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Unlabelled: Intravenous enzyme replacement therapy (ERT) with idursulfase for Hunter syndrome has not been demonstrated to and is not predicted to cross the blood-brain barrier. Nearly all published experience with ERT with idursulfase has therefore been in patients without cognitive impairment (attenuated phenotype). Little formal guidance is available on the issues surrounding ERT in cognitively impaired patients with the severe phenotype. An expert panel was therefore convened to provide guidance on these issues. The clinical experience of the panel with 66 patients suggests that somatic improvements (e.g., reduction in liver volume, increased mobility, and reduction in frequency of respiratory infections) may occur in most severe patients. Cognitive benefits have not been seen. It was agreed that, in general, severe patients are candidates for at least a 6-12-month trial of ERT, excluding patients who are severely neurologically impaired, those in a vegetative state, or those who have a condition that may lead to near-term death. It is imperative that the treating physician discuss the goals of treatment, methods of assessment of response, and criteria for discontinuation of treatment with the family before ERT is initiated.Conclusion: The decision to initiate ERT in severe Hunter syndrome should be made by the physician and parents and must be based on realistic expectations of benefits and risks, with the understanding that ERT may be withdrawn in the absence of demonstrable benefits. [ABSTRACT FROM AUTHOR]

We examined the mucosal barrier function during anaphylaxis induced by the hapten N.N′-di-2.4, dinitrophenyl-lysine (di-DNP-lysine) in BDFI female mice immunized with dinitrophenylated Ascaris suum extract. Immunized mice were garaged with 10 mg or 50 mg of ovalbumin (OVA) with or without N,N′-di-2,4,-DNP-lysine (di-DNP-lysine). Animals that received di-DNP-lysine under- went anaphylaxis and were observed to have significantly greater serum concentrations of immunoreactive OVA (iOVA) than control mice. The severity of anaphylaxis, which varied with the dose of di-DNP-lysine administered, influenced the uptake of OVA; greater amounts of iOVA were detected in serum of mice undergoing more severe anaphylaxis. On gel permeation of serum from both groups of mice, immunoreactive OVA was found to have a molecular size similar to native OVA. Di-DNP-lysine is a synthetic hapten that reliably induced anaphylaxis in sensitized animals challenged by garage. Anaphylaxis resulted in the uptake into the circulation of greater quantities of an unrelated protein antigen present in the intestinal lumen. The protein antigen that was taken up into the circulation appeared to be intact and thus may have an influence on the development of the immune response, or lack thereof, to this bystander antigen. [ABSTRACT FROM AUTHOR]

Small quantifies of dietary protein antigens cross the intestinal epithelium of the lactating mouse, enter the circulation, are transferred across the mammary gland into the milk and reach the suckling neonate. In this study, we sought to determine whether intestinal uptake of ovalbumin (OVA) was enhanced in lactating compared to control mice. OVA was administered by garage under ether anaesthesia. Blood was obtained at 15, 30, 60 and 120 min and immunoreactive OVA (iOVA) measured by enzyme immunoassay. At 30 and 60 min, a three- to four-fold higher concentration of iOVA was detected in lactating compared to control mice. Because this increase in concentration of iOVA might be explained by changes in plasma volume, rate of clearance of OVA from the circulation or altered uptake from the intestine, plasma volume was measured by isotope dilution after i.v. injection of 125I-bovine serum albumin (BSA) and clearance was assessed by measuring elimination of OVA from the circulation after i.v. injection of OVA. In comparison to controls, plasma volume of Day 7–10 lactating mice was increased two-fold and no difference in clearance rate was noted. Because the increase in concentration of iOVA in lactating mice is several-fold greater than in controls, we suggest that increased intestinal uptake of the protein occurs during lactation. [ABSTRACT FROM AUTHOR]

125I-BSA injected intravenously into lactating mice persisted in the circulation for 4 h, entered the mammary gland, and was transferred to the neonate via the milk. When injected with anti-BSA antibodies, it was rapidly cleared from the circulation. Although animals receiving anti-BSA antibodies transferred more radioactivity to the neonate via the milk, the radioactivity was not TCA- precipitable or bound to staphylococcal protein A, nor was it immunoreactive. These findings suggest that circulating maternal antibody can limit the transfer of specific protein antigen from mother to newborn. [ABSTRACT FROM AUTHOR]

Mucopolysaccharidosis VI (MPS VI) is a lysosomal storage disease with progressive multisystem involvement, associated with a deficiency of arylsulfatase B leading to the accumulation of dermatan sulfate. Birth prevalence is between 1 in 43,261 and 1 in 1,505,160 live births. The disorder shows a wide spectrum of symptoms from slowly to rapidly progressing forms. The characteristic skeletal dysplasia includes short stature, dysostosis multiplex and degenerative joint disease. Rapidly progressing forms may have onset from birth, elevated urinary glycosaminoglycans (generally >100 microg/mg creatinine), severe dysostosis multiplex, short stature, and death before the 2nd or 3rd decades. A more slowly progressing form has been described as having later onset, mildly elevated glycosaminoglycans (generally <100 microg/mg creatinine), mild dysostosis multiplex, with death in the 4th or 5th decades. Other clinical findings may include cardiac valve disease, reduced pulmonary function, hepatosplenomegaly, sinusitis, otitis media, hearing loss, sleep apnea, corneal clouding, carpal tunnel disease, and inguinal or umbilical hernia. Although intellectual deficit is generally absent in MPS VI, central nervous system findings may include cervical cord compression caused by cervical spinal instability, meningeal thickening and/or bony stenosis, communicating hydrocephalus, optic nerve atrophy and blindness. The disorder is transmitted in an autosomal recessive manner and is caused by mutations in the ARSB gene, located in chromosome 5 (5q13-5q14). Over 130 ARSB mutations have been reported, causing absent or reduced arylsulfatase B (N-acetylgalactosamine 4-sulfatase) activity and interrupted dermatan sulfate and chondroitin sulfate degradation. Diagnosis generally requires evidence of clinical phenotype, arylsulfatase B enzyme activity <10% of the lower limit of normal in cultured fibroblasts or isolated leukocytes, and demonstration of a normal activity of a different sulfatase enzyme (to exclude multiple sulfatase deficiency). The finding of elevated urinary dermatan sulfate with the absence of heparan sulfate is supportive. In addition to multiple sulfatase deficiency, the differential diagnosis should also include other forms of MPS (MPS I, II IVA, VII), sialidosis and mucolipidosis. Before enzyme replacement therapy (ERT) with galsulfase (Naglazyme), clinical management was limited to supportive care and hematopoietic stem cell transplantation. Galsulfase is now widely available and is a specific therapy providing improved endurance with an acceptable safety profile. Prognosis is variable depending on the age of onset, rate of disease progression, age at initiation of ERT and on the quality of the medical care provided. [ABSTRACT FROM AUTHOR]