Autoimmune hepatitis in 828 Brazilian children and adolescents: clinical and laboratory findings, histological profile, treatments, and outcomes

In this large clinical series of Brazilian children and adolescents, autoimmunehepatitis-1 was more frequent, and patients with autoimmune hepatitis-2 exhibited higherdisease remission rates with earlier response to treatment. Patients with autoimmune hepatitis-1 had a higher risk of death.sentation, laboratory findings, histological profile, treatments, and outcomes of children andadolescents with autoimmune hepatitis.Methods: The medical records of 828 children and adolescents with autoimmune hepatitiswere reviewed. A questionnaire was used to collect anonymous data on clinical presentation,biochemical and histological findings, and treatments.Results: Of all patients, 89.6% had autoimmune hepatitis-1 and 10.4% had autoimmunehepatitis-2. The female sex was predominant in both groups. The median age at symptomonset was 111.5 (6; 210) and 53.5 (8; 165) months in the patients with autoimmune hepatitis1 and autoimmune hepatitis-2, respectively. Acute clinical onset was observed in 56.1% and58.8% and insidious symptoms in 43.9% and 41.2% of the patients with autoimmune hepatitis-1and autoimmune hepatitis-2, respectively. The risk of hepatic failure was 1.6-fold higher forautoimmune hepatitis-2. Fulminant hepatic failure occurred in 3.6% and 10.6% of the patientswith autoimmune hepatitis-1 and autoimmune hepatitis-2, respectively; the risk was 3.1-foldhigher for autoimmune hepatitis-2. The gamma globulin and immunoglobulin G levels were sig-nificantly higher in autoimmune hepatitis-1, while the immunoglobulin A and C3 levels werelower in autoimmune hepatitis-2. Cirrhosis was observed in 22.4% of the patients; biochem-ical remission was achieved in 76.2%. The actuarial survival rate was 93.0%. A total of 4.6%underwent liver transplantation, and 6.9% died (autoimmune hepatitis-1: 7.5%; autoimmunehepatitis-2: 2.4%).Conclusions: In this large clinical series of Brazilian children and adolescents, autoimmunehepatitis-1 was more frequent, and patients with autoimmune hepatitis-2 exhibited higherdisease remission rates with earlier response to treatment. Patients with autoimmune hepatitis-1 had a higher risk of death.info:eu-repo/semantics/publishedVersio

Nonvirally Modified Autologous Primary Hepatocytes Correct Diabetes and Prevent Target Organ Injury in a Large Preclinical Model

BACKGROUND: Current gene- and cell-based therapies have significant limitations which impede widespread clinical application. Taking diabetes mellitus as a paradigm, we have sought to overcome these limitations by ex vivo electrotransfer of a nonviral insulin expression vector into primary hepatocytes followed by immediate autologous reimplantation in a preclinical model of diabetes. METHODS AND RESULTS: In a single 3-hour procedure, hepatocytes were isolated from a surgically resected liver wedge, electroporated with an insulin expression plasmid ex vivo and reimplanted intraparenchymally under ultrasonic guidance into the liver in each of 10 streptozotocin-induced diabetic Yorkshire pigs. The vector was comprised of a bifunctional, glucose-responsive promoter linked to human insulin cDNA. Ambient glucose concentrations appropriately altered human insulin mRNA expression and C-peptide secretion within minutes in vitro and in vivo. Treated swine showed correction of hyperglycemia, glucose intolerance, dyslipidemia and other metabolic abnormalities for > or = 47 weeks. Metabolic correction correlated significantly with the number of hepatocytes implanted. Importantly, we observed no hypoglycemia even under fasting conditions. Direct intrahepatic implantation of hepatocytes did not alter biochemical indices of liver function or induce abnormal hepatic lobular architecture. About 70% of implanted hepatocytes functionally engrafted, appeared histologically normal, retained vector DNA and expressed human insulin for > or = 47 weeks. Based on structural tissue analyses and transcriptome data, we showed that early correction of diabetes attenuated and even prevented pathological changes in the eye, kidney, liver and aorta. CONCLUSIONS: We demonstrate that autologous hepatocytes can be efficiently, simply and safely modified by electroporation of a nonviral vector to express, process and secrete insulin durably. This strategy, which achieved significant and sustained therapeutic efficacy in a large preclinical model without adverse effects, warrants consideration for clinical development especially as it could have broader future applications for the treatment of other acquired and inherited diseases for which systemic reconstitution of a specific protein deficiency is critical

