Watch, Discover, Think, and Act: a model for patient education program development.

In this report we describe the development of the Watch, Discover, Think and Act asthma self-management computer program for inner-city children with asthma. The intervention focused on teaching two categories of behaviors--asthma specific behaviors such as taking preventive medication and self-regulatory processes such as monitoring symptoms and solving asthma problems. These asthma self-management behaviors were then linked with empirical and theoretical determinants such as skills and self-efficacy. We then further used behavioral science theory to develop methods such as role modeling and skill training linked to the determinants. We matched these theoretical methods to practical strategies within the computer simulation and created a culturally competent program for inner-city minority youth. Finally, we planned a program evaluation that linked program impact and outcomes to the theoretical assumptions on which the intervention was based.

Treatment of the myeloproliferative disorders with 32P.

The use of radioactive phosphorus (32P) to treat the myeloproliferative disorders (chronic leukemia, polycythemia vera and essential thrombocythemia) began in 1939 when John H. Lawrence treated the first patient on the basis of work done in the laboratory animals that found localization of the radioisotope in the spleen, liver, bone and in leukemic cells sufficient to indicate a therapeutic potential. After World War II when 32P became widely available, it was used extensively to treat the chronic leukemias and polycythemia vera. Its use in the treatment of essential thrombocythemia began later in 1950. Today it is not widely used in the treatment of the chronic leukemia, if at all, its use in polycythemia vera appears to have decreased substantially and replaced by hydroxyurea, and its use in the management of essential thrombocythemia is not widespread. In each instance it has been replaced by a drug developed for use in cancer chemotherapy, and in some instances by interferon. It probably has wider use in polycythemia vera in the rest of Western Europe than in the UK, and there are cogent reasons to suggest that it may be the best tool for the treatment of polycythemia vera. Thus have we discarded a treatment modality that in polycythemia vera may be the best?

Measurement of total RBC volume relative to lean body mass for diagnosis of polycythemia.

An elevated total RBC volume (TRCV) in milliliters per kilogram of body weight has been an essential criterion for determining whether a person is polycythemic. This may be misleading in obese subjects as the TRCV per kilogram of fat is only one-tenth that of the TRCV of the lean body mass (LBM). Various formulas based on surface area have been used to account for this difference, but they are not always reliable. Direct measurement of TRCV per kilogram of lean body mass was obtained originally in studies in which body composition was determined by the combined body density and total body water measurement method. This is impractical as a routine procedure, but simple-to-use instruments are now available for direct measurement of a person's body composition and percentage of fat by impedance technology. Thus, the TRCV can be obtained by a direct measurement that discounts the effects of fat, and a graph has been designed to normalize the TRCV to milliliters per kilogram of LBM. The TRCV for men and women has been established as 36 mL/kg LBM; when it is more than 43 mL/kg LBM, a diagnosis of polychthemia can be made with confidence.

Diagnosis, pathogenesis and treatment of the myeloproliferative disorders essential thrombocythemia, polycythemia vera and essential megakaryocytic granulocytic metaplasia and myelofibrosis.

According to strict clinical, hematological and morphological criteria, the Philadelphia (Ph) chromosome negative chronic myeloproliferative disorders essential thrombocythemia (ET), polycythemia vera (PV), and agnogenic myeloid (megakaryocytic/granulocytic) metaplasia (AMM) or idiopathic myelofibrosis (IMF) are three distinct disease entities with regard to clinical manifestations, natural history and outcome in terms of life expectancy. As clonality studies have clearly demonstrated that fibroblast proliferation in AMM, as well as in many other conditions such as advanced stages of Ph(+)-essential thrombocythemia, Ph(+)-granulocytic leukemia, and Ph(-)-polycythemia vera, is polyclonal indicating that myelofibrosis is secondary to the megakaryocytic granulocytic metaplasia in these various conditions, AMM is illogically labeled as IMF. As abnormal megakaryocytic granulocytic metaplasia is the essential feature preceding the early prefibrotic stage of AMM, the term essential megakaryocytic granulocytic metaplasia (EMGM) can readily be used to characterize this condition more appropriately at the biological level. Clinical, hematological and morphological characteristics, in particular megakaryocytopoiesis and bone marrow cellularity, reveal diagnostic features, which enable a clear-cut distinction between ET, PV and EMGM or classical IMF. The characteristic increase and clustering of enlarged megakaryocytes with mature cytoplasm and multilobulated nuclei and their tendency to cluster in a normal or only slightly increased cellular bone marrow represent the hallmark of ET. The characteristic increase and clustering of enlarged mature and pleiomorphic megakaryocytes with multilobulated nuclei and proliferation of erythropoiesis in a moderate to marked hypercellular bone marrow with hyperplasia of dilated sinuses are the specific diagnostic features of untreated PV. EMGM, including the early prefibrotic stages as well as the various myelofibrotic stages of classical IMF appear to be a distinct neoplastic dual proliferation of abnormal megakaryopoiesis and granulopoiesis. The histopathology of the bone marrow in prefibrotic EMGM and in classical IMF is dominated by atypical, enlarged and immature megakaryocytes with cloud-like immature nuclei, which are not seen in ET and PV at diagnosis and during follow-up. Myelofibrosis in ET, PV and EMGM is graded into: no reticulin fibrosis (MF0), early reticulin fibrosis (MF1), advanced reticulin sclerosis with minor or moderate collagen fibrosis (MF2) and advanced collagen fibrosis with osteosclerosis (MF3). Myelofibrosis is not a feature of ET at diagnosis and during long-term follow-up. Myelofibrosis may be present in a minority of PV-patients at diagnosis and usually becomes apparent during long-term follow-up in the majority of PV-patients. Myelofibrosis secondary to the abnormal megakaryocytic and granulocytic myeloproliferation constitutes a prominent feature in the majority of EMGM/IMF at time of diagnosis and usually progresses more or less rapidly during the natural history of the disease. Life expectancy is normal in ET, normal during the 1st ten years and compromised during the 2nd ten years follow-up in PV, but significantly shortened in the prefibrotic stage of EMGM as well as in the various myelosclerotic stages of classical IMF. First line treatment options in prospective randomized clinical trials of newly diagnosed MPD-patients are control of platelet function with low-dose aspirin versus reduction of platelet count with anagrelide, interferon or hydroxyurea in ET; control of platelet and erythrocyte counts by interferon alone versus bloodletting plus hydroxyurea on indication in PV; interferon versus no treatment in the early stages of EMGM; a wait and see strategy in the fibrotic stages of EMGM or classical IMF with favorable prognostic factors, and bone marrow transplantation in classical IMF with poor prognostic factors at presentation or during short-term follow-up.

