Common clonal origin of chronic lymphocytic leukemia and high-grade lymphoma of Richter's syndrome

Patients with B-cell chronic lymphocytic leukemia (CLL) infrequently may develop high-grade B-cell lymphoma, or Richter's syndrome lymphoma (RS lymphoma). Such lymphomas differ from the original leukemia in both histology and clinical behavior. Studies seeking to define the clonal relationship between the cells of the two malignancies in any one patient have yielded conflicting reports. We examined the clonal relationship between the early and late neoplastic cells of a patient who underwent Richter's transformation. In contrast to the original leukemia cells, the secondary high-grade lymphoma was CD5-. However, both the leukemia cells and the evolved RS lymphoma expressed surface IgM lambda reactive with Lc1, a murine monoclonal antibody specific for a supratypic cross-reactive idiotype encoded by a subset of human Ig variable region genes of the VH4 subgroup. Nucleic acid sequence analyses of the heavy and light chain variable region genes expressed by both leukemia and lymphoma cells show that the CD5- B-cell lymphoma constitutes a clonal expansion of mutant cells derived from the original CD5+ B-cell leukemia. Moreover, certain sets of somatic mutations distinguish the Ig variable region genes used by RS lymphoma from those expressed by the CLL B cells. This is the first study to establish the clonal relationship between CLL and RS lymphoma through primary structural analyses of the expressed Ig genes.     

Biliary strictures after liver transplantation: Clinical picture, correlates and outcomes

We retrospectively examined 154 adults to ascertain the frequency, site of and pre-disposing factors for biliary strictures after liver transplantation, as well as their management and clinical outcome. Twenty patients (12.5%) were identified with biliary strictures; 16 were non-anastomotic and four were anastomotic strictures. The median time from transplantation to stricture diagnosis was 17 weeks (range 3–366). Of the 16 non-anastomotic strictures, six were intrahepatic, eight hilar and two extrahepatic (donor bile duct). A control group (n = 32) of patients transplanted immediately before and after index cases was used to examine for correlates in patients with non-anastomotic strictures. At the time of diagnosis in the non-anastomotic index cases, there was a higher incidence of: (i) biliary sludge (63 vs 0%; P< 0.001); and (ii) clinical cholangitis (75 vs 0%; P< 0.001) compared with controls. Primary sclerosing cholangitis was more often the diagnosis in index patients with non-anastomotic strictures compared with controls (31 vs 9%; P<0.05). There were no differences between index patients and controls (non-anastomotic group) in ABO blood group non-identity, cold allograft ischaemia time, use of OKT3 (murine monoclonal antibody to CD³) and hepatic artery thrombosis. Of 15 patients treated with balloon dilatation, seven required stent insertion although none have required surgery. As determined by liver function tests, there was evidence of persisting graft dysfunction in index patients compared with controls (SAP 381 vs 112 U/L, P< 0.001; GGT 529 vs 80 U/L, P< 0.001), but there was no difference in survival during a median follow-up time of 16 months (range: 3–48 months) from stricture diagnosis. In conclusion, biliary strictures tend to occur within 6 months of transplantation and are an important cause of ongoing graft dysfunction. Non-anastomotic strictures were more common in patients requiring transplantation for primary sclerosing cholangitis.     

Defective monocyte-to-macrophage maturation in patients with aplastic anemia

Macrophages (MAC) are important effector cells of the immune system but also play an essential role as regulatory cells in hematopoiesis. They originate from circulating monocytes (MO) as immature precursor cells that undergo terminal differentiation upon migration from the capillary bed into the various tissues. In the presence of serum, MAC maturation from blood MO is observed in vitro and can be followed by the expression of maturation-associated antigens (MAX.1, .3, .11, and .26; transferrin receptor, 13C2, CD16). We have tested blood MO from 22 patients with aplastic anemia (AA) for their capacity to undergo terminal maturation in vitro. After isolation, blood MO in six patients expressed CD14 molecules at low density when compared to normals. On culture for 7 days, in 15 patients various abnormalities could be shown by phenotype analysis using cell-enzyme-linked immunosorbent assay (ELISA) and an immunoperoxidase staining technique of single cells. Abnormalities ranged from the distinctive failure of mature MAC to express single surface antigens (eg, gp64-MAX.1) to complete inhibition of the development of a MAC maturation-associated phenotype. In three patients the maturational defect was found to persist in complete remission after successful therapy with antileukocyte globulin (ALG). Neither in other immunosuppressed or multiple-transfused patients nor in those with bone marrow hypoplasia secondary to cancer chemotherapy and during hematologic reconstitution following autologous bone marrow transplantation (BMT), defective MO maturation in vitro was seen. Our data provide evidence for the existence of serious disorders within the MO-MAC lineage in patients with AA. This observation may either reflect the stem-cell defect or indicate a MAC involvement in the pathogenesis of the disease.     

Glaucoma following congenital cataract surgery – the role of early surgery and posterior capsulotomy

Background  

To determine the rate of glaucoma following congenital cataract surgery at Moorfields Eye Hospital (MEH), and to investigate potential risk factors for glaucoma in our case series.     

PERMEABILITY OF THE DEVELOPING AND MATURE BLOOD-BRAIN BARRIERS TO THEOPHYLLINE IN RATS

1. In the present study, the uptake of theophylline and L-glucose into the adult and neonatal rat brain has been investigated. Steady state cerebrospinal fluid (CSF) and brain concentrations of theophylline were reached within 1 h following a single intraperitoneal (i.p.) injection, whereas steady state CSF and brain concentrations of L-glucose were not approached until after 5 h. 2. Steady state brain:plasma and CSF:plasma concentration ratios for theophylline and L-glucose in neonatal rats were significantly higher than ratios in adult rats. Erythrocyte:plasma ratios for theophylline in neonatal rats were also significantly higher than ratios in adult rats. Steady state ratios for theophylline were significantly higher than those for L-glucose in both neonatal and adult rats. 3. Respiratory acidosis (pH 6.9–7.0) did not affect steady state CSF:plasma or brain.-plasma ratios for theophylline in neonatal or adult rats. In contrast, steady state CSF:plasma and brain:plasma ratios for L-glucose were increased by respiratory acidosis. 4. The lower steady state CSF:plasma, brain:plasma and erythrocyte:plasma ratios for theophylline in adult rats are likely to be due to a higher concentration of plasma proteins in adult blood compared with neonates, with a greater retention of protein-bound (non-exchangeable) theophylline in adult blood, and are unlikely to be due to p-glycoprotein-mediated efflux of theophylline at the adult blood-brain barrier.