Successful domino liver transplantation in maple syrup urine disease using a related living donor

Maple syrup urine disease (MSUD) is an autosomal recessive disease associated with high levels of branched-chain amino acids. Children with MSUD can present severe neurological damage, but liver transplantation (LT) allows the patient to resume a normal diet and avoid further neurological damage. The use of living related donors has been controversial because parents are obligatory heterozygotes. We report a case of a 2-year-old child with MSUD who underwent a living donor LT. The donor was the patient’s mother, and his liver was then used as a domino graft. The postoperative course was uneventful in all three subjects. DNA analysis performed after the transplantation (sequencing of the coding regions of BCKDHA, BCKDHB, and DBT genes) showed that the MSUD patient was heterozygous for a pathogenic mutation in the BCKDHB gene. This mutation was not found in his mother, who is an obligatory carrier for MSUD according to the family history and, as expected, presented both normal clinical phenotype and levels of branched-chain amino acids. In conclusion, our data suggest that the use of a related donor in LT for MSUD was effective, and the liver of the MSUD patient was successfully used in domino transplantation. Routine donor genotyping may not be feasible, because the test is not widely available, and, most importantly, the disease is associated with both the presence of allelic and locus heterogeneity. Further studies with this population of patients are required to expand the use of related donors in MSUD

Successful domino liver transplantation in maple syrup urine disease using a related living donor

Maple syrup urine disease (MSUD) is an autosomal recessive disease associated with high levels of branched-chain amino acids. Children with MSUD can present severe neurological damage, but liver transplantation (LT) allows the patient to resume a normal diet and avoid further neurological damage. The use of living related donors has been controversial because parents are obligatory heterozygotes. We report a case of a 2-year-old child with MSUD who underwent a living donor LT. The donor was the patient’s mother, and his liver was then used as a domino graft. The postoperative course was uneventful in all three subjects. DNA analysis performed after the transplantation (sequencing of the coding regions of BCKDHA, BCKDHB, and DBT genes) showed that the MSUD patient was heterozygous for a pathogenic mutation in the BCKDHB gene. This mutation was not found in his mother, who is an obligatory carrier for MSUD according to the family history and, as expected, presented both normal clinical phenotype and levels of branched-chain amino acids. In conclusion, our data suggest that the use of a related donor in LT for MSUD was effective, and the liver of the MSUD patient was successfully used in domino transplantation. Routine donor genotyping may not be feasible, because the test is not widely available, and, most importantly, the disease is associated with both the presence of allelic and locus heterogeneity. Further studies with this population of patients are required to expand the use of related donors in MSUD

Gene-mediated Restoration of Normal Myofiber Elasticity in Dystrophic Muscles

Dystrophin mediates a physical link between the cytoskeleton of muscle fibers and the extracellular matrix, and its absence leads to muscle degeneration and dystrophy. In this article, we show that the lack of dystrophin affects the elasticity of individual fibers within muscle tissue explants, as probed using atomic force microscopy (AFM), providing a sensitive and quantitative description of the properties of normal and dystrophic myofibers. The rescue of dystrophin expression by exon skipping or by the ectopic expression of the utrophin analogue normalized the elasticity of dystrophic muscles, and these effects were commensurate to the functional recovery of whole muscle strength. However, a more homogeneous and widespread restoration of normal elasticity was obtained by the exon-skipping approach when comparing individual myofibers. AFM may thus provide a quantification of the functional benefit of gene therapies from live tissues coupled to single-cell resolution

Tradition in whole number arithmetic

The main topics discussed by the panel and the resulting questions to be answered are introduced along with some bibliographic references. The main topics of discussion concern the relationships between tradition and the verbal and non-verbal representations of numbers, numbers and artefacts of arithmetic, and the role of technological devices in emulating traditional abaci and allowing direct interaction with the screens of multi touch devices in counting activities. Another crucial issue concerns the different languages that can be present in a classroom for historical and cultural reasons. This represents a challenge for teachers, who must cope with the ways in which words can shape the specific connotations of the meanings of numbers. Although all of these facets of numbers need to be coordinated with the standard mathematical concepts, they also appear in the multimodal representations that are used to teach them, such as words, textbooks, notes and teachers’ and students’ gestures. All of these factors intertwine and sometimes conflict with the richness of the representations and practices that children encounter outside school in their everyday lives