabetes mellitus has been increasing for the past several decades. One of the reasons for this is the increase in the number of patients with diabetes. The increased proportion of aging and isolation in society is another reason. The author has discussed patients with these complaints: their epidemiology, pathophysiology, and management in the emergency department. Hyperglycemic crises include diabetic ketoacidosis (DKA), hyperosmolar hyperglycemic syndrome (HHS), and lactic acidosis (LA). Younger patients with type 1 diabetes suffer from DKA; inappropriate insulin therapy or infection is usually the trigger. Older patients with type 2 diabetes are at risk of HHS in the course of sepsis or in the perioperative period. The treatment of both types of patients is common. Sufficient amount of intravenous extracellular fluid and constant infusion of insulin are essential. The development of LA is not associated with the use of metformin, but with the severity of the pre-existing disease. Early recognition and aggressive treatment is vital to improving the prognosis of hyperglycemic emergencies and severe hypoglycemic episodes.

Association between hypoglycaemia and impaired hypoglycaemia awareness and mortality in people with Type 1 diabetes mellitus.

PubMed

Sejling, A-S; Schouwenberg, B; Faerch, L H; Thorsteinsson, B; de Galan, B E; Pedersen-Bjergaard, U

2016-01-01

To examine whether severe hypoglycaemia and impaired hypoglycaemic awareness, a principal predictor of severe hypoglycaemia, are associated with all-cause mortality or cardiovascular mortality in Type 1 diabetes mellitus. Mortality was recorded in two cohorts, one in Denmark (n = 269, follow-up 12 years) and one in the Netherlands (n = 482, follow-up 6.5 years). In both cohorts, awareness class was characterized and numbers of episodes of severe hypoglycaemia either during lifetime (Danish cohort) or during the preceding year (Dutch cohort) were recorded. In addition, episodes of severe hypoglycaemia were prospectively recorded every month for 1 year in the Danish cohort. Follow-up data regarding mortality were obtained through medical reports and registries (Danish cohort). All-cause mortality was 14% (n = 39) in the Danish and 4% (n = 20) in the Dutch cohort. In either cohort, neither presence of episodes with severe hypoglycaemia nor impaired hypoglycaemia awareness were associated with increased mortality in age-truncated Cox proportional hazard regression models. Variables associated with increased risk of all-cause mortality in both cohorts were evidence of macrovascular disease and reduced kidney function. Severe hypoglycaemia and hypoglycaemia unawareness are not associated with increased risk of all-cause or cardiovascular mortality in people with Type 1 diabetes mellitus. © 2015 The Authors. Diabetic Medicine © 2015 Diabetes UK.

Aphasia

MedlinePlus

... about 1 million people in the United States today suffer from aphasia. The type and severity of ... but cannot make sense of the words. (3) Global aphasia results from severe and extensive damage to ...

Thalassemia

MedlinePlus

... carries oxygen to the body. That leads to anemia. Thalassemias occur most often among people of Italian, ... severe. Some people have no symptoms or mild anemia. The most common severe type in the United ...

Spoken Language Comprehension of Phrases, Simple and Compound-Active Sentences in Non-Speaking Children with Severe Cerebral Palsy

ERIC Educational Resources Information Center

Geytenbeek, Joke J. M.; Heim, Margriet J. M.; Knol, Dirk L.; Vermeulen, R. Jeroen; Oostrom, Kim J.

2015-01-01

Background Children with severe cerebral palsy (CP) (i.e. "non-speaking children with severely limited mobility") are restricted in many domains that are important to the acquisition of language. Aims To investigate comprehension of spoken language on sentence type level in non-speaking children with severe CP. Methods & Procedures…

Spectral analysis of charcoal on soils: Implications for wildland fire severity mapping methods

Treesearch

Alistair M. S. Smith; Jan U. H. Eitel; Andrew T. Hudak

2010-01-01

Recent studies in the Western United States have supported climate scenarios that predict a higher occurrence of large and severe wildfires. Knowledge of the severity is important to infer long-term biogeochemical, ecological, and societal impacts, but understanding the sensitivity of any severity mapping method to variations in soil type and increasing charcoal (char...

New Developments in FPGA: SEUs and Fail-Safe Strategies from the NASA Goddard Perspective

NASA Technical Reports Server (NTRS)

Berg, Melanie D.; Label, Kenneth A.; Pellish, Jonathan

2016-01-01

It has been shown that, when exposed to radiation environments, each Field Programmable Gate Array (FPGA) device has unique error signatures. Subsequently, fail-safe and mitigation strategies will differ per FPGA type. In this session several design approaches for safe systems will be presented. It will also explore the benefits and limitations of several mitigation techniques. The intention of the presentation is to provide information regarding FPGA types, their susceptibilities, and proven fail-safe strategies; so that users can select appropriate mitigation and perform the required trade for system insertion. The presentation will describe three types of FPGA devices and their susceptibilities in radiation environments.

New Developments in FPGA: SEUs and Fail-Safe Strategies from the NASA Goddard Perspective

NASA Technical Reports Server (NTRS)

Berg, Melanie D.; LaBel, Kenneth; Pellish, Jonathan

2015-01-01

It has been shown that, when exposed to radiation environments, each Field Programmable Gate Array (FPGA) device has unique error signatures. Subsequently, fail-safe and mitigation strategies will differ per FPGA type. In this session several design approaches for safe systems will be presented. It will also explore the benefits and limitations of several mitigation techniques. The intention of the presentation is to provide information regarding FPGA types, their susceptibilities, and proven fail-safe strategies; so that users can select appropriate mitigation and perform the required trade for system insertion. The presentation will describe three types of FPGA devices and their susceptibilities in radiation environments.

3-methylglutaconic aciduria type 4 manifesting as Leigh syndrome in 2 siblings.

PubMed

Jareño, Nuria Muñoz; Fernández-Mayoralas, Daniel Martín; Silvestre, Celia Pérez-Cerdá; Cortés, Begoña Merinero; Pérez, Magdalena Ugarte; Campos-Castelló, Jaime

2007-02-01

The authors report the case of a pair of siblings with 3-methylglutaconic aciduria type 4 manifesting as Leigh syndrome. Disease progression was monitored from birth until the present. Both patients fulfilled the diagnostic criteria for Leigh syndrome along with increased urinary excretion of 3-methylglutaconic acid and 3-methylglutaric acid (biochemical markers of methylglutaric acid) in several determinations. No mitochondrial respiratory chain defects in muscle biopsy were detected. Although mitochondrial abnormalities are the most common known cause of Leigh syndrome, there have been several reports of links with nonmitochondrial metabolic disorders. Descriptions of 3-methylglutaric acid type 4 associated with Leigh syndrome are rare.

