Lysosomal Acid Lipase Deficiency: Report of Five Cases across the Age Spectrum

Lysosomal acid lipase (LAL) deficiency is an autosomal recessive lysosomal storage disorder caused by mutations in the LIPA gene that leads to premature organ damage and mortality. We present retrospective data from medical records of 5 Brazilian patients, showing the broad clinical spectrum of the disease.Peloton Advantage, LLC - Alexion Pharmaceuticals, Inc.Univ Fed Sao Paulo UNIFESP, Dept Pediat, Reference Ctr Inborn Errors Metab CREIM, Sao Paulo, SP, BrazilUniv Fed Sao Paulo UNIFESP, Lab Inborn Errors Metab, Sao Paulo, SP, BrazilUniv Fed Sao Paulo UNIFESP, Dept Pathol, Sao Paulo, SP, BrazilUniv Fed Sao Paulo UNIFESP, Dept Pediat, Reference Ctr Inborn Errors Metab CREIM, Sao Paulo, SP, BrazilUniv Fed Sao Paulo UNIFESP, Lab Inborn Errors Metab, Sao Paulo, SP, BrazilUniv Fed Sao Paulo UNIFESP, Dept Pathol, Sao Paulo, SP, BrazilWeb of Scienc

Comparative histopathology of endomyocardial biopsies in chagasic and non-chagasic heart transplant recipients

Background: Heart transplantation has been an option for the treatment of chagasic (C) cardiomyopathy despite difficulties concerning the control of rejection and reactivation. The parasite-host interaction under the influence of immunosuppressive therapy may affect the immunological response to the graft in a pattern different from that in non-chagasic (NC) patients. The aim of this study was to compare the major histopathological features in heart: transplantation in C and NC patients.Methods: We studied 293 endomyocardial biopsies from two groups of heart transplanted patients, including 18 C and 15 NC. Both groups had identical surgical and clinical procedure except immunosuppressive therapy was lower in C patients. The histopathological parameters evaluated were the Quilty effect, rejection, C myocarditis reactivation, fibrosis, hypertrophy, and ischemia. In addition, lymphocytic cellular infiltration of myocarditis due to rejection or reactivation was immunophenotyped in the biopsies of both groups with rejection grades 3 to 4, in biopsies with signs of reactivation, and in fragments of the receptor heart with chronic C myocarditis. A search for Trypanosoma cruzi was performed in all biopsies in the C group in which lymphocyte immunophenotyping was done. We used immunofluorescence and confocal microscopy.Results: The Quilty effect was present in 23% of the biopsies, involving 69.7% of the patients without a significant difference between groups (p = 0.509). Rejection was frequently observed in biopsies with the Quilty effect and the effect often recurred in the same patient. Rejection grades 3 to 4 was more frequent in the C group (p = 0,023). There were 5 episodes of Chagas' disease reactivation with myocarditis in 2 cases. The mean numbers of CD8+ and CD4+ T cells, and the CD4+-to-CD8+ ratio were similar for rejection in both groups (p > 0.05), while the CD4+-to-CD8+ ratio was significantly lower in chronic C myocarditis compared to rejection in the C group (p = 0.043). There was no significant difference in ischemic damage or interstitial fibrosis in the groups but there was a higher frequency of hypertrophy in the NC group (p = 0.007).Conclusions: The histopathological features of heart transplantation in C patients did not differ from that in NC patients in regard to the Quilty effect, development of myocardial fibrosis and ischemia. However, the higher involvement of the C group for rejection grades 3 to 4 suggested higher susceptibility to this event. The similarity of the lymphocytic cellular composition for rejection in both groups indicates that C patients respond to immunological stimulus in a similar pattern as NC patients.UNIFESP, Escola Paulista Med, Dept Patol, Sao Paulo, BrazilUNIFESP, Escola Paulista Med, Disciplina Cardiol, Sao Paulo, BrazilUNIFESP, Escola Paulista Med, Dept Microbiol Imunol & Parasitol, Sao Paulo, BrazilUNIFESP, Escola Paulista Med, Dept Patol, Sao Paulo, BrazilUNIFESP, Escola Paulista Med, Disciplina Cardiol, Sao Paulo, BrazilUNIFESP, Escola Paulista Med, Dept Microbiol Imunol & Parasitol, Sao Paulo, BrazilWeb of Scienc

Morphological and functional alterations of the intestine of rats with iron-deficiency anemia

