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Biomedical subjects

C Vogler

Publications and source records attributed to C Vogler.

At least 37 records · Page 2Linked to original sources
PubMed1995

Syngeneic bone marrow transplantation reduces the hearing loss associated with murine mucopolysaccharidosis type VII.

MPS VII mice are deficient in beta-glucuronidase and share many clinical, biochemical, and pathologic characteristics with human mucopolysaccharidosis type VII (MPS VII). We have shown that syngeneic bone marrow transplantation (BMT) prolongs survival and reduces lysosomal storage in many organs of the MPS VII mouse. In this report, we quantify the hearing loss and determine the impact of syngeneic BMT on the development of deafness and the associated pathology in the MPS VII mouse. Eleven weeks after syngeneic BMT performed at birth, treated MPS VII mice had normal auditory-evoked brainstem responses (ABR), whereas untreated MPS VII mice had ABR thresholds 43 dB higher than normal. Treated MPS VII mice had beta-glucuronidase-positive cells in the temporal bone and in the subepithelial connective tissue of the external auditory canal. There was less thickening of the tympanic membrane and middle ear mucosa and decreased distortion of the ossicles and the cochlear bone. Although transplanted MPS VII mice had increased ABR thresholds by 33 weeks of age, four of the six had thresholds 12 to 32 dB lower than untreated mutants. These data indicate that syngeneic BMT in newborn MPS VII mice prevents early hearing loss and, in some animals, results in long-term improved auditory function.

Animals↗
PubMed1995

Expression of proliferating cell nuclear antigen in Spitz nevus.

BACKGROUND: Epithelioid and spindle cell nevus (ESN; Spitz nevus) is a histologically well-described entity. We hypothesized that the features of ESN may reflect activation by a proliferative stimulus. OBJECTIVE: Nevocytes and keratinocytes in ESN and control specimens were examined for expression of the proliferation marker, proliferating cell nuclear antigen (PCNA). METHODS: Standard immunohistochemical methods were used to examine the expression of PCNA in a series of ESN, other nevi, and malignant melanoma. RESULTS: PCNA was detected in nevocytes in a significant percentage of ESN but not in other nevi. PCNA expression was increased in basilar keratinocytes in ESN when compared with staining of basilar keratinocytes in normal epidermis. In other melanocytic nevi and noninflamed melanoma, PCNA expression in keratinocytes was similar to that in normal control tissue. CONCLUSION: Increased PCNA labeling in nevocytes and keratinocytes in ESN suggests that a growth stimulus, present within some of these lesions, affects both keratinocytes and nevocytes.

Child↗
PubMed1994

Enzyme replacement therapy for murine mucopolysaccharidosis type VII.

Recombinant mouse beta-glucuronidase administered intravenously to newborn mice with mucopolysaccharidosis type VII (MPS VII) is rapidly cleared from the circulation and localized in many tissues. Here we determine the tissue distribution of injected enzyme and describe its effects on the histopathology in 6-wk-old MPS VII mice that received either one injection of 28,000 U recombinant beta-glucuronidase at 5 wk of age or received six injections of 28,000 U given at weekly intervals beginning at birth. These mice were compared with untreated 6-wk-old MPS VII mice. The single injection decreased lysosomal distention in the fixed tissue macrophage system. MPS VII mice that received multiple injections had 27.8, 3.5, and 3.3% of normal levels of beta-glucuronidase in liver, spleen, and kidney, respectively. Brain had detectable beta-glucuronidase, ranging from 2.0-12.1% of normal. Secondary elevations of alpha-galactosidase and beta-hexosaminidase in brain, spleen, liver, and kidney were decreased compared with untreated MPS VII mice. Although no improvement was observed in chondrocytes, glia, and some neurons, the skeleton had less clinical and pathological evidence of disease and the brain had reduced lysosomal storage in meninges and selected neuronal groups. These data show that recombinant beta-glucuronidase treatment begun in newborn MPS VII mice provides enzyme to most tissues and significantly reduces or prevents the accumulation of lysosomal storage during the first 6 wk of life. Whether therapy begun later in life can achieve this level of correction remains to be established.

Animals↗
PubMed1994

Pathology of the ear in murine mucopolysaccharidosis type VII. Morphologic correlates of hearing loss.

BACKGROUND: Patients with mucopolysaccharidosis commonly have hearing impairment but the morphologic alterations in the ear caused by these lysosomal storage diseases are incompletely defined. EXPERIMENTAL DESIGN: We studied a murine model of mucopolysaccharidosis VII with clinical features, including conductive hearing loss and biochemical, and pathologic features similar to those seen in human mucopolysaccharidoses. Gross morphology, radiography, light and electron microscopy were used to define the pathologic alterations in the ear that correlate with auditory dysfunction in mucopolysaccharidosis VII. RESULTS: Cerumen occluded the external auditory canal and there was a severe otitis media. The bone encasing the middle and inner ear was sclerotic and opaque and the temporal bone and the ossicles and their joints contained cells distended by enlarged lysosomes. Hair cell damage and multifocal lysosomal distention in endoneural fibroblasts and spiral ganglion neurons characterized the mucopolysaccharidosis VII cochlea. CONCLUSIONS: The external auditory canal obstruction, otitis media, and ossicle articular alterations in mucopolysaccharidosis VII mice cause a conductive hearing loss. The hair cell damage and neuronal storage may contribute to sensorineural deafness. This model allows investigation of the pathophysiology of auditory dysfunction in mucopolysaccharidosis and the effects of therapies on hearing loss.