48 CFR 9904.420-60 - Illustrations.

Code of Federal Regulations, 2010 CFR

2010-10-01

... typing its overhead cost pool. In submitting a proposal, the engineering department assigns several... established accounting practice does not charge the cost of typing directly to final cost objectives, the...

Dexamethasone Injection

MedlinePlus

... severe allergic reactions. It is used in the management of certain types of edema (fluid retention and ... needed for normal body functioning) and in the management of certain types of shock. Dexamethasone injection is ...

Thyroid Cancer

MedlinePlus

... body work normally. There are several types of cancer of the thyroid gland. You are at greater ... imaging tests, and a biopsy to diagnose thyroid cancer. Treatment depends on the type of cancer you ...

Next-generation sequencing and a novel COL3A1 mutation associated with vascular Ehlers-Danlos syndrome with severe intestinal involvement: a case report.

PubMed

Cortini, Francesca; Marinelli, Barbara; Seia, Manuela; De Giorgio, Barbara; Pesatori, Angela Cecilia; Montano, Nicola; Bassotti, Alessandra

2016-10-31

The vascular type of Ehlers-Danlos syndrome is an autosomal dominant connective tissue disorder caused by a mutation in the COL3A1 gene encoding pro-alpha1 chain of type III collagen. The vascular type of Ehlers-Danlos syndrome causes severe fragility of connective tissues with arterial and intestinal ruptures and complications in surgical and radiological treatments. We present a case of a 38-year-old Italian woman who was diagnosed as having the vascular type of Ehlers-Danlos syndrome. Genetic testing, conducted by Target Enrichment approach (Agilent Technologies), identified a new mutation c.1493G>A, p.G498D in exon 21 of COL3A1 gene (heterozygous state). This mutation disrupts the normal glycine-X-Y repetitions of type III procollagen by converting glycine to aspartic acid. We report a new genetic mutation associated with the vascular type of Ehlers-Danlos syndrome. We also describe clinical and genetic findings that are important to understand the genotype/phenotype correlation in patients with the vascular type of Ehlers-Danlos syndrome.

Analysis of Road Traffic Crashes-Related Maxillofacial Injuries Severity and Concomitant Injuries in 201 Patients Seen at the UCH, Ibadan.

PubMed

Aladelusi, Timothy; Akinmoladun, Victor; Olusanya, Adeola; Akadiri, Oladimeji; Fasola, Abiodun

2014-12-01

The objective of this study was to determine the prevalence of road traffic crashes (RTC)-related maxillofacial injuries, the concomitant injuries occurring with them, and to assess the relationship between the severity of maxillofacial and concomitant injuries. This was a prospective study involving 201 victims of RTC seen at the Accident and Emergency Department of the University College Hospital, Ibadan with maxillofacial injuries during the study period. Demographic data of the patients, the types of maxillofacial injuries, and concomitant injuries sustained were recorded. Severity of maxillofacial injury was determined using the maxillofacial injury severity scale (MFISS), while the severity of concomitant injuries was based on the ISS. Correlations between types and severity of maxillofacial injury and types and severity of concomitant injury were conducted to determine the predictability of concomitant injuries based on maxillofacial injury severity. Data were processed using SPSS Statistical software (SPSS, version 20.0 for windows, IBM SPSS Inc, Chicago, IL). Maxillofacial injuries constituted 25.4% of RTC-related admission by the Accident and Emergency Department. A total of 151 (75.1%) patients who presented with concomitant injuries participated in the study. Eighty-one (53.6%) sustained injuries to more than one body region. Head injury was the commonest (99, 65.6%) concomitant injury, followed by orthopedic injury (69, 45.7%). Increasing severity of maxillofacial injury showed a positive correlation with increasing ISS. Also, positive correlation was noted with increasing severity of maxillofacial injury and presence of polytrauma (p = 0.01), traumatic brain injury (p = 0.034), and eye injuries (p = 0.034). There was a high prevalence of maxillofacial injuries in victims of RTC. There was a high incidence of concomitant injuries noted with these maxillofacial injuries. Significantly, this study showed a direct relationship between the severity of maxillofacial injury and head, ocular and polytrauma. This study further emphasizes the need for thorough examination of patients presenting with RTC-related maxillofacial injuries.

Management of severe skeletal Class III malocclusion with bimaxillary orthognathic surgery

PubMed Central

Haryani, Jitesh; Nagar, Amit; Mehrotra, Divya; Ranabhatt, Rani

2016-01-01

Orthognathic surgery in conjunction with fixed orthodontics is a common indication for interdisciplinary management of severe skeletal Class III malocclusion. A thorough analysis of pretreatment investigations and development of a surgical visual treatment objective is essential to plan the type of surgical technique required. Bimaxillary orthognathic surgery is the most common type of surgical procedure for severe skeletal discrepancies. The present case report is a combined ortho-surgical team management of a skeletally Class III patient. The severity of the case required bilateral upper first premolar extraction for dentoalveolar decompensation and simultaneous “Two-jaw surgery” with maxillary advancement of 4 mm and mandibular setback of 7 mm. Postsurgery, a pleasing good facial profile was achieved with Class II molar relation and positive overjet. PMID:27994433

Temporal changes in frequency of severe hypoglycemia treated by emergency medical services in types 1 and 2 diabetes: a population-based data-linkage cohort study.