The present study was designed to assess the intestinal absorption of D-xylose and jejunal morphometry in rats with iron-deficiency anemia. Male Wistar rats were randomly divided into a control group (diet containing 50 mg Fe/kg, N = 12) and an anemic group (diet containing <5 mg Fe/kg, N = 12). The animals were housed in individual metabolic cages and deionized water and diet were provided ad libitum for 6 weeks. Hemoglobin and hematocrit were determined at 0, 2, 4, and 6 weeks. At the end of the study the rats were submitted to a D-xylose absorption test (50 mg/100 g body weight) and sacrificed and a jejunal specimen was obtained for morphometric study. At the end of the study the hemoglobin and hematocrit of the anemic rats (8.7 ± 0.9 g/dl and 34.1 ± 2.9%, respectively) were significantly (P < 0.05) lower than those of the controls (13.9 ± 1.4 g/dl and 47.1 ± 1.5%, respectively). There was no statistical difference in D-xylose absorption between the anemic (46.5 ± 7.4%) and control (43.4 ± 9.0%) groups. The anemic animals presented statistically greater villus height (445.3 ± 36.8 µm), mucosal thickness (614.3 ± 56.3 µm) and epithelial surface (5063.0 ± 658.6 µm) than control (371.8 ± 34.3, 526.7 ± 62.3 and 4401.2 ± 704.4 µm, respectively; P < 0.05). The increase in jejunum villus height, mucosal thickness and epithelial surface in rats with iron-deficiency anemia suggests a compensatory intestinal mechanism to increase intestinal iron absorption

Glicina reduz a peroxidação lipídica tecidual em enterocolite necrosante induzida por hipóxia-reoxigenação em ratos

PURPOSE: To assess the protective effect of glycine in an experimental model of Neonatal Necrotizing Enterocolitis (NEC). METHODS: Fifty (50) neonatal Wistar rats, from a litter of six female rats and weighing 4 to 6 grams, were used. Five animals were cannibalized and the 45 remaining were distributed into three groups: the G1 normal control group (n=12); the G2 Group (n=16), of animals that underwent hypoxia-reoxygenation (HR); the G3 Group of animals (n=17) that underwent HR following a 5% intraperitoneal glycine infusion. The animals underwent hypoxia in a CO2 chamber receiving an air flow of 100% CO2 for 5 minutes and reoxygenation receiving an O2 flow at 100% for 5 minutes. One centimeter long small bowel and colon segments were prepared for histological analysis. The rest of the bowel was removed in a block and frozen at minus 80&deg;C for homogenization and determination of tissue malondialdehyde (MDA). Tissue lesions were classified as Grade 0 to Grade 5, according to the level of damaged mucosa. RESULTS: The animals in Group G1 had levels of small bowel and colon lesion significantly smaller as compared to the animals in Groups G2 and G3. The G2 group had mean MDA values significantly higher than the animals in the G1 (p = .015) and G3 (p=0.021) groups. MDA values did not differ significantly (p = 0.992) for the animals in groups G1 and G3. CONCLUSION: Glycine reduces tissue MDA levels (a measurement of lipid peroxidation) following HR in neonatal rats.OBJETIVO: Avaliar o efeito protetor da glicina, num modelo experimental de ECN. MÉTODOS: Foram utilizados 50 ratos Wistar recém-nascidos, com peso variando de 4 a 6 gramas, provenientes da ninhada de seis ratas. Cinco animais foram canibalizados e, os 45 restantes, foram distribuídos em três grupos: controle G1(n=12); G2(n=16), animais que foram submetidos à hipóxia-reoxigenação; G3(n=17), animais submetidos à hipóxia-reoxigenação após uma infusão intraperitoneal de glicina 5%. Os animais foram submetidos à hipóxia em uma câmara de CO2 recebendo um fluxo de ar contendo 100% de CO2, durante 5 minutos e à reoxigenação recebendo um fluxo de O2 a 100% por 5 minutos. Segmentos de intestino delgado e cólon de 1 cm de extensão foram preparados para análise histológica. O restante do intestino foi removido em bloco e congelado a menos 80&deg;C para homogeneização e dosagem de malondialdeído tecidual (MDA). Classificou-se as lesões teciduais de Grau 0 a Grau 5, de acordo com a extensão da lesão mucosa. RESULTADOS: Os animais do Grupo G1 apresentaram graus de lesão de intestino delgado e cólon significantemente menores do que os animais dos Grupos G2 e G3. O grupo G2 apresentou valores médios de MDA significantemente maiores do que os animais do grupo G1 (p = .015) e G3 (p=0.021). Os animais dos grupos G1 e G3 apresentaram valores de MDA que não diferiram de forma significante (p = 0.992). CONCLUSÃO: A glicina diminuiu os níveis de MDA intestinais (um marcador da peroxidação lipídica) em ratos neonatais submetidos à hipóxia-reoxigenação

P-glycoprotein, erb2 and p53 expression in high-grade human osteosarcomas and their correlation with anaplasia

