Molecular basis of infantile reversible cytochrome c oxidase deficiency myopathy

Childhood-onset mitochondrial encephalomyopathies are usually severe, relentlessly progressive conditions that have a fatal outcome. However, a puzzling infantile disorder, long known as `benign cytochrome c oxidase deficiency myopathy` is an exception because it shows spontaneous recovery if infants survive the first months of life. Current investigations cannot distinguish those with a good prognosis from those with terminal disease, making it very difficult to decide when to continue intensive supportive care. Here we define the principal molecular basis of the disorder by identifying a maternally inherited, homoplasmic m.14674T > C mt-tRNA(Glu) mutation in 17 patients from 12 families. Our results provide functional evidence for the pathogenicity of the mutation and show that tissue-specific mechanisms downstream of tRNA(Glu) may explain the spontaneous recovery. This study provides the rationale for a simple genetic test to identify infants with mitochondrial myopathy and good prognosis.

Inflammation and Remodeling in Infantile, Juvenile, and Adult Allergic Sensitized Mice

Background: Airway structural changes occur early in childhood asthma, but it is unknown whether the development of airway alterations in children is similar to that of adults. We compared inflammation and remodeling parameters in allergic sensitized infantile, juvenile, and adult mice. Methods: Infantile mice (18D) were sensitized with three intraperitoneal injections (i.p.) of ovalbumin (OVA) at days 5 and 7 and challenged with OVA at days 14-16. The 18D1 group received an additional challenge at days 9-11. The juvenile mice (40D) received challenges at days 22-24 and 36-38. Adult mice (100D) were sensitized at days 60-62 and received three inhalations at days 77-79 and 96-98. Animals were submitted to whole body plethysmography. Airway eosinophils, CD3+ T-lymphocytes, IL-5+ cells, mucus content, collagen and reticular fibers density, and smooth muscle thickness were quantified. Results: All sensitized animals presented with airway hyperresponsiveness, without differences in eosinophil cell density The density of CD3+ T-cells was higher in the 100D and 1801 groups than in the 18D and 40D groups. Infantile sensitized groups demonstrated increased interleukin-5 expression in the airways. Infantile mice demonstrated more mucus in the bronchiolar epithelium than the 40D and 100D mice. The 18D animals demonstrated less collagen than the 18D1 group. Juvenile and adult mice had increased airway smooth muscle thickness when compared to age-matched controls, but no differences were observed in the infantile groups. Conclusion: We have shown that infantile mice develop inflammatory and structural alterations in the airways that are partially different from those developed in older animals. Pediatr Pulmonol. 2011;46:650-665. (C) 2011 Wiley-Liss, Inc.

Ultrasound findings in infantile systemic hyalinosis

To describe clinical and ultrasound findings in a patient with infantile systemic hyalinosis (ISH). A 5-month-old boy was evaluated of joint contractures. In addition to clinical and laboratory investigations, an ultrasound of his joints was done and compared to a child with similar age. On examination, a short neck, gingival hyperplasia and papular rash were noted. Joint examination showed painful passive movement, reduced range of motion, and joint contractures in knees, elbows, and small joints of the hands, without any evidence of synovial thickness. Ultrasound of the affected joints showed irregular cortical surface of MCPs and PIP, the presence of osteophytes and bone erosions, increased synovial fluid without evidence of synovial hyperplasia. This is the first report to show evidence of US findings in ISH. Ultrasound findings may help to distinguish ISH from JIA in early stages.

As relações entre construção da imagem corporal, função paterna e hiperatividade: reflexões a partir da Pesquisa IRDI

A partir da psicanálise, 31 indicadores clínicos de risco para o desenvolvimento infantil (IRDI) foram construídos e aplicados em 727 crianças entre 0 e 18 meses. Uma subamostra de 280 crianças foi avaliada com a idade de três anos. Uma primeira análise de resultados mostra uma relação entre imagem do corpo, dificuldade de separação, agitação motora e vínculos corporais estreitos com as mães. Esses resultados são discutidos criticamente à luz da noção atual de hiperatividade.