PubMed

Wang, Huan; Donnan, Peter T; Leese, Callum J; Duncan, Edward; Fitzpatrick, David; Frier, Brian M; Leese, Graham P

2017-01-01

Almost 20 years ago, the frequencies of severe hypoglycemia requiring emergency medical treatment were reported in people with types 1 and 2 diabetes in the Tayside region of Scotland. With subsequent improvements in the treatment of diabetes, concurrent with changes in the provision of emergency medical care, a decline in the frequency of severe hypoglycemia could be anticipated. The present population-based data-linkage cohort study aimed to ascertain whether a temporal change has occurred in the incidence rates of hypoglycemia requiring emergency medical services in people with types 1 and 2 diabetes. The study population comprised all people with diabetes in Tayside, Scotland over the period 1 January 2011 to 31 December 2012. Patients' data from different healthcare sources were linked anonymously to measure the incidence rates of hypoglycemia requiring emergency medical services that include treatment by ambulance staff and in hospital emergency departments, and necessitated hospital admission. These were compared with data recorded in 1997-1998 in the same region. In January 2011 to December 2012, 2029 people in Tayside had type 1 diabetes and 21,734 had type 2 diabetes, compared to 977 and 7678, respectively, in June 1997 to May 1998. In people with type 2 diabetes, the proportion treated with sulfonylureas had declined from 36.8 to 22.4% ( p  < 0.001), while insulin-treatment had increased from 11.7 to 18.7% ( p  < 0.001). The incidence rate of hypoglycemia requiring emergency medical treatment had significantly fallen from 0.115 (95% CI: 0.094-0.136) to 0.082 (0.073-0.092) events per person per year in type 1 diabetes ( p  < 0.001), and from 0.118 (0.095-0.141) to 0.037 (0.003-0.041) in insulin-treated type 2 diabetes ( p  = 0.008). However, the absolute annual number of hypoglycemia events requiring emergency treatment was 1.4-fold higher. Although from 1998 to 2012 the incidences of hypoglycemia requiring emergency medical services appeared to have declined by a third in type 1 diabetes and by two thirds in insulin-treated type 2 diabetes, because the prevalence of diabetes was higher (2.7 fold), the number of severe hypoglycemia events requiring emergency medical treatment was greater.

[Study on the heterogeneity of edema in severe preeclampsia].

PubMed

Shi, Junmei; Yang, Zi; Chen, Lei

2014-05-06

The aim of this study was to analysis the clinical edema forms and explore the heterogeneity of edema in severe preeclampsia (PE) . From February 2002 to February 2009, Peking University Third Hospital admitted with severe preeclampsia 228 cases who were enrolled in this study. The form is divided into no edema (A-type), pure interstitial edema (B-type), a simple cavity gap edema (C-type) and mixed interstitial edema that coexist with lacunar edema (D-type). Analysis and comparison of various types of edema in patients with different clinical manifestations of prenatal care models, laboratory parameters, the incidence of gestational age, complications and obstetric and perinatal outcomes, and analyze the relationship between different types of edema and albumins and the peak value of proteinuria. Edema was seen in 86% (197/228) of all of cases. Compared the cases who have regular prenatal care with those who have irregular care, differences were statistically significant in edema type composition ratio (P < 0.01) and the incidence of serious complications (P < 0.01), and serum albumin levels (P < 0.01), but not in the peak value of proteinuria (P > 0.05); Compared early-onset PE and late-onset PE patients, differences were statistically significant in edema type composition ratio (P < 0.01) and peak value of proteinuria (P < 0.01), but not in serum albumin levels and the incidence of serious complications (P > 0.05). Comparison between the various types of edema, differences were statistically significant in serum albumin levels and peak value of proteinuria and incidence of serious complications and the gestational week at PE onset and the incidence of treatment preterm labor (P < 0.05).Occurrence of placental abruption, heart failure and HELLP syndrome had statistical significance in different types of edema(P < 0.05). The varying degrees of interstitial edema were correlated with serum albumin levels (r = -0.19, P < 0.05) and serious complication occurrence (r = -0.232, P < 0.05), but no correlation displayed with the peak value of urinary protein (P > 0.05). The manifestations of edema were diverse in severe preeclampsia. The forms of edema were related to the PE onset of gestational age and serious complication involving in different organs.Strengthen prenatal care and early detection of edema may improve adverse obstetric outcomes.

A unifying concept: pancreatic ductal anatomy both predicts and determines the major complications resulting from pancreatitis.

PubMed

Nealon, William H; Bhutani, Manoop; Riall, Taylor S; Raju, Gottumukkala; Ozkan, Orhan; Neilan, Ryan

2009-05-01

Precepts about acute pancreatitis, necrotizing pancreatitis, and pancreatic fluid collections or pseudocyst rarely include the impact of pancreatic ductal injuries on their natural course and outcomes. We previously examined and established a system to categorize ductal changes. We sought a unifying concept that may predict course and direct therapies in these complex patients. We use our system categorizing ductal changes in pseudocyst of the pancreas and severe necrotizing pancreatitis (type I, normal duct; type II, duct stricture; type III, duct occlusion or "disconnected duct"; and type IV, chronic pancreatitis). From 1985 to 2006, a policy was implemented of routine imaging (cross-sectional, endoscopic retrograde cholangiopancreatography, or magnetic resonance cholangiopancreatography). Clinical outcomes were measured. Among 563 patients with pseudocyst, 142 resolved spontaneously (87% of type I, 5% of type II, and no type III, and 3% of type IV). Percutaneous drainage was successful in 83% of type I, 49% of type II, and no type III or type IV. Among 174 patients with severe acute pancreatitis percutaneous drainage was successful in 64% of type I, 38% of type II, and no type III. Operative debridement was required in 39% of type I and 83% and 85% of types II and III, respectively. Persistent fistula after debridement occurred in 27%, 54%, and 85% of types I, II, and III ducts, respectively. Late complications correlated with duct injury. Pancreatic ductal changes predict spontaneous resolution, success of nonoperative measures, and direct therapies in pseudocyst. Ductal changes also predict patients with necrotizing pancreatitis who are most likely to have immediate and delayed complications.

Application of quantitative PCR assays for diagnosing Ikeda and other Theileria orientalis types to examine associations between severity of anaemia and parasitaemia in bovine anaemia outbreaks.

