Longitudinal changes in liver fibrosis in children with sickle cell disease undergoing chronic transfusion therapy.

BACKGROUND AND STUDY AIMS: The progression of liver injury from transfusional iron overload in sickle cell disease (SCD) is poorly understood. We sought to identify predictors liver fibrosis development over time. PATIENTS AND METHODS: We performed a retrospective cohort study of chronically transfused SCD patients who had > or = 2 serial liver biopsies. Core biopsies were scored for fibrosis in a blinded fashion. Primary analyses evaluated longitudinal changes in liver fibrosis and changes in surrogate markers. Secondary analyses determined the relationship between liver iron concentration (LIC) and serum biomarkers. RESULTS: 26 people had > or = 2 serial biopsies for evaluation (n = 70 biopsies total). Fibrosis was Ishak grade 0 or 1 in all biopsies. Evaluation of the first 2 biopsies showed fibrosis regression (n = 6), development (n = 2), persistence (n = 1), and absence (n = 17). There was no consistent association of fibrosis with LIC over time, or between changes in fibrosis status and surrogate markers. For predicting fibrosis on a cross-sectional basis, ALT and ferritin performed moderately (AUCs 0.80 and 0.63, respectively) but LIC performed poorly (AUC 0.30). The highest positive likelihood ratios for fibrosis were for ferritin cutoff of 5000 ng/mL (LR + 5.7) and ALT cutoff of 65 U/L (LR + 5.2). CONCLUSIONS: Liver fibrosis progression is minimal in chronically transfused SCD. LIC does not correlate well with fibrosis development. We propose routine liver biopsies are not necessary components in the standard monitoring of chronically transfused SCD patients.

Lymphocyte reconstitution following non-myeloablative hematopoietic stem cell transplantation follows two patterns depending on age and donor/recipient chimerism.

The effect of mixed chimerism on the pace of post-transplant immune reconstitution is unknown. Using flow cytometry, recall and neo-antigen vaccine responses, and T cell receptor recombination excision circle (TREC) quantification, we evaluated phenotypic and functional characteristics of T and B cells in nine patients following non-myeloablative, HLA-identical peripheral blood stem cell transplantation for chronic granulomatous disease. Engraftment of T cell, B cell, and myeloid lineages proceeded at similar paces within each patient, but engraftment kinetics segregated patients into two groups: adults, who became full donor T cell chimeras before 6 months (rapid engrafters) and children, who became full donor T cell chimeras after 6 months or not at all (slow engrafters). Quantitative B cell recovery was achieved by 6 weeks after transplantation in children, but was delayed until 1 year in adults. Early quantitative B cell recovery was not accompanied by an early humoral immune response to tetanus toxoid (TT). Emergence of TT-specific T cell responses coincided with naive T cell reconstitution, as measured by CD4/CD45RA T cell recovery and TREC quantification. These data suggest that immune reconstitution occurs faster in pediatric patients who have prolonged mixed hematopoietic chimerism compared to adults, who have rapid donor stem cell engraftment.

beta-mannosidase deficiency in a female infant with epileptic encephalopathy.

We report a female infant with an isolated deficiency of beta-mannosidase activity. At nine months of age dysmorphism was absent except for brachecephaly. There was moderate developmental delay and a startle response to sound. At 12 months there was a sudden onset of tonic-clonic seizures which were unresponsive to drug therapy, requiring paralysis and mechanical ventilation for control. The child died suddenly aged 15 months. beta-mannosidase activity was markedly reduced in white cells and cultured skin fibroblasts whilst other lysosomal enzymes were normal. The disaccharide ManGlcNAc was excreted in urine but urinary mucopolysaccharides were normal.

Autoradiographic visualization of kappa opioid receptors with labelled dynorphins in guinea pig brain.

The distribution of kappa opioid receptors in guinea pig brain was measured by in vitro receptor autoradiography using [3H]dynorphin A1-9, [3H]dynorphin A1-8 and [3H]bremazocine as ligands. The sites labelled by the two dynorphins had identical, heterogeneous distributions in brain sections. High levels of kappa receptors were seen in striatum, claustrum, nucleus accumbens and laminae V and VI of the cerebral cortex. The substantia nigra and superior colliculus also had high dynorphin binding levels. The [3H]dynorphin autoradiographs were closely similar to those obtained using [3H]bremazocine in the presence of mu and delta receptor displacers. It is concluded that tritiated dynorphin A fragments can be used for autoradiographic studies of kappa opioid receptors in brain.