Transfusion-associated graft-versus-host disease.

Transfusion-associated graft-versus-host disease (TA-GVHD) is a devastating immunologic complication of blood transfusion. Patients at highest risk include premature infants and other patients who are immunosuppressed as a result of either congenital or acquired disease or because of the administration of immunosuppressive therapy. An additional high-risk group is immunocompetent patients who are heterozygous at a particular HLA locus and who receive blood from a donor who is homozygous at the same locus. The clinical syndrome consists of fever, skin rash, diarrhea, hepatic dysfunction, and bone marrow aplasia. The outcome is nearly always fatal, despite attempted treatments that have included the use of immunosuppressive agents. Hemorrhage and infection are the most common causes of death. Both humoral and cytotoxic mechanisms have been implicated in the pathophysiology of TA-GVHD. The complication of TA-GVHD can be prevented by the use of irradiated blood components. The use of ultraviolet B light-irradiated blood products and leukoreduction filters are also being investigated as potential preventive treatment modalities.

Prenatal diagnosis of Rambam-Hasharon syndrome.

Rambam-Hasharon syndrome (RHS) is a newly recognized autosomal recessive inborn error in fucose metabolism. Mental retardation, short stature, coarse facies, and recurrent infections are the main clinical findings. Several fucosilated proteoglycans are deficient in these patients. Leukocyte adhesion deficiency type 2 is associated with lack of the membrane glycoprotein sialyl-Lewisx (CD15s). In the red blood cells (RBCs), lack of the membrane glycoprotein H is manifested as a Bombay (Oh) blood type. Two consecutive pregnancies it risk for RHS were monitored during mid-trimester by cordocentesis. One fetus expressed H substance and her blood phenotype was O Rh+. The second fetus, a female, was 2 weeks smaller than expected by dates and had the Bombay blood type. The placenta of the affected fetus was small and irregular. This is the first prenatal diagnosis of this syndrome and the first case found in a female. The documentation of the syndrome in patients of both sexes and the parental consanguinity support an autosomal recessive inheritance. Two apparent recombinations between fucosyl-transferase 1 (FUT1, the H gene) and fucosyl-transferase 2 (secretor) are suggestive of non-allelic heterogeneity. We believe that the Bombay phenotype in this family is caused by a mutated gene, other than FUT1, which is causing multiple deficiencies of fucosilated proteoglycans.

An STS-based map of the human genome.

A physical map has been constructed of the human genome containing 15,086 sequence-tagged sites (STSs), with an average spacing of 199 kilobases. The project involved assembly of a radiation hybrid map of the human genome containing 6193 loci and incorporated a genetic linkage map of the human genome containing 5264 loci. This information was combined with the results of STS-content screening of 10,850 loci against a yeast artificial chromosome library to produce an integrated map, anchored by the radiation hybrid and genetic maps. The map provides radiation hybrid coverage of 99 percent and physical coverage of 94 percent of the human genome. The map also represents an early step in an international project to generate a transcript map of the human genome, with more than 3235 expressed sequences localized. The STSs in the map provide a scaffold for initiating large-scale sequencing of the human genome.

Anemia of uremia is associated with reduced in vitro cytokine secretion: immunopotentiating activity of red blood cells.

Many in vitro studies demonstrate various stimulatory effects of red blood cells (RBC) on T cell reactivity. Only a few suggest a role for RBC in vivo, such as decreased B and T cell function in iron deficiency anemia. Immune deficiency of uremia is only partially corrected by dialysis treatment. We postulated therefore that this anemia may contribute in part to the immune deficiency of uremia. The aim of our study was to evaluate this postulate and to investigate the role RBC may have in the immune system in vivo. The in vitro secretion of interleukin-2 (IL-2), gamma-interferon (gamma-IFN), tumor necrosis factor (TNF) and colony stimulating factor (CSF) by human peripheral blood mononuclear cells isolated from patients and controls was used as a measure of immune function. The following protocols were carried out: IL-2 secretion was measured in patients with end-stage renal disease (ESRD) and in controls. RBCs were transfused to patients with ESRD and secretion of cytokines was measured before, and 4 hours, 4, 7 and 14 days afterwards; patients with ESRD received recombinant human erythropoietin (rHuEpo) and secretion of cytokines was measured before treatment and two and four months later. Finally, the effect of phlebotomy and transfusion of the autologous blood on cytokine secretion in healthy subjects was measured. Secretion of IL-2 by patients with ESRD was substantially lower than that of healthy subjects. In each group, IL-2 secretion correlated positively with hemoglobin level, r = 0.73, P < 0.01 and r = 0.71, P < 0.01.(ABSTRACT TRUNCATED AT 250 WORDS)

Rambam-Hasharon syndrome of psychomotor retardation, short stature, defective neutrophil motility, and Bombay phenotype.

We describe 2 Arab patients, both offspring of unrelated consanguineous matings, with unusual facial appearance, severe mental retardation, microcephaly, cortical atrophy, seizures, hypotonia, dwarfism, and recurrent infections with neutrophilia. Neutrophil motility was markedly decreased but the opsonophagocytic activity was normal. Both patients lack the red blood cell (RBC) H antigen and manifest the Bombay (hh) phenotype. Familial endocardial fibroelastosis and familial tetralogy of Fallot segregated independently in one family. The occurrence of the same syndrome in 2 unrelated families suggests that the various aspects of the disorder are the pleiotropic effects of a single mutation. Homozygosity-by-descent for a deletion involving contiguous genes may explain the findings in this syndrome. Alternatively, a mutation which involves an ubiquitous GDP fucose donor rather than the enzyme (alpha 2-L-fucosyltransferase) or its substrate (glcNAc) may account for the pleiotropic manifestations in this syndrome.