PubMed

Gias, E; Pulford, D J; Lawrence, K; McFadden, Amj

2016-01-01

To use quantitative PCR assays to detect Theileria orientalis Ikeda type in cattle presumed infected with T. orientalis, to examine the relationship between theilerial piroplasm count and haematocrit (HCT), and the relationship with quantification cycle threshold (Cq) values. Blood samples in EDTA (n=1,024), derived from herds affected by anaemia associated with T. orientalis infection (TABA) between April and October 2013, were submitted for testing using quantitative PCR (qPCR) assays for T. orientalis and Ikeda type. Nucleotide sequencing of the major piroplasm surface protein (MPSP) gene was performed on 16 samples to identify T. orientalis types. Blood smear and/or HCT results were supplied with most samples. For data analysis, the number of theilerial piroplasm per 1,000 erythrocytes counted was categorised as negative (0), low (1-9), moderate (10-100) or high (>100). HCT was categorised as severely anaemic (<0.15 L/L), mildly anaemic (0.15-0.24 L/L) or not anaemic (>0.24 L/L). Differences between categories in proportion of samples positive for Ikeda type or mean Cq value were examined using χ(2) tests or analysis of variance, respectively. Of 1,022 samples containing amplifiable DNA, 916 (90%) were positive for T. orientalis and 789 (77%) were positive for Ikeda type. Nucleotide sequencing of MPSP amplicons also identified the presence of Chitose and Buffeli types in 11 samples without Ikeda. Ikeda was detected in a greater proportion of severely anaemic (288/302; 95%) than mildly anaemic (227/252; 90%) cattle (p=0.02). In non-anaemic cattle, 344/406 (85%) were positive for T. orientalis and 247/406 (60%) were positive for Ikeda type. In samples from cattle that were piroplasm-positive, a greater proportion of anaemic (483/505, 96%) than non-anaemic (211/307; 69%) cattle were positive for Ikeda type (p<0.001). In piroplasm-negative cattle, 20/37 (54%) anaemic and 25/78 (32%) non-anaemic cattle were Ikeda-positive (p<0.05). The distributions of Cq values differed between piroplasm count and HCT categories (p<0.001). Mean Cq differed between high and negative, and low piroplasm categories (p<0.001), but not between high and moderate categories (p=0.81), and differed between severely anaemic and mildly anaemic (p<0.001), and non-anaemic categories (p<0.001). The Ikeda type was found in a high proportion of cattle during outbreaks of TABA in New Zealand. Analysis of Cq values suggested a relationship of Ikeda parasitaemia with severity of anaemia, but further investigation is required to better understand the role of parasitaemia in the pathogenesis of TABA.

Enhancing the MeSH thesaurus to retrieve French online health resources in a quality-controlled gateway.

PubMed

Douyère, Magaly; Soualmia, Lina F; Névéol, Aurélie; Rogozan, Alexandrina; Dahamna, Badisse; Leroy, Jean-Philippe; Thirion, Benoît; Darmoni, Stefan J

2004-12-01

The amount of health information available on the Internet is considerable. In this context, several health gateways have been developed. Among them, CISMeF (Catalogue and Index of Health Resources in French) was designed to catalogue and index health resources in French. The goal of this article is to describe the various enhancements to the MeSH thesaurus developed by the CISMeF team to adapt this terminology to the broader field of health Internet resources instead of scientific articles for the medline bibliographic database. CISMeF uses two standard tools for organizing information: the MeSH thesaurus and several metadata element sets, in particular the Dublin Core metadata format. The heterogeneity of Internet health resources led the CISMeF team to enhance the MeSH thesaurus with the introduction of two new concepts, respectively, resource types and metaterms. CISMeF resource types are a generalization of the publication types of medline. A resource type describes the nature of the resource and MeSH keyword/qualifier pairs describe the subject of the resource. A metaterm is generally a medical specialty or a biological science, which has semantic links with one or more MeSH keywords, qualifiers and resource types. The CISMeF terminology is exploited for several tasks: resource indexing performed manually, resource categorization performed automatically, visualization and navigation through the concept hierarchies and information retrieval using the Doc'CISMeF search engine. The CISMeF health gateway uses several MeSH thesaurus enhancements to optimize information retrieval, hierarchy navigation and automatic indexing.

Stuttering in English-Mandarin bilingual speakers: the influence of language dominance on stuttering severity.

PubMed

Lim, Valerie P C; Lincoln, Michelle; Chan, Yiong Huak; Onslow, Mark

2008-12-01

English and Mandarin are the 2 most spoken languages in the world, yet it is not known how stuttering manifests in English-Mandarin bilinguals. In this research, the authors investigated whether the severity and type of stuttering is different in English and Mandarin in English-Mandarin bilinguals, and whether this difference was influenced by language dominance. Thirty English-Mandarin bilinguals who stutter (BWS), ages 12-44 years, were categorized into 3 groups (15 English-dominant, 4 Mandarin-dominant, and 11 balanced bilinguals) using a self-report classification tool. Three 10-min conversations in English and Mandarin were assessed by 2 English-Mandarin bilingual clinicians for percent syllables stuttered (%SS), perceived stuttering severity (SEV), and types of stuttering behaviors using the Lidcombe Behavioral Data Language (LBDL; Packman & Onslow, 1998; Teesson, Packman, & Onslow, 2003). English-dominant and Mandarin-dominant BWS exhibited higher %SS and SEV scores in their less dominant language, whereas the scores for the balanced bilinguals were similar for both languages. The difference in the percentage of stutters per LBDL category between English and Mandarin was not markedly different for any bilingual group. Language dominance appeared to influence the severity but not the types of stuttering behaviors in BWS. Clinicians working with BWS need to assess language dominance when diagnosing stuttering severity in bilingual clients.

Severe psychomotor delay in a severe presentation of cat-eye syndrome.

PubMed

Jedraszak, Guillaume; Receveur, Aline; Andrieux, Joris; Mathieu-Dramard, Michèle; Copin, Henri; Morin, Gilles

2015-01-01

Cat-eye syndrome is a rare genetic syndrome of chromosomal origin. Individuals with cat-eye syndrome are characterized by the presence of preauricular pits and/or tags, anal atresia, and iris coloboma. Many reported cases also presented with variable congenital anomalies and intellectual disability. Most patients diagnosed with CES carry a small supernumerary bisatellited marker chromosome, resulting in partial tetrasomy of 22p-22q11.21. There are two types of small supernumerary marker chromosome, depending on the breakpoint site. In a very small proportion of cases, other cytogenetic anomalies are reportedly associated with the cat-eye syndrome phenotype. Here, we report a patient with cat-eye syndrome caused by a type 1 small supernumerary marker chromosome. The phenotype was atypical and included a severe developmental delay. The use of array comparative genomic hybridization ruled out the involvement of another chromosomal imbalance in the neurological phenotype. In the literature, only a few patients with cat-eye syndrome present with a severe developmental delay, and all of the latter carried an atypical partial trisomy 22 or an uncharacterized small supernumerary marker chromosome. Hence, this is the first report of a severe neurological phenotype in cat-eye syndrome with a typical type 1 small supernumerary marker chromosome. Our observation clearly complicates prognostic assessment, particularly when cat-eye syndrome is diagnosed prenatally.