Polycythemia vera: a retrospective and reprise.

This article, by two of the late John H. Lawrence's fellows of the 1940s, traces the development of the knowledge of polycythemia vera from Vaquez, who wrote the first description of this disease, and Osler, who recognized it as "a new clinical entity," through John H. Lawrence and the use of 32P as a treatment for polycythemia vera, to the formation of French and Italian polycythemia study groups. In particular, the history of polycythemia vera after the Second World War, and its more recent history, can be traced through the development of an algorithm for evaluating an elevated hematocrit and the development of the first (O1) protocol of the Polycythemia Vera Study Group (PVSG), a randomized trial of the efficacy of 32P, chlorambucil, and phlebotomy for treating polycythemia vera. It was in 1948, only 9 years after the first use of 32P for treating polycythemia vera, that Byron Hall reported the occurrence of acute leukemia following this use of the isotope. This led to the formation of the PVSG. After completing enrollment of patients in the first protocol of the PVSG, an attempt to find a replacement for 32P as a myelosuppressive agent led to the testing of hydroxyurea as a putative non-leukemogenic drug for this purpose. However, the use of hydroxyurea for treating polycythemia vera is coming into question, as is the ability to maintain patients with phlebotomy alone. The PVSG as such no longer exists as an operational group; its files are maintained at the Mount Sinai School of Medicine in New York City. However, the French group created for the study of polycythemia vera has had a consensus conference, and the Italian group has developed a low-dose aspirin protocol for treating the disease.

The metabolism service.

The Metabolism Branch, originally the Metabolism Service, created by Mider and Zubrod largely in the image that Mider had projected, has had two leaders: Berlin (1956-1971) and Waldmann (1971-present). The original design of a comparatively small senior staff of five Senior Investigators and 10 Clinical Associates (fellows), together with an 11-bed patient care unit in close proximity to the offices and laboratories, has in essence continued to the present with a comparatively small expansion under Waldmann. This unit has served as a training ground. Among its present members and alumni there are 18 members of the Association of American Physicians (AAP) and 22 members of the American Society of Clinical Investigation (ASCI). In 1994, two of the presidents of the clinical research societies, Rosenberg of the AAP and Berzofsky of the ASCI, are from the Service's ranks. This model, some would say paradigm, for the organization and function of clinical research units could be an answer to what Ahrens has called a crisis. The Metabolism Branch had the benefit of strong leadership from the NCI, particularly Endicott, The Director in the 1960s, and Mider and Zubrod, the Scientific Directors. There can be no doubt that the Branch benefited substantially, some would say enormously, from the doctor draft of the 1950s and 1960s and from the funding of the intramural research program as an integral part of the funding of each of the National Institutes.

Therapeutic recommendations in polycythemia vera based on Polycythemia Vera Study Group protocols.

The PVSG was organized in 1967 to establish effective diagnostic criteria for polycythemia vera, to study the natural history of the disease and to define the optimal treatment. Although polycythemia vera and the other myeloproliferative diseases are relatively uncommon, the PVSG was able to accumulate well over 1,000 patients with these various disorders and to study them according to a total of 15 different protocols. PVSG-01, a long-term randomized controlled study of phlebotomy alone compared with the myelosuppressive agents, 32P or chlorambucil supplemented by phlebotomy, continues to receive follow-up data on 93% of surviving patients 18 years after initiation of the study. During its lifetime, PVSG has developed a widely accepted and highly effective set of criteria for the specific diagnosis of polycythemia vera as well as useful criteria for the diagnosis of essential thrombocythemia. It has gathered an enormous volume of data on the natural history of the myeloproliferative diseases and in particular on the nature of the prevalent complications, such as thrombotic events and hematologic and nonhematologic malignancies. With respect to the final question, the optimal treatment for polycythemia vera, it is apparent that the expectation of a single optimal therapy that would apply to all patients at all ages and stages of the disease was naive. Nevertheless considerable progress has been made. Moreover, the group has defined more precisely than ever before the nature of the complications of the disease and the association of the risks of specific complications with specific forms of therapy. It thus has made it possible to pose the next series of therapeutic questions that must be addressed in this disorder with a greater degree of sophistication than was previously possible.