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MIXED DONOR CHIMERISM AND LOW LEVEL IDURONIDASE EXPRESSION MAY BE ADEQUATE FOR NEURODEVELOPMENTAL JENNIFER CONWAY, MD, SARAH DYACK, MD, FRCPC, FCCMG, BRUCE N. A. CROOKS, MB, CHB, BSC, MRCP, Hurler syndrome is a lysosomal storage disease resulting in fatal cardiac or neurologic sequelae unless alpha-iduronidase production is reconstituted with hematopoietic stem cell transplantation. We report on a 4-year, 6-month-old boy with mixeddonor chimerism and low enzyme levels but a normal neurodevelopmental trajectory. (J Pediatr 2005;147:106-8) Children with Hurler syndrome lack the lysosomal enzyme alpha-L-iduronidase. This results in glycosaminoglycan (GAG) accumulation with progressive mental retardation and death.Recombinant alpha-L-iduronidase appears toameliorate some of the systemic effects in Hurler syndrome, but hematopoietic stem cell transplantation remains the only means of preventing the neurologic deterioration.
Children with Hurler syndrome have normal intelligence at birth, but on average their IQ declines by 2 standard deviations within the first 2 years of life (30-point decrease in IQ).The negative correlation between age and IQ has been found to besignificant (r = 20.82, P # .0003).Good neuropsychological outcomes after bone marrow transplantation (BMT) aredependent on multiple factors including age at transplantation (<24 months), mental developmental indexes >70 beforetransplantation, adequate engraftment (as measured by full donor chimerism), and posttransplantation iduronidase activity.We report the case of a patient with Hurler syndrome in whom a good neurologic outcome was achieved in spite of poor sustainedengraftment and very low serum alpha-L-iduronidase activity after BMT.
At 9 months of age, the patient presented with coarse facies and a lumbar gibbus. He had dysostosis multiplex and a positive mucopolysaccharide (MPS) screen result. Hurlersyndrome was confirmed by the absence of alpha-L-iduronidase activity in peripheralblood leukocytes. He had a homozygous mutation of his IDUA gene, W402X, common tothose with a severe Hurler phenotype.
At 15 months of age, the patients underwent BMT from a male matched related donor. Conditioning regimen included cyclophosphamide (50 mg/kg 3 4 doses), busulfan(based on targeted AUC 18mg/kg divided every 6 hours over 4 days), and low-dose totalbody irradiation (300 cGy). The patient was transplanted with 5.6 3 108 nucleated cells/ kg. He had no unexpected transplant-related toxicity and specifically no central nervous After BMT, his musculoskeletal abnormalities persisted but were stable, his facial the IWK Health Centre and DalhousieUniversity, Halifax, Nova Scotia.
features softened, and airway obstruction resolved. An echocardiogram obtained 2 years after transplantation showed resolution of both his atrial septal defect and mild valvular 2005; accepted Mar 3, 2005.
Reprint requests: Conrad Fernandez Initially he fully engrafted. He was followed by chimerisms on whole blood and alpha-L-iduronidase levels on unfractionated peripheral leukocytes. He expressed normal levels of alpha-L-iduronidase after transplantation but failed to sustain these beyond 4 9700, Halifax, Nova Scotia B3K 6R8Canada. E-mail: months after BMT. The patient has remained at very low levels of activity ( 0022-3476/$ - see front matterCopyright ª 2005 Elsevier Inc. All rightsreserved.
Based on clinical evaluation and developmental achieve- Table. Measured levels of alpha-L-iduronidase and ments, it was felt that his pretransplantation development was normal. He sat at 6½ months, stood at 7 months, had singlewords at 10 months, and walked at 13 months. Two years after BMT (age 3 years, 3 months), a formal neuropsychologicalevaluation demonstrated development in the normal range.
Full Scale intelligence testing revealed average intelligence (45th percentile). There was a minor discrepancy between his verbal (average range) and performance intelligence (low- average range). He had mild difficulties with visual spatial skills, primarily with block design. His language skills were normal on the Token Test for children.
His most-recent evaluation at age 4 years 5 months revealed dramatic improvements on the Peabody Develop- mental Motor Skills, with an age equivalent of 41 months.
(This minor delay was attributed to his Hurler syndrome– induced flexion contractures of his fingers). He continued to do well in school and was communicating in both English and *Alpha iduronidase enzyme activity was measured using a standardized French. Repeat neuropsychological testing at that time assay on unfractionated peripheral blood leukocytes.
y revealed average full-scale intelligence with no discrepancy Chimerism was determined by restriction fragment length polymorphism on the recipient’s whole blood sample.
between his verbal and performance skills.
zBelieved to be secondary to assay problems.