Untangling the relative contribution of maltreatment severity and frequency to type of behavioral outcome in foster youth

PubMed Central

Jackson, Yo; Gabrielli, Joy; Fleming, Kandace; Makanui, P. Kalani; Tunno, Angela M.

2014-01-01

Within maltreatment research, type, frequency, and severity of abuse are often confounded and not always specifically documented. The result is that samples are often heterogeneous, and the role of components of maltreatment in predicting outcome is unclear. The purpose of the present study was to identify and test the potential unique role of type, frequency, and severity of maltreatment to elucidate each variable’s role in predicting outcome behavior. Data from 309 youth in foster care (ages 8–22) and their caregivers were collected using the Modified Maltreatment Classification System and the Behavioral Assessment System for Children, 2nd Edition (BASC2), to measure maltreatment exposure and behavioral outcome respectively. A measurement model of the BASC2 was completed to determine model fit within the sample data. A second confirmatory factor analysis (CFA) was completed to determine the unique contributions of frequency and severity of maltreatment across four types of abuse to externalizing, internalizing, and adaptive behavior. The result of the CFA determined good fit of the BASC2 to the sample data after a few modifications. The result of the second CFA indicated that the paths from severity to externalizing behavior and adaptive behavior (reverse loading) were significant. Paths from frequency of abuse were not predictive of behavioral outcome. Maltreatment is a complex construct and researchers are encouraged to avoid confounding components of abuse that may be differentially related to outcome behavior for youth. Untangling the multifaceted nature of abuse is important and may have implications for identifying specific outcomes for youth exposed to maltreatment. PMID:24612908

Differences in Characteristics of Aviation Accidents During 1993-2012 Based on Aircraft Type

NASA Technical Reports Server (NTRS)

Evans, Joni K.

2015-01-01

Civilian aircraft are available in a variety of sizes, engine types, construction materials and instrumentation complexity. For the analysis reported here, eleven aircraft categories were developed based mostly on aircraft size and engine type, and these categories were applied to twenty consecutive years of civil aviation accidents. Differences in various factors were examined among these aircraft types, including accident severity, pilot characteristics and accident occurrence categories. In general, regional jets and very light sport aircraft had the lowest rates of adverse outcomes (injuries, fatal accidents, aircraft destruction, major accidents), while aircraft with twin (piston) engines or with a single (piston) engine and retractable landing gear carried the highest incidence of adverse outcomes. The accident categories of abnormal runway contact, runway excursions and non-powerplant system/component failures occur frequently within all but two or three aircraft types. In contrast, ground collisions, loss of control - on ground/water and powerplant system/component failure occur frequently within only one or two aircraft types. Although accidents in larger aircraft tend to have less severe outcomes, adverse outcome rates also differ among accident categories. It may be that the type of accident has as much or more influence on the outcome as the type of aircraft.

Association of serum vitamin D levels and diabetic retinopathy in Asian Indians with type 2 diabetes.

PubMed

Ashinne, Beteal; Rajalakshmi, Ramachandran; Anjana, Ranjit M; Venkat Narayan, K M; Jayashri, Ramamoorthy; Mohan, Viswanathan; Hendrick, Andrew M

2018-05-01

Vitamin D deficiency (VDD) is a condition that has been associated with diabetic retinopathy (DR) in various populations, but has not been studied in Asian Indians. To evaluate the association of serum 25-hydroxyvitamin D (25(OH)D) levels with presence and severity of DR among Asian Indians with type 2 diabetes. We collected information on individuals with type 2 diabetes that received care at a tertiary diabetes centre in India, between 2012 and 2015. Patients were 18 years of age or older, underwent retinal examinations with DR severity grading and had serum 25(OH)D measurements. Serum 25(OH)D levels were lower in patients with retinopathy compared to those without (11.9 ± 2.2 ng/ml vs. 13.7 ± 2.1 ng/ml, p < 0.001). Stratifying patients by DR grade, reduced geometric means of 25(OH)D levels were associated with increased retinopathy severity. After adjusting for six key covariates, VDD was associated with increased rates of proliferative DR (OR 2.05; 95% CI 1.35-3.11; p = 0.001). In Asian Indians with type 2 diabetes, lower serum 25(OH)D was associated with increased severity of DR and the presence of VDD was associated with a two-fold increased risk for proliferative DR. Copyright © 2018 Elsevier B.V. All rights reserved.

Eczema

MedlinePlus

Eczema is a term for several different types of skin swelling. Eczema is also called dermatitis. Most types cause dry, ... red, and to swell and itch even more. Eczema is not contagious. The cause is not known. ...

Effects of enzyme replacement therapy for cardiac-type Fabry patients with a Chinese hotspot late-onset Fabry mutation (IVS4+919G>A)

PubMed Central

Lin, Hsiang-Yu; Liu, Hao-Chuan; Huang, Yu-Hsiu; Liao, Hsuan-Chieh; Hsu, Ting-Rong; Shen, Chia-I; Li, Shao-Tzu; Li, Cheng-Fang; Lee, Li-Hong; Lee, Pi-Chang; Huang, Chun-Kai; Chiang, Chuan-Chi; Lin, Ching-Yuang; Lin, Shuan-Pei; Niu, Dau-Ming

2013-01-01

Objective Current studies of newborn screening for Fabry disease in Taiwan have revealed a remarkably high prevalence of cardiac-type Fabry disease with a Chinese hotspot late-onset Fabry mutation (IVS4+919G>A). Design Retrospective cohort study. Setting Tertiary medical centre. Participants 21 patients with cardiac-type Fabry disease (15 men and 6 women) as well as 15 patients with classic Fabry disease (4 men and 11 women) treated with biweekly intravenous infusions of agalsidase β (1 mg/kg) or agalsidase α (0.2 mg/kg) for at least 6 months. Outcome measures These data were collected at the time before enzyme replacement therapy (ERT) began and followed up after ERT for at least 6 months, including patient demographics, medical history, parameter changes of cardiac status and renal functions, plasma globotriaosylsphingosine (lyso-Gb3) and Mainz Severity Score Index. Results After 6–39 months of ERT, plasma lyso-Gb3 was found to be reduced in 89% (17/19) and 93% (14/15) of patients with cardiac-type and classic Fabry disease, respectively, which indicated an improvement of disease severity. For patients with cardiac-type Fabry disease, echocardiography revealed the reduction or stabilisation of left ventricular mass index (LVMI), the thicknesses of intraventricular septum (IVS) and left posterior wall (LPW) in 83% (15/18), 83% (15/18) and 67% (12/18) of patients, respectively, as well as 77% (10/13), 73% (11/15) and 60% (9/15) for those with classic type. Most patients showed stable renal function after ERT. There were statistically significant improvements (p<0.05) between the data at baseline and those after ERT for values of plasma lyso-Gb3, LVMI, IVS, LPW and Mainz Severity Score Index. No severe clinical events were reported during the treatment. Conclusions ERT is beneficial and appears to be safe for Taiwanese patients with cardiac-type Fabry disease, as well as for those with the classic type. PMID:23864212

Racial/Ethnic and gender prevalences in reported common pains in a national sample.

