The glucose-6-phosphate dehydrogenase (G6PD) gene is X-linked. There are numerous mutations that cause a deficiency of this enzyme in erythrocytes. G6PD deficiency can produce anemia, both when drugs are administered and under the stress Induced by infection. Functionally severe variants cause hereditary non-spherocytic hemolytic anemia, i,e, anemia even in the absence of stress. Neonatal jaundice occurs in G6PD deficiency, but it is likely that it is largely due to impairment of liver function, rather than to hemolysis, It has been suggested that there are clinical manifestations of G6PD deficiency that are related to other tissues, but the existence of these is not well documented. Some mutations that produce G6PD deficiency in red cells exist at polymorphic frequencies. Individuals with such mutations seem to have enjoyed a selective advantage because of resistance to falciparum malaria. Different mutations, each characteristic of certain populations, are found, and have been characterized at the deoxyribonucleic acid (DNA) level, G6PD A-(202A376G) is th, most common African mutation. G6PD Mediterranean(563r) is found in Southern Europe, the Middle East and in the Indian subcontinent. Several other mutations are common in Asia, Genetic variability of G6PD has played an important role in the understanding of a variety of development processes.
In addition to presentation of antigen, T cells require additional or 'costimulatory' signals from antigen-presenting cells. Failure to receive costimulation following antigen presentation renders T cells anergic, and these cells are functionally incapable of proliferating or secreting cytokines in response to subsequent rechallenge. Recent evidence has demonstrated that a critical costimulatory signal is delivered by members of the B7 family. B7-1 (CD80) and B7-2 (CD86) provide costimulation through CD28, their ligand on the T cell. Dysregulation of expression of B7 may be implicated in the pathogenesis of autoimmune disease. In contrast, lack of expression of B7 on tumor cells may explain in part the lack of immune response against the majority of tumors. It may now be possible to exploit this pathway to induce immunological response against tumors. Blockade of this pathway will likely have significant impact on transplantation biology, to induce T-cell anergy and prevent graft rejection and graft-versus-host disease.
Vasocclusive events in the sickle-cell syndromes have multiple determinants: first and foremost is the capacity of red cells to undergo intracellular polymerization of deoxy HbS. However, the impact of the sicklable red cell is not limited to mechanical obstruction of the microcirculation, but also results in other and sometimes unexpected consequences. For example, red-cell destruction leads to large numbers of young red cells with enhanced vascular adhesion and increased K:CI cotransport expression, in addition to an elevated percent of erythrocytic HbF. These pleiotropic effects, that is, multiple phenotypic effects from a single gene, can be further modulated by the action of epistatic effects, that is, the action of other genes besides beta(s). The interaction of epistatic and pleiotropic effects leads to the interindividual phenotypic variations characteristic of sickle-cell disease. Further understanding of pleiotropic effects (i.e. mechanism of red-cell adhesion, production of vasoactive substances by damaged endothelium, etc.), will uncover new epistatic effects. At the end, we will be able to define not only the genotype, but also the phenotypic severity. This review covers the present knowledge of the red-cell and non-red-cell determinants of vasocclusion, and proposes models to explain the acute painful crises that commonly afflict these patients.
Hereditary spherocytosis is a common and very heterogeneous hemolytic anemia caused by defects of the red cell membrane proteins. In recent years, major advances in our understanding of the red cell membrane skeleton and a better characterization of its individual components have allowed a brighter insight into the pathogenesis of the disease. In this article, we present an overview of the erythrocyte skeleton and its individual constituents. We also review the clinical aspects of the disease and describe the currently known molecular defects involving the membrane proteins which have been shown to play an essential role in the underlying mechanism of hereditary spherocytosis. Finally we examine several models that have been proposed in an attempt to clarify the mechanism leading from the initial molecular insult to the clinical phenotype.
Leeching is considered by many to be a discredited medical relic of the past, This view is not justified, since leeches still play an important part in modern medicine, as in microsurgery and in the treatment of patients with post-phlebitic syndrome. Hirudin, the potent thrombin inhibitor of leech saliva, has been cloned and is used in the treatment of cardiological and hematological disorders, In our search for other antihemostatic factors in Hirudo medicinalis saliva, we found inhibitors of platelet aggregation induced by thrombin, collagen, adenosine 5'-diphosphate, epinephrine, platelet-activating factor and arachidonic acid. We purified apyrase (adenosine 5'-triphosphate diphosphohydrolase), which is a non-specific inhibitor of platelet aggregation by virtue of its action on adenosine 5'-diphosphate. We isolated and characterized the platelet-activating factor antagonist and also identified and recovered an inhibitor of coagulation factor Xa from leech saliva. This report summarizes our findings and those of other investigators, as well as the experience of one of us (A.E.) in leech therapy.