Avaliação da memória de trabalho em crianças com transtorno do déficit de atenção e hiperatividade

Esse projeto investigou as habilidades cognitivas da Memória de Trabalho de crianças e adolescentes com o “Transtorno do Déficit de Atenção e Hiperatividade” (TDAH). Foi aplicado teste TIHC - Teste Infantil de Habilidades Cognitivas informatizado, avaliando principalmente cinco habilidades cognitivas Raciocínio Indutivas (RI), Memória de Armazenamento Auditiva (MAA) e Visual e Memória de Trabalho Auditiva (MTA) e Visual (MTV) usando o modelo de Cattell-Horn-Carroll. O teste foi aplicado em 62 sujeitos sendo 32 com TDAH do Hospital das Clínicas-SEPIA-USP e 30 sujeitos controle “normal” do Ensino Fundamental da rede municipal de 1ª à 8ª séries com idades entre 7 e 15 anos, de ambos os sexos. As análises executadas indicaram a existência de diferenças em diversos aspectos relacionados à memória nos tipos peculiares de crianças com TDAH. Verificou-se que as crianças com TDAH obtiveram bom desempenho nas provas de memória visual em detrimento as provas de memória auditiva. A correlação dos resultados do TIHC verificara que o tempo de reação da prova de memória de armazenamento visual manteve uma correlação significativa com a prova de cálculo.

Prevalência de sobrepeso e obesidade em crianças de dois a seis anos matriculadas em escolas particulares no município de São Paulo

OBJETIVO: verificar a prevalência de sobrepeso e obesidade segundo sexo e idade em crianças de 2 a 6 anos de idade, alunos de escolas particulares no município de São Paulo. MÉTODO: foram realizadas medidas de peso e de altura para verificação do estado nutricional de oitocentos e seis crianças de ambos os sexos. Para a classificação do estado nutricional das crianças foram utilizadas as curvas de percentis do Índice de Massa Corporal (IMC = Peso (kg) / Altura² (cm)) para idade, conforme padrão de referência do Multicentre Growth Study, recomendado pela Organização Mundial de Saúde que classifica como sobrepeso valores de percentis > 85 e < 97 e para a obesidade valores < 97. Para análise da relação entre sexo, idade da criança e estado nutricional utilizou-se modelo linear generalizado de regressão múltipla (glm) com ligação logarítmica e família binomial, que permite, diretamente, a estimação das razões de prevalências. A prevalência de sobrepeso+obesidade foi 37,2 por cento para o sexo masculino e 33,4 por cento para o sexo feminino. A razão de prevalência (RP) mostrou que não existe diferença significativa entre obesidade e sobrepeso+obesidade para sexo e idade. CONCLUSÃO: observaram-se prevalências de sobrepeso e de obesidade superiores às prevalências médias da população brasileira. Os resultados encontrados neste estudo reforçam a preocupação com a obesidade infantil que aparentemente vem crescendo, em idades mais precoces como dos pré-escolares

Economic impact of a rotavirus vaccine in Brazil

The study was done to evaluate the cost-effectiveness of a national rotavirus vaccination programme in Brazilian children from the healthcare system perspective. A hypothetical annual birth-cohort was followed for a five-year period. Published and national administrative data were incorporated into a model to quantify the consequences of vaccination versus no vaccination. Main outcome measures included the reduction in disease burden, lives saved, and disability-adjusted life-years (DALYs) averted. A rotavirus vaccination programme in Brazil would prevent an estimated 1,804 deaths associated with gastroenteritis due to rotavirus, 91,127 hospitalizations, and 550,198 outpatient visits. Vaccination is likely to reduce 76% of the overall healthcare burden of rotavirus-associated gastroenteritis in Brazil. At a vaccine price of US$ 7-8 per dose, the cost-effectiveness ratio would be US$ 643 per DALY averted. Rotavirus vaccination can reduce the burden of gastroenteritis due to rotavirus at a reasonable cost-effectiveness ratio.