PubMed

Plesh, Octavia; Adams, Sally H; Gansky, Stuart A

2011-01-01

To compare prevalences of self-reported temporomandibular joint and muscle disorders (TMJMD)-type pain, headaches, and neck and back pains in the 2000 to 2005 US National Health Interview Survey (NHIS) by gender and age for non-Hispanic Whites (Whites), Hispanics, and non-Hispanic Blacks (Blacks). Data from the 2000 to 2005 NHIS included information on gender, age, race, ethnicity, and different common types of pain specifically: TMJMD-type pain, severe headaches/migraine, neck, and low back pains. A total of 189,992 people were included: 52% female and 48% male, 73% White, 12% Hispanic, 11% Black, and 4% "Other." The overall prevalence of TMJMD-type pain was 4.6%; severe headaches/migraine was 15.4%; neck, 14.9%; and low back, 28.0%. Survey logistic regression models estimating race-specific, age-adjusted curves revealed race by age pain differences. For TMJMD-type pain, White females presented the highest prevalence at younger ages, decreasing after age 40. Prevalences for Hispanic and Black females, although lower at younger ages, increased up to age 60 and remained higher than Whites. Males showed less racial/ethnic and age variation. Severe headaches/migraines presented an age pattern similar to TMJMD-type pain for White females and little overall variation for males, but without racial differences. Neck pain showed some similarities to TMJMD-type pain: higher in Whites at younger ages, lower at older ages, with Hispanics having the highest rates after their 60's. For low back pain, the rates peaked around the sixth decade for all racial/ethnic groups. The patterns of TMJMD-type pain varied greatly within and across racial/ethnic groups by gender and across the adult lifespan. Similarities and differences for the other pains were noted.

Disaster Distress Helpline: Wildfires

MedlinePlus

... Tips Anniversaries and Trigger Events Types of Disasters Tornadoes and Severe Storms Hurricanes and Tropical Storms Floods ... While not reported as often as floods or tornadoes and severe storms , they, too, can cause emotional ...

Severe perineal lacerations in nulliparous women and episiotomy type.

PubMed

Aytan, Hakan; Tapisiz, Omer L; Tuncay, Gorkem; Avsar, Filiz A

2005-07-01

To determine the patient-related factors associated with severe perineal lacerations in nulliparous women and to evaluate the effect of episiotomy type on the risk of severe perineal tears. In all, 400 nulliparous women admitted in labor between June and December 2001 were prospectively enrolled. Maternal height, perineal length, fetal birth weight, fetal head circumference, and severe perineal lacerations (third and fourth degrees) were recorded. The rate of severe perineal lacerations was 2% (8/400); 3% with midline, 1% with mediolateral groups. In patients with severe lacerations, perineal length was significantly (p < 0.001) shorter and the head circumference of their babies in the midline significantly (p < 0.05) greater than normal, and birth weights were also significantly (p < 0.05) greater in the mediolateral group. A cut-off value for perineal length of 3.05 cm was found for severe lacerations in the midline group. If episiotomy is to be performed, it must be borne in mind that patients with a perineal length of < or = 3 cm have an elevated risk of severe perineal lacerations, and if clinical or ultrasound examination suggests that the fetal head is large, mediolateral episiotomy may be preferred. Otherwise, midline episiotomy must be considered.

Conversion of multiple analyte cation types to a single analyte anion type via ion/ion charge inversion.

PubMed

Hassell, Kerry M; LeBlanc, Yves; McLuckey, Scott A

2009-11-01

Charge inversion ion/ion reactions can convert several cation types associated with a single analyte molecule to a single anion type for subsequent mass analysis. Specifically, analyte ions present with one of a variety of cationizing agents, such as an excess proton, excess sodium ion, or excess potassium ion, can all be converted to the deprotonated molecule, provided that a stable anion can be generated for the analyte. Multiply deprotonated species that are capable of exchanging a proton for a metal ion serve as the reagent anions for the reaction. This process is demonstrated here for warfarin and for a glutathione conjugate. Examples for several other glutathione conjugates are provided as supplementary material to demonstrate the generality of the reaction. In the case of glutathione conjugates, multiple metal ions can be associated with the singly-charged analyte due to the presence of two carboxylate groups. The charge inversion reaction involves the removal of the excess cationizing agent, as well as any metal ions associated with anionic groups to yield a singly deprotonated analyte molecule. The ability to convert multiple cation types to a single anion type is analytically desirable in cases in which the analyte signal is distributed among several cation types, as is common in the electrospray ionization of solutions with relatively high salt contents. For analyte species that undergo efficient charge inversion, such as glutathione conjugates, there is the additional potential advantage for significantly improved signal-to-noise ratios when species that give rise to 'chemical noise' in the positive ion spectrum do not undergo efficient charge inversion.

Informed walks: whispering hints to gene hunters inside networks' jungle.

PubMed

Bourdakou, Marilena M; Spyrou, George M

2017-10-11

Systemic approaches offer a different point of view on the analysis of several types of molecular associations as well as on the identification of specific gene communities in several cancer types. However, due to lack of sufficient data needed to construct networks based on experimental evidence, statistical gene co-expression networks are widely used instead. Many efforts have been made to exploit the information hidden in these networks. However, these approaches still need to capitalize comprehensively the prior knowledge encrypted into molecular pathway associations and improve their efficiency regarding the discovery of both exclusive subnetworks as candidate biomarkers and conserved subnetworks that may uncover common origins of several cancer types. In this study we present the development of the Informed Walks model based on random walks that incorporate information from molecular pathways to mine candidate genes and gene-gene links. The proposed model has been applied to TCGA (The Cancer Genome Atlas) datasets from seven different cancer types, exploring the reconstructed co-expression networks of the whole set of genes and driving to highlighted sub-networks for each cancer type. In the sequel, we elucidated the impact of each subnetwork on the indication of underlying exclusive and common molecular mechanisms as well as on the short-listing of drugs that have the potential to suppress the corresponding cancer type through a drug-repurposing pipeline. We have developed a method of gene subnetwork highlighting based on prior knowledge, capable to give fruitful insights regarding the underlying molecular mechanisms and valuable input to drug-repurposing pipelines for a variety of cancer types.