Antithrombin is the major proteinase inhibitor of thrombin and other blood coagulation proteinases. Antithrombin has two functional domains, a heparin binding site and a reactive centre (that complexes and inactivates the proteinase). Its deficiency results in an increased risk of venous thromboembolism, Appreciable progress has been made in recent years in understanding the structure and function of this protein, the genetic cause of inherited deficiency and its clinical consequence, The structure of antithrombin is now considered in terms of the models derived from X-ray crystallography, which have provided explanations for the function of its heparin interaction site and of its reactive loop. The structural organization of the antithrombin gene has been defined and numerous mutations have been identifed that are responsible for antithrombin deficiency: these may reduce the level of the protein (Type I deficiency), alter the function of the protein (Type II deficiency, altering heparin binding or reactive sites), or even have multiple or 'pleiotropic effects' (Type II deficiency, altering both functional domains and the level of protein).
Major histocompatibility complex Class II deficiency or bare lymphocyte syndrome is a rare combined immunodeficiency that accounts for 5% of all cases of severe combined immunodeficiency. The syndrome is characterized by a lack of human leucocyte antigen Class II gene expression, absence of cellular and humoral T-cell immune response to foreign antigens, and impaired antibody production, resulting in extreme susceptibility to viral, bacterial and fungal infections, In some patients, there is a reduced cell surface expression of human leucocyte antigen Class I molecules also. Major histocompatibility complex Class II deficiency is an autosomal recessive disease, most frequent in the Mediterranean area. The disease is caused by impaired gene regulation involving trans-acting proteins. Somatic cell genetics using cell fusion experiments identified four complementation groups, all resulting in the same clinical manifestation. Two regulatory genes have been identified so far: Class II trans activator and regulatory factor X5, Supportive treatment includes intravenous gammaglobulin and prophylaxis against Pneumocystis carinii. The only curative treatment is bone-marrow transplantation.
This review sets out to synthesize and critically evaluate the current reported data regarding therapeutic options for the neutropenia associated with Felty syndrome (Felty neutropenia). A MEDLINE search and bibliographies from recent reviews were used to identify trials and case reports that provided sufficient data to evaluate the effect of various interventions on both the neutropenia and the clinical course of patients with Felty syndrome. Data were obtained on baseline hematologic profiles, bone-marrow biopsies, and patient characteristics; length of follow-up; hematologic and clinical responses to the various interventions; and side-effect profiles. Treatment with hemopoietic growth factors or methotrexate can produce sustained hematologic and clinical responses with an acceptable side-effect profile. Splenectomy produces a long-term hematologic response in 80% of patients. Patients who do not respond hematologically have a higher incidence of non-fatal infections, but a significant minority (46%) do not experience any infections; the incidence of fatal infections is 12%, regardless of whether a hematologic response occurs. Of the patients who had infections prior to surgery, 55% did not experience further infections after splenectomy. Initial treatment of Felty neutropenia should consist of hemopoietic growth factors because of their rapid onset of action and relatively low incidence of side-effects, Splenectomy is a reasonable option if growth factors are ineffective and rapid amelioration of neutropenia is needed. Methotrexate offers a potentially promising alternative for the treatment of both the rheumatologic and the hematologic manifestations of Felty syndrome.
The modification of DNA by cytosine methylation is crucial for normal development. DNA methylation patterns are distinctive between tissues and are maintained with high fidelity during cell division. DNA methylation probably exerts its effects through alterations in chromatin structure, with a resultant effect on genetic transcription. 5-methylcytosine is also prone to spontaneous hydrolytic deamination to thymine. Whilst most G:T mismatches so produced are repaired, failure of mismatch repair leads to established mutation. Indeed, mutations that are the result of 5-methylcytosine transitions account for a disproportionate number of genetic mutations described in malignant and non-malignant disease. There is also evidence for substantial deregulation of DNA methylation in malignancy. Whether this deregulation is crucial for the transformation. process, or simply an epiphenomenon associated with it, is still not established.
Maternal thrombocytopenia is a common finding during pregnancy. The rapid determination of its cause can often be difficult, with the diagnosis only being made in retrospect once the course of the platelet count is known. The majority of patients with thrombocytopenia in pregnancy will have incidental thrombocytopenia of pregnancy which is of no clinical significance.
The anticancer drug 2-chloro-2'-deoxyadenosine (CdA) belongs to the family of purine nucleoside analogs. CdA is exquisitely cytotoxic both to the dividing and to the non-dividing lymphocyte, which supports its use in lymphoproliferative disorders of low-grade malignancy, Indeed, the best clinical results with CdA are achieved in hairy-cell leukemia, in chronic lymphocytic leukemia, in Waldenstrom's macroglobulinemia and in low-grade malignant lymphoma. Most patients with hairy-cell leukemia achieve a complete response with a single course of CdA. However, the disease is not eradicated and a fraction of complete responders will eventually relapse, In chronic lymphocytic leukemia and in malignant lymphoma, complete or partial responses can be achieved in approximately 40% of previously treated patients, even after classical chemotherapy has failed, However, few responses sustain beyond 1 to 2 years, while longer unmaintained responses may be obtained in Waldenstrom's macroglobulinemia. More responses (70-80%) are achieved in patients with chronic lymphoproliferative disorders treated de novo with CdA but their impact on survival remains to be established, More than 10 years after its first use in clinical practice, late adverse consequences of the severe and sustained immunosuppression induced by CdA have not been reported but should still be closely monitored.