BACKGROUND: Osteosarcomas (OS), the most frequent primary malignant bone tumors, have aggressive local behavior and high rate of metastatization. The events that allow tumor growth and dissemination are still controversial. The studies about carcinogenesis and tumor progression in this neoplasia, which are based on c-erb-B2, P-glycoprotein (P-gp) and p53 immunoexpression, show conflicting results as to the real prognostic value and its correlations with histological parameters. Anaplasia in childhood neoplasias is a histological parameter of tumor aggressiveness and chemoresistance. In primary or metastatic OS, its meaning remains controversial. On the other hand, in other human neoplasias, c-erb-B2 expression is associated with p53, nuclear grade and other aggressiveness parameters. OBJECTIVE: The aim of the present study was to evaluate p53, c-erb-B2 and P-gp immunoexpression in OS, correlating the parameters with the presence of anaplasia. METHODS: This study included 96 pre-chemotherapy biopsies in patients with high-grade OS diagnosed between 1991 and 2000. The immunohistochemical evaluation of p53 and c-erb-B2 was carried out with the streptavidin-biotin-peroxidase technique. Cases were considered positive when there was immunoexpression in 10% or more neoplastic cells. Only membrane staining (for c-erb-B2 and P-gp), and nuclear staining (for p53) were considered positive. Anaplasia was defined as Wilms' tumor, and considered present or absent. RESULTS: Anaplasia was present in 29 out of 82 cases (35.36%); p53 immunoexpression was detected in 25 out of 60 cases (36.23%); P-gp, in 30 out of 73 cases (41.1%); and c-erb-B2, in 22 out of 55 cases (40%). The results demonstrated an association between c-erb-B2 and p53 immunoexpression (p = 0.042), p53 and parameter of anaplasia (p = 0.015), anaplasia and P-gp (p = 0.034). CONCLUSIONS: The p53, c-erb-B2 and P-gp immunoexpression is relatively frequent in high-grade, metastatic and non-metastatic OS. The results reinforce the hypotheses that in the presence of anaplasia adverse events may occur simultaneously in this neoplasm. Anaplasia may become a histological marker for P-gp and/or p53 status in some high-grade OS, and it may indicate chemoresistance. There was no positive association between p53 and P-gp.INTRODUÇÃO: Osteossarcoma (OS), o mais freqüente tumor primário maligno do osso, tem comportamento local agressivo e alto índice de disseminação sistêmica. Os eventos que permitem o crescimento e a disseminação tumoral ainda permanecem controversos. Os estudos sobre a carcinogênese e a progressão dessa neoplasia, com base na imunoexpressão de c-erb-B2, P-glicoproteína (P-gp) e p53, apresentam resultados conflitantes acerca do real valor prognóstico e suas correlações com parâmetros histológicos. A anaplasia, em neoplasias na infância, constitui parâmetro histológico de agressividade tumoral e quimiorresistência. Nos OS primários ou metastáticos, seu significado permanece controverso. Por outro lado, em outras neoplasias humanas, a expressão do c-erb-B2 relaciona-se com p53, grau nuclear e outros parâmetros de agressividade. OBJETIVO: Avaliar a imunoexpressão de p53, c-erb-B2 e P-gp em OS, correlacionando os parâmetros entre si e com a presença de anaplasia. MÉTODO: O estudo incluiu 96 biópsias pré-quimioterapia de pacientes com OS de alto grau, diagnosticados entre 1991 e 2000. A pesquisa imuno-histoquímica de p53, P-gp e c-erb-B2 foi feita pela técnica da estreptoavidina-biotina-peroxidase. Foram considerados positivos os casos onde havia imunoexpressão em 10% ou mais das células neoplásicas. Somente colorações membranosa (para cerb-B2 e P-gp) e nuclear (para p53) foram consideradas positivas. Anaplasia foi definida como no tumor de Wilms, sendo considerada presente ou ausente. RESULTADOS: Anaplasia pôde ser avaliada em 82/96 casos, estando presente em 29 (35,36%). Imunoexpressão de p53 foi detectada em 25 dos 60 casos (36,23%); de P-gp, em 30 dos 73 casos (41,1%); e de c-erb-B2, em 22 dos 55 casos (40%). Os resultados demonstraram associação entre as imunoexpressões de c-erb-B2 e p53 (p = 0,042), p53 e o parâmetro anaplasia (p = 0,015), anaplasia e Pg (p = 0.034) CONCLUSÕES: A imunoexpressão de p53, c-erb-B2 e P-gp é evento relativamente freqüente em OS de alto grau, metastáticos e não-metastáticos ao diagnóstico. Os resultados reforçam a hipótese de que nessa neoplasia na presença de anaplasia ocorrem simultaneamente eventos adversos, que atuam conjuntamente. A anaplasia constitui marcador histológico do status da P-gp e/ou do p53 em parte dos OS de alto grau e nestes talvez seja indicativa de quimiorresistência. Não houve associação positiva entre p53 e P-gp