Medical error identification, disclosure, and reporting: do emergency medicine provider groups differ?

PubMed

Hobgood, Cherri; Weiner, Bryan; Tamayo-Sarver, Joshua H

2006-04-01

To determine if the three types of emergency medicine providers--physicians, nurses, and out-of-hospital providers (emergency medical technicians [EMTs])--differ in their identification, disclosure, and reporting of medical error. A convenience sample of providers in an academic emergency department evaluated ten case vignettes that represented two error types (medication and cognitive) and three severity levels. For each vignette, providers were asked the following: 1) Is this an error? 2) Would you tell the patient? 3) Would you report this to a hospital committee? To assess differences in identification, disclosure, and reporting by provider type, error type, and error severity, the authors constructed three-way tables with the nonparametric Somers' D clustered on participant. To assess the contribution of disclosure instruction and environmental variables, fixed-effects regression stratified by provider type was used. Of the 116 providers who were eligible, 103 (40 physicians, 26 nurses, and 35 EMTs) had complete data. Physicians were more likely to classify an event as an error (78%) than nurses (71%; p = 0.04) or EMTs (68%; p < 0.01). Nurses were less likely to disclose an error to the patient (59%) than physicians (71%; p = 0.04). Physicians were the least likely to report the error (54%) compared with nurses (68%; p = 0.02) or EMTs (78%; p < 0.01). For all provider and error types, identification, disclosure, and reporting increased with increasing severity. Improving patient safety hinges on the ability of health care providers to accurately identify, disclose, and report medical errors. Interventions must account for differences in error identification, disclosure, and reporting by provider type.

Synoptic and Mesoscale Climatologies of Severe Local Storms for the American Midwest.

NASA Astrophysics Data System (ADS)

Arnold, David Leslie

This study investigates the synoptic and mesoscale environments associated with severe local storms (SELS) in the heart of the American Midwest. This region includes west-central Illinois, most of Indiana, the extreme western counties of Ohio, and a small part of northeastern Kentucky. The primary objectives of this study are to determine the surface and middle-tropospheric synoptic circulation patterns and thermodynamic and kinematic environments associated with SELS event types (tornadoes, hail, severe straight -line winds), and to assess the degree to which the synoptic circulation patterns and meso-beta scale kinematic and thermodynamic climatology of the Midwest differ from that of the Great Plains. A secondary objective is to investigate the possible role that land-surface atmosphere interactions play in the spatial distribution of SELS. A new subjective synoptic typing scheme is developed and applied to determine the synoptic-scale circulation patterns associated with the occurrence of SELS event types. This scheme is based on a combination of surface and middle -tropospheric patterns. Thermodynamic and kinematic parameters are analyzed to determine meso-scale environments favorable for the development of SELS. Results indicate that key synoptic-scale circulation patterns, and specific ranges of thermodynamic and kinematic parameters are related to specific SELS event types. These circulation types and ranges of thermodynamic and kinematic parameters may be used to help improve the medium-range forecasting of severe local storms. Results of the secondary objective reveal that the spatial distribution of SELS events is clustered within the study region, and most occur under a negative climate division-level soil moisture gradient; that is, a drier upwind division than the division in which the event occurs. Moreover, the spatial distribution of SELS events is compared against a map of soil types and vegetation. The resulting distribution depicts a visual correlation between the primary soil and vegetative boundaries and clusters of SELS. This supports the likely role of meso-scale land-surface-atmosphere interactions in severe weather development for humid lowlands of the Midwest United States.

Prevalence and Impact of Migraine and Tension-Type Headache in Korea

PubMed Central

Kim, Byung-Kun; Chu, Min Kyung; Lee, Te Gyu; Kim, Jae-Moon; Chung, Chin-Sang

2012-01-01

Background and Purpose The epidemiology and impact of headache disorders are only partially documented for Asian countries. We investigated the prevalence and impact of migraine and tension-type headache - which are the two most common primary headache disorders - in a Korean population. Methods A stratified random population sample of Koreans older than 19 years was selected and evaluated using a 29-item, semistructured interview. The questionnaire was designed to classify headache types according to the criteria of the International Classification of Headache Disorders, second edition, including migraine and tension-type headache. The questionnaire also included items on basic demographics such as age, gender, geographical region, education level, and income, and the impact of headache on the participant. Results Among the 1507 participants, the 1-year prevalence of all types of headaches was 61.4% (69.9% in women and 52.8% in men). The overall prevalence rates of migraine and tension-type headaches were 6.1% (9.2% in women and 2.9% in men) and 30.8% (29.3% in women and 32.2% in men), respectively. The prevalence of migraine peaked at the age of 40-49 years in women and 19-29 years in men. In contrast to migraine, the prevalence of tension-type headache was not influenced by either age or gender. Among individuals with migraine and tension-type headache, 31.5% and 7% reported being substantially or severely impacted by headache, respectively (Headache Impact Test score ≥56). Overall, 13.4% of all headache sufferers reported being either substantially or severely impacted by headache. Conclusions The 1-year prevalence rates of migraine and tension-type headache in the studied Korean population were 6.1% and 30.8%, respectively. One-third of migraineurs and some individuals with tension-type headache reported being either substantially or severely impacted by headache. PMID:23091530

Efficacy of vildagliptin in combination with insulin in patients with type 2 diabetes and severe renal impairment

PubMed Central

Lukashevich, Valentina; Schweizer, Anja; Foley, James E; Dickinson, Sheila; Groop, Per-Henrik; Kothny, Wolfgang

