Studies of bilirubin kinetics in normal adults.

This report describes studies of bilirubin kinetics in 13 healthy young adults. The plasma content of unconjugated bilirubin-(14)C was determined at frequent intervals for 24-30 hr after the intravenous injection of a tracer dose of unconjugated isotopic bilirubin. Fecal and urinary radioactivity were measured for 7 days. During this time cumulative recovery averaged 96% of the injected dose. The plasma curves were processed by digital computer. For the 30 hr experimental period, a sum of three exponentials, with average half-times of 18, 81, and 578 min, was required to describe the data. Using the plasma curve integral method, the hepatic bilirubin clearance (47 +/-10 ml/min, mean +/-SD), the bilirubin production rate (3.8 +/-0.6 mg/kg per day), and the mean red blood cell life span (101 +/-13 days) were calculated directly from the parameters of this function. To gain further insight into the metabolism of unconjugated bilirubin, the data were also used to determine the parameters of a multicompartmental model. In the model proposed, plasma unconjugated bilirubin exchanges with two additional pools one of which is thought to represent extrahepatic extravascular, and the other intrahepatic unconjugated bilirubin. Bilirubin is eliminated from the system via the proposed intrahepatic pool. From the data and the model, pool sizes and exchange rates between compartments were calculated, and the liver: plasma concentration gradient estimated. These studies provide a detailed analysis of the kinetics of unconjugated bilirubin in a healthy normal population and are intended to serve as a reference point for studies of abnormal states.

Quantitative studies of the delivery of hepatic-synthesized bilirubin to plasma utilizing -aminolevulinic acid-4- 14 C and bilirubin- 3 H in man.

After the simultaneous intravenous administration of unconjugated bilirubin-(3)H and delta-aminolevulinic acid-4-(14)C, the plasma disappearance curves of unconjugated bilirubin-(3)H and the plasma appearance curves of biosynthesized unconjugated bilirubin-(14)C have been defined in seven patients, three of whom had acute intermittent porphyria (AIP). The incorporation of (14)C into plasma unconjugated bilirubin, derived by an analysis which involves deconvolution of the two plasma curves, varied between 13.1 and 23.5% (mean 19.3%) of the injected dose in the nonporphyric patients and between 5.4 and 13.6% (mean 8.3%) of the injected dose in the porphyric patients. In five of the patients, the stercobilin-(14)C specific activity in a pooled specimen of feces was measured, enabling the following further values to be calculated: (a) the total (14)C radioactivity incorporated into bilirubin (21.0 and 25.3% [mean 23.2%] of the injected dose in two of the nonporphyric patients and between 8.5 and 25.3% [mean 14.2%] of the injected dose in the porphyric patients), and (b) the proportion of hepatic synthesized bilirubin delivered directly to plasma in the unconjugated form (between 0.520 and 0.904; mean for nonporphyric patients 0.712; mean for porphyric patients 0.614). The results demonstrate that a large proportion of bilirubin derived from hepatic hemes passes through the plasma in the unconjugated form before conjugation and secretion into bile.

Reversible pancytopenia following OKT3. Use in the context of multidrug immunosuppression for kidney allografting.

We present two instances of pancytopenia in kidney transplant patients associated with a course of OKT3 therapy. In one case, OKT3 was used prophylactically, in the other therapeutically to treat biopsy-proved rejection. They both occurred in the setting of multi-drug immunosuppression, including Minnesota anti-lymphocyte globulin, and recovered with supportive therapy. Previous antihypertensive medication, antibiotics, and azathioprine were restarted without hematologic sequelae. Evidence implicating OKT3, and resultant gamma-interferon-induced marrow suppression is discussed.

Effect of therapy on T cell subpopulations in patients with chronic lymphocytic leukemia.

We have previously demonstrated functional and quantitative imbalances in two human thymic (T) cell subpopulations, T gamma and T mu, in chronic lymphocytic leukemia (CLL) patients. Serial evaluations of the numbers of T gamma and T mu subsets in CLL were performed in order to delineate more completely the patterns of T cell abnormalities two groups of CLL patients were studied: (I) previously untreated (n = 3) and (II) stable CLL on chemotherapy (n = 12). In Group I, two of three patients had significantly increased percentages of T gamma cells (mean +/- S.E.M. = 57 +/- 5 vs 18 +/- 2 for controls). There was defective in vitro appearance of T mu cells in both groups. In Group II, repeated studies of T cell subsets revealed persistently elevated T gamma cells despite various modes of oral chemotherapy. In three CLL patients who required splenectomy a dramatic decrease in the percentages of T gamma cells was noted post-splenectomy (51 +/- 3 to 15 +/- 3). In all cases the spleen was diffusely involved with CLL. These findings indicate: (1) abnormalities of T cell subsets are present early in CLL, (2) chemotherapy does not affect the levels of T gamma cells in stable patients and (3) removal of infiltrated CLL spleens results in a dramatic decrease in the proportion of T gamma cells. This latter finding plus the increase in T gamma cells in progressive disease post-splenectomy suggest T gamma cells may be an important determinant of the course of CLL.