Animals↗
PubMed1994

Mucopolysaccharidosis VII: postmortem biochemical and pathological findings in a young adult with beta-glucuronidase deficiency.

The postmortem biochemical and pathological findings in the first patient reported with mucopolysaccharidosis VII are described. Clinical, radiographic, and biochemical features of this 19-yr-old black man were initially reported in 1973 when, at age 2 1/2 yr his enzymatic defect, deficiency of beta-glucuronidase, was identified. The autopsy findings are now described with biochemical data further characterizing the enzyme deficiency and resultant glycosaminoglycan accumulation. He had dysostosis multiplex and extensive cardiovascular lesions including arterial stenosis, and marked fibrous thickening of the atrioventricular and aortic valves. Microscopic evidence of lysosomal storage was found in bone, cartilage, arteries and cardiac valves, liver, spleen, lymph nodes, eyes, adrenal, pituitary, and the central nervous system. In the brain, storage was localized to specific regions, primarily intraneuronal, and appeared ultrastructurally as delicate whorled filamentous accumulations in lysosomes. Similar filamentous storage also occurred in medial cells of the aorta. Multiple postmortem tissues contained only trace amounts of beta-glucuronidase and elevated glycosaminoglycans, predominantly chondroitin 4- and 6-sulfate.

Adult↗
PubMed1993

Enzyme replacement with recombinant beta-glucuronidase in the newborn mucopolysaccharidosis type VII mouse.

beta-Glucuronidase injected i.v. into newborn mucopolysaccharidosis VII mice was cleared from the circulation in less than 1 h and taken up by tissues in a distribution corresponding to the location of the mannose 6-phosphate receptor. One h after a 3.5-mg/kg beta-glucuronidase injection, beta-glucuronidase levels were equal to or greater than normal in every organ examined with the exception of the brain, where 31% normal activity was present. Enzyme was detectable histochemically in the major sites of pathology for mucopolysaccharidosis VII including bone, brain, heart, and fixed tissue macrophages. The half-life of recombinant beta-glucuronidase activity in various organs of injected mucopolysaccharidosis VII mice was 1.5 to 4.5 d. These studies show that recombinant beta-glucuronidase administered to newborn mice reaches the sites of clinically important storage in murine mucopolysaccharidosis VII.

Animals↗
PubMed1993

Treatment of murine mucopolysaccharidosis type VII by syngeneic bone marrow transplantation in neonates.

BACKGROUND: Bone marrow transplantation (BMT) proved an effective therapy for murine mucopolysaccharidosis type VII (MPS VII) in adult gusmps/gusmps mice with well developed clinical and pathologic characteristics of the disease. MPS VII mice transplanted as adults had a marked decrease in lysosomal storage material in many organs, although not in the skeleton and brain (1). Since untreated newborn MPS VII mice appear normal and have minimal lysosomal storage material detectable microscopically, we postulated that BMT in newborn mice might prevent the subsequent accumulation of storage material. EXPERIMENTAL DESIGN: One-day-old mutant and phenotypically normal mice were exposed to 2, 4, 6 and 8 Gray and then injected intravenously with syngeneic bone marrow cells from homozygous normal females. Transplanted mice were examined biochemically and microscopically at 10 weeks and 10 months of age. RESULTS: Newborn mice receiving BMT lived longer than untreated mutants, had less severe facial dysmorphism, and better mobility. beta-Glucuronidase activity in liver, spleen, kidney and brain increased with increasing radiation dose. The secondary elevations of alpha-galactosidase and beta-hexosaminidase observed in MPS VII, were significantly reduced in liver and spleen in all radiation groups. Treated mutants had less histologic evidence of lysosomal storage disease in bones, joints and periarticular tissue as compared with untreated mutants. Neonatal BMT also reduced storage in the leptomeninges, ependyma and retinal pigment epithelium and caused a slight decrease in neuronal storage at high radiation dose. Radiation dose dependent cerebellar and retinal dysplasia and long bone growth retardation was observed when the therapy was initiated in newborn mice but not when the animals were transplanted as adults. CONCLUSIONS: BMT is a more effective therapy for MPS VII when it is performed at birth rather than in adults. Alternate means of ablating host hematopoietic stem cells should be employed as a pretreatment for BMT due to the severe side effects of radiation on newborns.

Animals↗
PubMed1991

Role of influenza B virus in hepatic steatosis and mitochondrial abnormalities in a mouse model of Reye syndrome.