central levels of GAGs before and after BMT in a patient with Hurler syndrome is a progressive disease that leads to Hurler syndrome. After BMT, peripheral enzyme activity was coarse facial features, corneal clouding, hernias, hepatospleno- greater than 50% of normal (13 nmol/mg/protein/h with megaly, skeletal deformities, and progressive mental retarda- normal 28 ± 7) but never achieved complete engraftment. At tion.Death results from heart disease or respiratory failure the patient’s 2-year follow-up, in spite of low enzyme activity, the levels of central GAGs were stable, routine neuroimaging Cleary and Wraitshowed that normal developmental results were normal, and the child had a 28-point increase in milestones over the first year of life were achieved by all of IQ.This is the first neuroimaging evidence that peripheral their patients. However, neurodevelopment does not continue enzyme activity may be limited in predicting CNS enzyme along a normal trajectory after the first year.Therefore activity. Our case adds support to this notion.
our patient should have had evidence of neurologic deterio- Limitations of this report include that it may be too ration if there were inadequate cerebral alpha-L-iduronidase early to predict our patient’s ultimate neurologic outcome, although if enzyme activity in the CNS were inadequate, he The rationale for BMT lies in the provision of donor should have shown cognitive decline by age 4. Although de- histiocytes that migrate to the central nervous system (CNS), layed or minimal cognitive problems are seen in attenuated differentiate into microglial cells, and provide an ongoing forms of MPS1, such as Hurler-Scheie syndrome, our patient source of functional enzyme.We postulate that this presented with significant symptoms before 1 year of age, occurred in our patient at sufficient levels to provide neuro- and his IDUA mutations are associated with a severe MPS1 protection in spite of an inadequate peripheral engraftment.
phenotype. Thus we are confident he has Hurler syndrome.
Peters et showed that iduronidase activity post BMT Our case illustrates that normal peripheral blood alpha- less than or equal to that of a heterozygous carrier donor (~50%) L-iduronidase levels may not be required to sustain normal was associated with a poor neurologic outcome (Mental neuropsychological development in patients with Hurler Development Index [MDI] #80). A statistically significant syndrome after BMT. If techniques can be developed to correlation was subsequently found between MDI at follow-up identify prospectively those patients who are destined to and peripheral enzyme activity in these patients (0.59, P = .02).
have a good neurologic outcome in spite of low peripheral Other studies have reported adequate developmental outcomes blood alpha-L-iduronidase levels (for example by functional in children with less than 90% chimerism (although all had at neuroimaging or other central nervous system biochemical least 50% chimerism).Our patient’s outcome suggests markers), we may avoid the morbidity and mortality of a that even very low levels of peripheral enzyme activity level can be associated with normal development.
Data regarding the presence of alpha-iduronidase activity in the CNS after BMT is indirectly derived from cerebrospinal fluid and neuroimaging stTakahashi Cleary MA, Wraith JE. The presenting features of mucopolysaccha- et alused magnetic resonance spectroscopy to measure ridosis Type IH (Hurler Syndrome). Acta Paediatric 1995;84:337-9.
Mixed Donor Chimerism And Low Level Iduronidase Expression May Be AdequateFor Neurodevelopmental Protection In Hurler Syndrome Shapiro EG, Lockman LA, Balthazor M, Krivit W. Neuropsychological Krivit W, Peters C, Shapiro EG. Bone marrow transplant as effective outcomes of several storage diseases with or without bone marrow transplant.
treatment of central nervous system disease in globoid cell leukodystrophy, metachromatic leukodystrophy, adrenoleukodystrophy, mannosidosis, fuco- Wraith JE, Clarke LA, Beck M, Kolodny EH, Pastores GM, sidosis, aspartylglucosaminuria, Hurler, Marteaux-Lamy, and Sly syndromes Muenzer J, et al. Enzyme replacement therapy for mucopolysacchari- and Gaucher disease type III. Curr Opin Neurol 1999;12:167-76.
dosis I: a randomized, double-blinded, placebo-controlled, multinational Cowan MJ. Bone marrow transplant for the treatment of genetic disease.
study of recombinant human alpha-L-iduronidase. J Pediatrics 2004; Clinical Biochemistry 1991;24:375-81.
Guffon N, Souillet G, Maire I, Straczek J, Guibaud P. Follow-up of Peters C. Neuropsychological development of children with Hurler nine patients with Hurler Syndrome after bone marrow transplant. J Pediatr syndrome following hematopoietic stem cell transplant. Pediatr Transplant 10. Takakashi Y, Sukegawa K, Aoki M, Suzuki K, Sakaguchi H, Watanabe Peters C, Shapiro E, Anderson J, Henslee-Downey JP, Klemperer MR, M, et al. Evaluation of accumulated mucoploysaccharides in the brain Cowan MJ, et al. Hurler syndrome: II. Outcome of HLA-genotypically if patients with mucopolysaccharidoses by H-magnetic resonance spectros- identical sibling and HLA haploidentical related donor bone marrow copy before and after bone marrow transplant. Pediatr Res 2001;49: transplantation in 54 children. Blood 1998;7:2601-8.
Peters C, Balthazor M, Shapiro EG, King JR, Kollman C, Hegland JD, 11. Whitley CB, Kumar GB, Chang PN, Summers CG, Blazar BR, Tsai et al. Outcome of unrelated donor bone marrow transplantation in 40 children MY, et al. Long term outcome of Hurler syndrome following BMT. Am J with Hurler syndrome. Blood 1996;87:4894-902.
The Journal of Pediatrics  July 2005


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