Recurrent chromosomal defects are found in most patients with non-Hodgkin's-lymphoma.

Using methotrexate cell synchronization, we successfully analyzed chromosomal preparations of 40 lymph node biopsies and one bone marrow sample from 44 patients with non-Hodgkin's, non-Burkitt's lymphoma. All of the 41 patients successfully analyzed showed clonal chromosomal abnormalities. In 25 of the 41 (61%), the defects were found to be consistent with (A) a deletion 6q in five of seven patients with diffuse large cell lymphoma, (B) a t(11;14), a del 11q, or a + 12 in seven of nine patients with small cell lymphocytic lymphoma, and (C) a t(14;18) in 12 of 15 patients with follicular lymphoma (small cleaved and mixed small and large cleaved) and in a single case of diffuse large cell lymphoma. In three patients with small cell lymphocytic lymphoma whose biopsies exhibited a t(11;14), lymphocytes were cultured and chromosomes examined for the presence of fragile sites. In two, frequent breaks at band 11q13.3 were observed. Such findings suggest a possible relationship between a fragile site and a predisposition to a specific chromosomal rearrangement in human neoplasia.

Retinal surgery complicated by a spontaneously acquired factor VIII inhibitor.

We studied a factor VIII inhibitor spontaneously occurring in an otherwise healthy patient who underwent retinal reattachment. The clotting defect first manifested itself as a delayed hemorrhagic choroidal detachment. His bleeding diathesis was successfully managed by infusion of factor VIII concentrate, prednisone, and cyclophosphamide. Surgical procedures in patients with severe bleeding disorders present a difficult therapeutic problem which can be effectively managed by the close cooperation of the surgeon, hematologist, coagulation laboratory, and blood bank.

Anemia in the elderly. Common causes and suggested diagnostic approach.

Anemia is a frequent finding in the elderly. Hypochromic microcytic anemia, usually secondary to iron deficiency, is the most common type. Macrocytic anemia, usually caused by folic acid or vitamin B12 deficiency, is the next most common. Both iron and vitamin B deficiencies are easy to treat with supplements, but the clinician must make a careful search for the cause of the deficiency. Normochromic normocytic anemia can be caused by a number of conditions. The only effective treatment is arrest or cure of the underlying disorder.

Youth justice reform and the rights of the child: a step forward or backward?

Our purpose is to examine Canada's new Youth Criminal Justice Act in light of Canada's obligations under the UN Convention on the Rights of the Child and in contrast to the Young Offenders Act. After reviewing the Convention and the Young Offenders Act, we examine the new act to determine its consistency with the Convention. We conclude that the new act is a step forward because of its greater focus on rehabilitation and social reintegration. However, it is an inadequate step because it does not fully ensure the protection, provision, and participation rights of the child as defined by the Convention.

Protein A immunoadsorption treatment in hematology: an overview.

Staphylococcal protein A efficiently binds immunoglobulins and circulating immune complexes (CIC) and provides an effective medium to remove immunoglobulins and CICs from plasma while sparing albumin and most coagulation proteins. Although it activates the complement system its clinical use abrogates the need for plasma expanders necessitated by plasma exchange. Despite anecdotal reports of utility in several hematologic syndromes, publications of clinical trials are available only for autoimmune thrombocytopenic purpura (AITP) and refractoriness to platelet transfusions (RFT) associated with alloimmunization. In the former situation Snyder et al. (Blood 79:2237-2245, 1992) reported on 72 patients with AITP all of whom had failed at least two previous therapies including splenectomy in 68%. Forty-six percent achieved improved platelet counts following treatment. The response was durable (8-26 mo) in all but 10%. Spleen-intact patients could not be differentiated from those who had been splenectomized. Both responders and nonresponders showed significant decreases in CIC and platelet-directed immunoglobulin (PDIG), but responders achieved near-normal levels. The beneficial response of these factors, particularly in spleen-intact patients, warrants a prospective study. In our studies at the University of Minnesota twelve patients with thrombocytopenia secondary to bone marrow failure who were refractory to platelet transfusion were treated with protein A immunoadsorption. Ten had demonstrable antiplatelet Abs (Anti-HLA, HPA, ABO). Seven of 12 demonstrated improved platelet counts and post-transfusion corrected count increments after treatment. This was associated with decreased platelet utilization and clinical bleeding. A prospective controlled clinical trial is justified.

Effect of phototherapy on serum bilirubin levels and red blood cell survival in congenitally jaundiced Gunn rats.

Although phototherapy with blue fluorescent light effectively lowered the serum bilirubin concentration in congenitally jaundiced Gunn rats, no effect on red blood cell surivival as determined by chromium-51 labeling of homologous red blood cells and carboxyhemoglobin concentration was observed. Furthermore, attempts to demonstrate metabolic stress to the red blood cells failed to show increased glucose consumption. No oxidant damage to red cells as reflected by methemoglobin production and Heinz body formation was observed. Thus the anticipated hemolysis secondary to oxidant damage to red blood cells from phototherapy was not found.