The hepatic steatosis observed in the influenza B virus mouse model of Reye syndrome has been attributed to infectious virus or, alternately, to decreased food intake in the virus-treated mice or impurities in the virus preparation. To resolve this issue, 4- to 6-wk-old male Balb C mice were given, by intravenous injection, 12,800 hemagglutination units of influenza B Lee/40 virus in phosphate buffered saline/1% bovine serum albumin using virus prepared by ultra-centrifugation from infected allantoic fluid, by sucrose density-gradient purification of virus prepared by ultracentrifugation from infected allantoic fluid or by irradiation of virus prepared by ultracentrifugation from infected allantoic fluid to inactivate virus. The infectivity titer of virus prepared by ultracentrifugation from infected allantoic fluid was much higher than that of sucrose density-gradient purified virus prepared from infected allantoic fluid: 50% egg infectious dose for virus prepared by ultracentrifugation from infected allantoic fluid was 3.9 x 10(4)/hemagglutination unit vs. 8.7 50% egg infectious dose/hemagglutination unit for sucrose density-gradient purified virus prepared from infected allantoic fluid. Control mice received phosphate-buffered saline/1% bovine serum albumin or uninfected allantoic fluid diluted in phosphate-buffered saline/1% bovine serum albumin. Mice were fasted to eliminate dietary variation, and livers were obtained 36 hr after virus administration. Of the above treatments, only virus prepared by ultracentrifugation from infected allantoic fluid caused clinical illness and increased hepatic triglycerides (p less than 0.02) compared with controls. Hepatic triglycerides in virus prepared by ultracentrifugation from infected allantoic fluid correlated with histopathological vacuolization scores (r = 0.5773; p less than 0.03).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Focal mucinosis of the upper aerodigestive tract in children.

Cutaneous mucinosis is an uncommon lesion characterized by mucin accumulation in the dermis. Rarely, mucinosis may arise in the oral cavity; reported cases have been observed in patients older than 16 years. We identified two children younger than 5 years of age with focal mucinosis of the upper aerodigestive tract. A 3-year-old boy had been intubated at age 2 months, suffered from recurrent respiratory infections, and developed mucinosis of the larynx, a previously unreported site for this unusual lesion. The second patient, a 4-year-old girl with a cleft palate, developed palatine mucinosis.

Child, Preschool↗
PubMed1990

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

We recently described a murine model for mucopolysaccharidosis VII in mice that have an inherited deficiency of beta-glucuronidase (beta-D-glucuronoside glucuronosohydrolase, EC 3.2.1.31). Affected mice, of genotype gusmps/gusmps, 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 enlarge vesicles and correlates biochemically with accumulation of undegraded and partially degraded glycosaminoglycans. In this report we describe the consequences of introducing the human beta-glucuronidase gene, GUSB, into gusmps/gusmps 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 gusmps/gusmps mice and that human beta-glucuronidase corrects the murine mucopolysaccharidosis storage disease.

Animals↗
PubMed1990

Acridine orange--RNA histofluorescence of sarcomas and small round cell tumors of childhood.

Forty-nine pediatric malignant neoplasms were stained with acridine orange (AO) fluorochrome to qualitatively evaluate cytoplasmic RNA content. The application of AO as a supplementary stain in surgical pathologic diagnosis is based on the premise that specific neoplastic cell types characteristically and consistently contain few or many cytoplasmic ribosomes. Primitive tumors such as Ewing's sarcoma and primitive neuroectodermal tumors showed negative or low-intensity AO-RNA cytoplasmic staining. Differentiated sarcomas such as rhabdomyosarcomas and lymphomas exhibited moderate to strong AO-RNA cytoplasmic fluorescence. Acridine orange--RNA staining provides an easy, convenient, and inexpensive adjunct in the histopathologic differential diagnosis of sarcomas. It is particularly useful for distinguishing Ewing's sarcomas from other small round cell sarcomas of childhood.

Acridine Orange↗
PubMed1990

A murine model of mucopolysaccharidosis VII. Gross and microscopic findings in beta-glucuronidase-deficient mice.

This report describes the clinical and pathologic alterations found in mice that have a recessively inherited, essentially complete deficiency of the lysosomal enzyme beta-glucuronidase. Affected animals have a shortened life span and are dysmorphic and dwarfed. Abnormal gait and decreased joint mobility correlate with glycosaminoglycan accumulation in articular tissue and cartilaginous and bony lesions result in extensive skeletal deformation. In these enzyme-deficient animals, lysosomes, distended by fine fibrillar and granular storage material, are particularly prominent in the macrophage system but also occur in other tissues including the skeletal and central nervous systems. The clinical and pathologic abnormalities in these mutant mice closely parallel those identified in humans with mucopolysaccharidoses (MPS). Therefore, these mice provide a well-defined genetic system for the analysis of the pathophysiology of mucopolysaccharidosis type VII, which has many features in common with the other MPS. The mutant mice provide an attractive animal model to test potential therapies for lysosomal storage disease.

Animals↗
PubMed1989

Electron microscopy in the diagnosis of pediatric disease.

Electron microscopy, although not able to solve all diagnostic dilemmas, is an essential adjunct to the analysis of pathologic processes. The importance of correct specimen handling for ultrastructural study is highlighted. Some diseases encountered in pediatrics, in which the ultrastructural findings are well established, are illustrated. New technologies that show promise for wider application to problems in pathology also are considered in this article.

Child↗