Metabolic bone disease is a major cause of morbidity and mortality in patients suffering from multiple myeloma. This usually results from an imbalance between the osteoclast and osteoblast activity of bone resorption and formation due to the secretion of an osteoclast-activating factor by the myeloma cells. This generally takes the form of lytic lesions, hypercalcaemia and osteoporosis but, in a minority of patients, osteosclerosis is a striking feature. In a proportion of patients with gammopathy and the osteosclerotic form of the disease, there appears to be an association with other symptom complexes including Polyneuropathy, organomegaly, endocrine changes, and skin abnormalities. This article summarizes the clinical, radiological and laboratory features of this syndrome, which is known by the acronym 'POEMS'. It is important to recognize this condition, as it carries a better prognosis than the more common lytic form of the disease and because vincristine, and agents frequently used to treat this condition, may severely exacerbate the neuropathy and should be avoided. This syndrome is also important because it may give some insight into the pathophysiology of the plasma-cell dyscrasias.
Neutropenia occurs when the production of neutrophils by the bone marrow is outpaced by utilization in the periphery. Abnormalities of hematopoietic stem-cell development and decreased proliferation of neutrophil precursors in the marrow can reduce production of neutrophils. Conversely, decreased neutrophil survival in the peripheral circulation can also give rise to neutropenia. Non-malignant neutropenia of acute onset can be caused by infection, antibody-mediated destruction, or an idiosyncratic reaction to a drug. Severe chronic neutropenia is a global, descriptive term for several disorders of varied etiologies in which neutrophil levels are consistently or recurrently at levels less than 0.5 x 10(9)/L. Despite this heterogeneity of origin, administration of recombinant human granulocyte colony stimulating factor to individuals with severe chronic neutropenia results in an increase in neutrophil counts in most patients associated with a significantly improved quality of life.
The porphyrias are a group of disorders caused by deficiencies in the activities of the enzymes of the heme biosynthetic pathway, As a result, abnormally elevated levels of porphyrins and/or their precursors, e,g, delta-aminolevulinic acid and porphobilinogen are produced in excess, accumulate in tissues, and are excreted in urine and stool, Two cardinal symptoms of the porphyrias are cutaneous photosensitivity and neurologic disturbances. Acute intermittent porphyria is the most important form of hepatic porphyria because of its frequency and severe clinical symptoms.
Until 1943, blood-grouping tests were performed mainly on glass slides or tiles but, following the description of the antiglobulin test, tube techniques became widespread. With increasing workloads and pressure to be ever more cost-efficient, other 'reaction vessels' such as microplates have been developed for blood-group serological testing. The indirect antiglobulin test has been shown to be the most effective and reliable method for detecting clinically significant antibodies. As a result, this test has been developed, for example by the introduction of enhancement media such as low-ionic-strength saline and polyethylene glycol. However, the problems and inconvenience associated with the labelling and washing of large numbers of tubes were not overcome until the introduction of the solid-phase antiglobulin test and the newer microtubes containing gel or glass microbeads. These techniques are now replacing the conventional tube tests, but they too have their own limitations. There is still no single technique that will detect all clinically significant red-cell antibodies. Therefore, the safe transfusion of red cells that would survive optimally in the recipient depends not on a single test but on a series of tests and procedures, such as correct patient identification, blood-grouping, antibody-screening and compatibility-testing.
Developments in the characterization of growth factors and the recognition of their potential for clinical use has advanced through a number of stages. The development of clonogenic haemopoietic colony assays in the 1960s led to the discovery of colony-stimulating activity in the conditioned medium produced by certain cell lines. This activity was then purified and the colony-stimulating factors were identified. With rapid progress in molecular biology techniques in the 1980s, many further growth factors were cloned and produced on an industrial scale. Although erythropoietin, interferons, G-CSF, GM-CSF and IL-2 were all introduced into clinical practice as single agents, cytokines have more recently been investigated for use either in combination, or sequentially. Clinical trials are currently in progress to examine the optimum combinations and timing of administration. Current clinical applications include optimization of methods for mobilization of peripheral blood progenitor cells and amelioration of cytopenias following chemotherapy and bone-marrow transplantation. In the future, cytokines will be employed to expand stem and progenitor cells ex vivo, to improve gene transduction strategies, possibly to protect the gastrointestinal epithelium and as immunomodulators, both in vivo and in vitro. This review will focus on recently characterized growth factors including c-kit ligand/stem cell factor, flt3 ligand, c-mpl ligand/thrombopoietin and interleukins-11, 4, 7, 10, 12, and 13
High-dose chemotherapy with autologous hematopoietic progenitor-cell support is increasingly used for the treatment of hematologic malignancies and solid tumors, Over the last few years, the major source of progenitor cells for clinical use has shifted from bone marrow to peripheral blood. The current approaches on peripheral blood progenitor-cell mobilization and collection is examined, The isolation of CD34-positive cells from peripheral blood progenitor-cell grafts for tumor purging in the autologous transplant setting and for T-cell depletion in the allogeneic transplant setting is also discussed.