Cuidado à saúde de crianças Kaiowá e Guarani: notas de observação de campo

Inicia-se uma discussão sobre as práticas de saúde e cuidado utilizadas pelos Kaiowá e Guarani da Terra Indígena de Caarapó no enfrentamento das doenças diarréicas na infância. Utilizou-se de uma contribuição etnográfica, através do uso da técnica da observação participante e de entrevistas aberta com moradores da comunidade. Em se tratando de uma sociedade que vivencia permanentes transformações de ordem social advindas das relações interétnicas e da sucessiva presença dos serviços de saúde, observa-se que o significado de diarréia infantil, assim como as decisões relativas à prevenção e ao seu tratamento, refletem comportamentos diferenciados e complexos. A diarréia, também conhecida como chiri, é definida através de sinais que, de certa forma, são semelhantes aos biomédicos. No entanto, nem sempre as explicações de causalidade e as formas de tratamento seguem, unicamente, a abordagem biomédica. A variedade de causas da doença diarréica entre as crianças indígenas implica na escolha do processo terapêutico, que pode ser desde a procura por um especialista tradicional, realização de chás e infusões e, ainda, procura pelos serviços de saúde. Tais explicações e formas de tratamento pressupõem a existência de um processo de negociação entre pessoas de uma mesma cultura e de culturas distintas. Neste sentido, os serviços de saúde ao tratar a criança com diarréia, devem considerar não apenas a perspectiva biomédica, mas também dialogar com a percepção e as práticas indígenas na identificação da causalidade, na definição do diagnóstico e do tratamento, sobretudo, pela coexistência destas práticas no contexto local

Etiology of childhood diarrhea in the northeast of Brazil: significant emergent diarrheal pathogens

In a study conducted in Joao Pessoa, northeast of Brazil, 2344 Escherichia coli isolated from 290 infants with diarrhea and 290 healthy matched controls were analyzed for virulence traits. Enteroaggregative E. coli (EAEC) was the most prevalent pathogen associated to acute diarrhea. Based on the results of colony blot hybridization, serotyping, and HEp-2 cell adherence assays, strains were separated in categories as typical enteropathogenic E. coli (EPEC) (1.7%), atypical EPEC (a-EPEC) (9.3%), EAEC (25%), enterotoxigenic E. coli (10%), and enteroinvasive E. coli (EIEC) (1.4%). No enterohemorrhagic E. coli strains were isolated. Other enteropathogens were found, including Salmonella (7.9%), Shigella spp. (4.1%), thermophilic Campylobacter spp. (2.4%), Giardia lamblia (9.3%), and Entamoeba histolytica (5.8%). All enteropathogens were associated with diarrhea (P < 0.01). However, the association was lower for EPEC and EIEC (P < 0.03). Different pathogens associated with diarrhea may have been changing in Brazil where EAEC and a-EPEC seem to be the most prevalent pathogens among them. (C) 2010 Elsevier Inc. All rights reserved.

Clonal relationships determined by multilocus sequence typing among enteropathogenic Escherichia coli isolated in Brazil

Enteropathogenic Escherichia coli (EPEC) infections are a leading cause of infantile diarrhea in developing nations. Multilocus sequence typing (MLST) characterizes bacterial strains based on the sequences of internal fragments in housekeeping genes. Little is known about strains of EPEC analyzed by MLST from Brazil. In this study, a diverse collection of 29 EPEC strains isolated from patients with diarrhea, admitted to the University Hospital of Ribeirao Preto, was characterized by MLST. Strain analysis demonstrated 22 different sequence types (STs), of which almost half (48%) were new, indicating a high genotype diversity. The 22 STs were divided by eBURST into 12 clonal complexes. It was not possible to correlate typical and atypical EPEC with other strains in the MLST database. This is the first study that analyzed EPEC strains from South America that are included in the E. coli MLST database. Nine (31%) out of 29 strains are part of the CC10 clonal complex, the major clonal complex in the database, which comprises 174 strains and 86 different STs, suggesting that these strains might be the most important intestinal pathogenic E. coli worldwide. Genetic relationships between typical and atypical EPEC, enterohemorrhagic E. coli, and enteroaggregative E. coli strains were not established by MLST.