2013-01-01

Background The purpose of this study was to evaluate the efficacy of vildagliptin 50 mg once daily in patients with severe renal impairment (estimated glomerular filtration rate < 30 mL/min/1.73 m2) and longstanding type 2 diabetes not adequately controlled with insulin therapy, which is a difficult-to-treat population, with limited therapeutic options and a high susceptibility to hypoglycemia. Methods This was a post hoc subanalysis of data obtained during a previously described randomized, double-blind, parallel-group, 24-week study comparing the efficacy and safety of vildagliptin 50 mg once daily versus placebo in patients with type 2 diabetes and moderate or severe renal impairment. The present data derive from 178 patients with severe renal impairment (baseline estimated glomerular filtration rate approximately 21 mL/min/1.73 m2, 100 randomized to vildagliptin, 78 randomized to placebo), all of whom were receiving insulin therapy (alone or in combination with an oral antidiabetic agent) for longstanding type 2 diabetes (mean approximately 19 years). Results With vildagliptin in combination with insulin, the adjusted mean change (AMΔ) in HbA1c from baseline (7.7% ± 0.1%) was −0.9% ± 0.4% and the between-treatment difference (vildagliptin – placebo) was −0.6% ± 0.2% (P < 0.001). The percentage of patients achieving endpoint HbA1c < 7.0% was significantly higher with vildagliptin than placebo (45.2% versus 22.8%, P = 0.008). When added to insulin, vildagliptin and placebo had comparable hypoglycemic profiles and did not cause weight gain. Both treatments were similarly well tolerated, with comparable incidences of adverse events, serious adverse events, and deaths. Conclusion When added to insulin therapy in patients with severe renal impairment and longstanding type 2 diabetes, vildagliptin 50 mg once daily was efficacious, eliciting HbA1c reductions consistent with those previously reported for a patient population with much more recent onset of type 2 diabetes and normal renal function, and had a hypoglycemic profile comparable with placebo. Accordingly, vildagliptin is a suitable treatment option for patients with advanced type 2 diabetes and impaired renal function who require insulin therapy and present a serious therapeutic challenge in clinical practice. PMID:23378769

The interaction between awareness of one's own speech disorder with linguistics variables: distinctive features and severity of phonological disorder.

PubMed

Dias, Roberta Freitas; Melo, Roberta Michelon; Mezzomo, Carolina Lisbôa; Mota, Helena Bolli

2013-01-01

To analyze the possible relationship among the awareness of one's own speech disorder and some aspects of the phonological system, as the number and the type of changed distinctive features, as well as the interaction among the severity of the disorder and the non-specification of distinctive features. The analyzed group has 23 children with diagnosis of speech disorder, aged 5:0 to 7:7. The speech data were analyzed through the Distinctive Features Analysis and classified by the Percentage of Correct Consonants. One also applied the Awareness of one's own speech disorder test. The children were separated in two groups: with awareness of their own speech disorder established (more than 50% of correct identification) and without awareness of their own speech disorder established (less than 50% of correct identification). Finally, the variables of this research were submitted to analysis using descriptive and inferential statistics. The type of changed distinctive features weren't different between the groups, as well as the total of changed features and the severity disorder. However, a correlation between the severity disorder and the non-specification of distinctive features was verified, because the more severe disorders have more changes in these linguistic variables. The awareness of one's own speech disorder doesn't seem to be directly influenced by the type and by the number of changed distinctive features, neither by the speech disorder severity. Moreover, one verifies that the greater phonological disorder severity, the greater the number of changed distinctive features.

Astrocytes surviving severe stress can still protect neighboring neurons from proteotoxic injury

PubMed Central

Gleixner, Amanda M.; Posimo, Jessica M.; Pant, Deepti B.; Henderson, Matthew P.; Leak, Rehana K.

2015-01-01

Astrocytes are one of the major cell types to combat cellular stress and protect neighboring neurons from injury. In order to fulfill this important role, astrocytes must sense and respond to toxic stimuli, perhaps including stimuli that are severely stressful and kill some of the astrocytes. The present study demonstrates that primary astrocytes that managed to survive severe proteotoxic stress were protected against subsequent challenges. These findings suggest that the phenomenon of preconditioning or tolerance can be extended from mild to severe stress for this cell type. Astrocytic stress adaptation lasted at least 96 hours, the longest interval tested. Heat shock protein 70 (Hsp70) was raised in stressed astrocytes, but inhibition of neither Hsp70 nor Hsp32 activity abolished their resistance against a second proteotoxic challenge. Only inhibition of glutathione synthesis abolished astrocytic stress adaptation, consistent with our previous report. Primary neurons were plated upon previously stressed astrocytes and the co-cultures were then exposed to another proteotoxic challenge. Severely stressed astrocytes were still able to protect neighboring neurons against this injury and the protection was unexpectedly independent of glutathione synthesis. Stressed astrocytes were even able to protect neurons after simultaneous application of proteasome and Hsp70 inhibitors, which otherwise elicited synergistic, severe loss of neurons when applied together. Astrocyte-induced neuroprotection against proteotoxicity was not elicited with astrocyte-conditioned media, suggesting that physical cell-to-cell contacts may be essential. These findings suggest that astrocytes may adapt to severe stress so that they can continue to protect neighboring cell types from profound injury. PMID:26374549

Soil organic matter composition and quality across fire severity gradients in coniferous and deciduous forests of the southern boreal region

NASA Astrophysics Data System (ADS)

Miesel, Jessica R.; Hockaday, William C.; Kolka, Randall K.; Townsend, Philip A.

2015-06-01

Recent patterns of prolonged regional drought in southern boreal forests of the Great Lakes region, USA, suggest that the ecological effects of disturbance by wildfire may become increasingly severe. Losses of forest soil organic matter (SOM) during fire can limit soil nutrient availability and forest regeneration. These processes are also influenced by the composition of postfire SOM. We sampled the forest floor layer (i.e., full organic horizon) and 0-10 cm mineral soil from stands dominated by coniferous (Pinus banksiana Lamb.) or deciduous (Populus tremuloides Michx.) species 1-2 months after the 2011 Pagami Creek wildfire in northern Minnesota. We used solid-state 13C NMR to characterize SOM composition across a gradient of fire severity in both forest cover types. SOM composition was affected by fire, even when no statistically significant losses of total C stocks were evident. The most pronounced differences in SOM composition between burned and unburned reference areas occurred in the forest floor for both cover types. Carbohydrate stocks in forest floor and mineral horizons decreased with severity level in both cover types, whereas pyrogenic C stocks increased with severity in the coniferous forest floor and decreased in only the highest severity level in the deciduous forest floor. Loss of carbohydrate and lignin pools contributed to a decreased SOM stability index and increased decomposition index. Our results suggest that increases in fire severity expected to occur under future climate scenarios may lead to changes in SOM composition and dynamics with consequences for postfire forest recovery and C uptake.