Plasmapheresis with immunosuppression in amyotrophic lateral sclerosis.

Four patients with amyotrophic lateral sclerosis and one with progressive muscular atrophy were treated with large-volume plasmapheresis combined with immunosuppression. Assessment of muscle strength and functional ability was performed during a period of time ranging from 6.2 to 13 months. Patients were compared with a clinically matched control group. Both treated and untreated patients continued to show similar deterioration. The results of this study failed to show any therapeutic benefit of plasmapheresis with immunosuppression in patients with amyotrophic lateral sclerosis.

An anti-neutrophil antibody associated with a propylthiouracil-induced lupus-like syndrome.

A 15-year-old woman with thyrotoxicosis controlled by propylthiouracil presented with chills, fever, splenomegaly, anemia, thrombocytopenia, leukopenia, hypergammaglobulinemia, immune complexes, a positive anti-nuclear antibody test, and a cellular marrow with normal maturation. Anti-neutrophil antibody was detected by cytotoxicity testing. The activity was restricted to the IgM fraction and was absorbed optimally at 4 degrees C. The antibody activity was recovered in both heat and ether eluates made from granulocytes. Lymphocytes, platelets, and red blood cells failed to absorb reactivity. The antibody did not inhibit superoxide production or bacterial killing. Propylthiouracil was discontinued and all signs and symptoms resolved.

Current trends in whole blood and red cell therapy.

Modern blood bank technology has made available a variety of red cell and other blood products in addition to whole blood. The concept of component blood therapy should not discourage physicians from using whole blood in certain situations. The clinical indications for whole blood and red cell products are reviewed in this article.

Partial plasma exchange using albumin replacement: removal and recovery of normal plasma constituents.

Using albumin and crystalloid as the only replacement fluids, the effect of partial plasma exchange on the removal and recovery of normal plasma constituents was studied. The results of 30 procedures on 10 individuals were evaluated. Four patterns of removal are described: reduction in the concentration of fibrinogen and C3 were greater than would be expected based upon the extent of the exchange, while IgG, IgM, cholesterol, alkaline phosphatase and SGPT were removed as expected. Reduction of serum glutamicoxalacetic transaminase (SGOT), lactate dehydrogenase (LDH), amylase, and creatine phosphokinase (CPK) averaged 17% less, and uric acid, calcium and K+ averaged 53% less than expected. Concentrations of HCO-3 and glucose did not change. The mean recovery for all constituents except fibrinogen, C3, cholesterol. IgG and IgM was near 100% at 48-72 hr postpheresis. The 72-hr recovery of fibrinogen and complement was 66% and 60%, respectively. Cholesterol recovery was also slow, requiring a minimum of 1 wk to reach prepheresis levels. Measured at a time when quantitative IgM levels were still reduced, alloantibody agglutinating activity (anti-A and anti-B) in a postpheresis sample exceeded prepheresis agglutinating activity. These data demonstrated that, depending upon quantity and frequency of pheresis, partial plasma exchange using albumin replacement may cause progressive marked reduction in concentrations of immunoglobulin, complement, fibrinogen, and cholesterol. Furthermore, newly synthesized antibody may have increased biologic activity.

Improvement of platelet function following plateletpheresis in patients with myeloproliferative diseases.

Four patients with myeloproliferative diseases and acute hemorrhagic or thrombotic complications of thrombocytosis were treated with plateletpheresis by discontinuous-flow centrifugation. Reduction of platelet counts was achieved rapidly, without complications and was associated with clinical improvement. In all four cases, abnormal platelet aggregation testing was present before pheresis, but improved immediately after pheresis. Platelet-sizing data obtained in one case suggested that during the pheresis procedure, a population of larger volume platelets was selectively removed. The efficacy of plateletpheresis in these clinical situations may be related to the selective removal of a large abnormal platelet population.

Cyclic scheduling via integer programs with circular ones.

A fundamental problem of cyclic staffing is to size and schedule a minimum-cost workforce so that sufficient workers are on duty during each time period. This may be modeled as an integer linear program with a cyclically structured 0-1 constraint matrix. We identify a large class of such problems for which special structure permits the ILP to be solved parametrically as a bounded series of network flow problems. Moreover, an alternative solution technique is shown in which the continuous-valued LP is solved and the result rounded in a special way to yield an optimum solution to the ILP.

Primary biliary cirrhosis and cold autoimmune hemolytic anemia: effect of partial plasma exchange.

The previously unreported occurrence of primary biliary cirrhosis with cold autoimmune hemolytic anemia is described. Red cell survival studies showed a t1/2 of 11.1 days. Partial plasma exchange increased red cell survival to 15.8 days. Concomitantly, alkaline phosphatase, SGOT, SGPT, and bilirubin was reduced in predictable amounts but rebounded to prepheresis levels quickly. Although partial plasma exchange was effective in increasing red cell survival and in reducing the level of selected abnormal plasma components, the patient died 3 mo after initiation of plasma exchange therapy. Partial plasma exchnage did not appear to have any long-term beneficial effects on either liver disease or the hemolytic process.

Use of plasmapheresis and partial plasma exchange in the management of patients with cryoglobulinemia.

The management of patients with cryoglobulins often meets with limited success. Reported here is the use of plasmapheresis and/or partial plasma exchange in the management of five patients with cryoglobulinemia. The procedure was carried out at room temperature with reinfusion through a blood warmer. Circulating levels of mixed cryoglobulins and monoclonal IgM cryoglobulins were more easily reduced than were IgG cryoproteins. Improvement in symptoms was associated with removal of the cryoprotein. Pheresis can be used as primary therapy for reduction of cryoglobulin levels in cases of symptomatic essential cryoglobulinemia. Where an etiology for cryoglobulinemia is known and specific treatment exists, pheresis can be used as effective adjunct therapy.