Tyrosine hydroxylase deficiency: a treatable disorder of brain catecholamine biosynthesis

Tyrosine hydroxylase deficiency is an autosomal recessive disorder resulting from cerebral catecholamine deficiency. Tyrosine hydroxylase deficiency has been reported in fewer than 40 patients worldwide. To recapitulate all available evidence on clinical phenotypes and rational diagnostic and therapeutic approaches for this devastating, but treatable, neurometabolic disorder, we studied 36 patients with tyrosine hydroxylase deficiency and reviewed the literature. Based on the presenting neurological features, tyrosine hydroxylase deficiency can be divided in two phenotypes: an infantile onset, progressive, hypokinetic-rigid syndrome with dystonia (type A), and a complex encephalopathy with neonatal onset (type B). Decreased cerebrospinal fluid concentrations of homovanillic acid and 3-methoxy-4-hydroxyphenylethylene glycol, with normal 5-hydroxyindoleacetic acid cerebrospinal fluid concentrations, are the biochemical hallmark of tyrosine hydroxylase deficiency. The homovanillic acid concentrations and homovanillic acid/5-hydroxyindoleacetic acid ratio in cerebrospinal fluid correlate with the severity of the phenotype. Tyrosine hydroxylase deficiency is almost exclusively caused by missense mutations in the TH gene and its promoter region, suggesting that mutations with more deleterious effects on the protein are incompatible with life. Genotype-phenotype correlations do not exist for the common c.698G > A and c.707T > C mutations. Carriership of at least one promotor mutation, however, apparently predicts type A tyrosine hydroxylase deficiency. Most patients with tyrosine hydroxylase deficiency can be successfully treated with l-dopa.

Two distinct regions in 2q24.2-q24.3 associated with idiopathic epilepsy

P>Approximately 50% of all carriers of 2q21-q31 deletions present epileptic seizures. The band 2q24 constitutes the smallest commonly deleted segment in these patients, and contains the voltage-gated sodium channel genes SCN1A and SCN2A, associated with Dravet syndrome and benign familial neonatal-infantile seizures, respectively. A further putative locus involving epilepsy in the region was previously identified through disruption of the SLC4A10 gene by translocation. In the course of performing high-resolution DNA copy number analyses on syndromic mentally impaired individuals, we encountered three patients with overlapping deletions in chromosome region 2q24. Two of these patients exhibited epileptic seizures in addition to mental deficiency. The deletion in one of the epileptic patients did not include the SCN cluster, demonstrating that a less severe form of epilepsy maps to an adjacent genomic region. This second region comprises about 3 Mb and contains the candidate gene SLC4A10, providing further support for the potential role of this gene in epilepsy.

Immunohistochemical detection of polyductin and co-localization with liver progenitor cell markers during normal and abnormal development of the intrahepatic biliary system and in adult hepatobiliary carcinomas

The longest open reading frame of PKHD1 (polycystic kidney and hepatic disease 1), the autosomal recessive polycystic kidney disease (ARPKD) gene, encodes a single-pass, integral membrane protein named polyductin or fibrocystin. A fusion protein comprising its intracellular C-terminus, FP2, was previously used to raise a polyclonal antiserum shown to detect polyductin in several human tissues, including liver. In the current study, we aimed to investigate by immunohistochemistry the detailed polyductin localization pattern in normal (ductal plate [DP], remodelling ductal plate [RDP], remodelled bile ducts) and abnormal development of the primitive intrahepatic biliary system, known as ductal plate malformation (DPM). This work also included the characterization of polyductin expression profile in various histological forms of neonatal and infantile cholestasis, and in cholangiocellular carcinoma (CCC) and hepatocellular carcinoma (HCC). We detected polyductin expression in the intrahepatic biliary system during the DP and the RDP stages as well as in DPM. No specific staining was found at the stage of remodelled bile ducts. Polyductin was also detected in liver biopsies with neonatal cholestasis, including mainly biliary atresia and neonatal hepatitis with ductular reaction as well as congenital hepatic fibrosis. In addition, polyductin was present in CCC, whereas it was absent in HCC. Polyductin was also co-localized in some DP cells together with oval stem cell markers. These results represent the first systematic study of polyductin expression in human pathologies associated with abnormal development of intrahepatic biliary tree, and support the following conclusions: (i) polyductin expression mirrors developmental properties of the primitive intrahepatic biliary system; (ii) polyductin is re-expressed in pathological conditions associated with DPM and (iii) polyductin might be a potential marker to distinguish CCC from HCC.