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Recent studies have generated data demonstrating significant clinical activity of alpha-interferon therapy in each of six hematological malignancies, chronic myeloid leukaemia, essential thrombocythemia, polycythemia rubra vera, non-Hodgkin's lymphomas, multiple myelomatosis and hairy cell leukaemia.

The Transthoracic electrical impedance (TEI) was measured using the Bomed NCCOM3 non-invasive cardiac output monitor in 27 patients with polycythemia rubra vera (PCRV) and in a control group of 27 patients with normal haematocrits. The mean haematocrit was 49.4% (SD 2.61) in the patients with PCRV and 42.1% (SD 2.95) in the control group, a difference that was significant (p less than 0.001). The mean TEI was also significantly higher in patients with PCRV than in the control group (p less than 0.05), the respective values being 31.25 (5.48) Ohms and 27.5 (3.31) Ohms. The mean values for cardiac output (CO) and cardiac index (CI) were similar in both groups.

In this paper the current knowledge on water-induced pruritus is reviewed. To the present, three forms, namely aquagenic pruritus (AP), aquagenic pruritus of the elderly (APE) and water-related itching in polycythemia rubra vera (PRV) have been recognized. Despite clinical similarities it appears that the pathophysiology is different in the three forms. The currently most effective treatment for AP is addition of sodium bicarbonate to the water, control of xerosis with emollients for APE and aspirin for water-induced itching in PRV.

Publisher Summary This chapter discusses blood disorders. The anemias are a common group of disorders affecting the red blood cells, characterized by either a decrease in the number of circulating red blood cells or a decrease in the amount of hemoglobin in each cell or both. Although retinal changes in anemia are common, they are usually innocuous and rarely of diagnostic importance. The three main findings are hemorrhages, cotton-wool spots, and venous tortuosity. Retinal venous tortuosity may also be seen in anemic patients and it seems to be related to the reduction in hematocrit and severity of anemia. Chronic leukemias typically affect the elderly and the presentation is usually more vague and gradual. In some cases, the diagnosis is made by chance. Chemotherapy often does not prolong survival, although it may improve the quality of life. Hyperviscosity syndromes are a diverse group of rare disorders characterized by increased blood viscosity because of increased number of red cells in polycythemia rubra vera and secondary polycythemia, or increased number of white cells in the chronic leukemias. Sickling hemoglobinopathies are because of the presence of one, or a combination of abnormal hemoglobins which cause the red blood cells to adopt an anomalous shape under conditions of hypoxia and acidosis.

Introduction: Lenalidomide (LD) is an oral thalidomide analog with both immunomodulatory and anti-angiogenic properties. It is approved for use in myelodysplastic syndromes (MDS), specifically low-risk and intermediate 1 with 5Q-. LD has also been approved for relapsed multiple myeloma (MM). A major complication associated with LD includes venous thromboembolism (VTE), especially in combination with steroid and erythropoetin (EPO). VTE occurs in 2% of MDS, but range from 6.6% as monotherapy in MM to 8.5%–13.5% when combined with dexamethasone. Zonder reports a preliminary incidence of 75% (9/12 patients) in the SWOG 0302 trial of LD and dexamethasone in previously untreated myeloma. With the addition of ASA in these patients the incidence dropped to 19%. Patients with polycythemia rubra vera (PRV) have a higher incidence of VTE (5.1%> age 70). JAK-2 mutation (tyrosine kinase mutation) occurs as a sporadic event in 75% of patients with PRV and is associated with an older age group, inferior survival, myelofibrosis, acute leukemia and thromboembolic events. Recent studies with LD in this group of PRV and spent-phase myelofibrosis have shown encouraging results. LD has an activity of 46% in myelofibosis by decreasing transfusions and splenomegaly. It would seem to have activity in spent-phase PRV. We report a seminal event of splenic infarction in a patient with PRV and myelofibrosis treated with LD. Case Presentation: A 73 y/o male was diagnosed with PRV 16 yrs earlier. He underwent phlebotomy and received ASA. With a hyperproliferative phase he received hydrea as he was intolerant of IFN-A and anagrelide. Three months earlier, he developed fever, sweats, splenomegaly, and became transfusion dependent. His marrow confirmed myelofibrosis with dysplastic features. LD was begun at 25 mg daily. Three weeks later he developed pneumonia with bronchospasm and required hospitalization for antibiotics and steroids. He improved but returned 4 days later with left upper quadrant pain with CT findings consistent with multiple splenic infarcts. Prednisone was stopped and enoxaparin resulted in marked improvement. Currently, he has marked diminution in the size of his spleen from 13 cm to 4 cm. Currently, he is transfusion independent with marked clinical improvement. Discussion: This report points several dynamic issues within the field of myeloproliferative syndromes. The JAK-2 mutation offers fertile areas of research within MPD disorders as a causative or sporadic mutation and as an associated with several adverse events including VTE and myelofibrosis. We report here a unique occurrence of VTE in the form of multiple splenic infarctions within the context of treatment of the spent-phase of PVR with JAK-2 mutation receiving LD. VTE events associated with LD are associated with DVT or pulmonary embolus and have not been associated with splenic infarction. Splenic infarction has also been reported in myelofibrosis. As further studies confirm efficacy with myelofibrosis it should be suggested that prophylaxis with warfarin or enoxaparin, especially in JAK-2 mutation patients, be considered. Physicians should be encouraged to report their experience in patients with MPD and lenalidomide.

Patients with hematology malignancies have an increased risk of deep vein thrombosis and lower limb lymphedema which is often increased by an intensive chemioterapy or by a myeloablative regimen that often requires multiple platelet-transfusion. Hypercoagulability in cancer patients is associated to phlogosis (the mRNA levels for pro-inflammatory cytokines IL-1, IL-8, LIF, MIP2-alfa were also increased), dysprotidemia, age, bed rest, cancer cell prothrombotic properties (including activation of blood coagulation), impairment of fibrinolytic pathways, alterations of endothelium, increase of the clotting activation markers, and up-regulation of such genes as those coding for transcription factors (c.fos EGR-1, ETO101, c-Myc, Fry-1), over-expression of TF, over-expression of heparanase and formation of a fibrin coat. Both the over-expression of TF and the formation of the TF/VIIa complex induce multiple cellular responses that include proteolytic activity, calcium fluxes, p44/p42 mitogen activated protein kinase phosphorylation, and generation of thrombin. The over-expression of heparanase increased angiogenesis, tumor growth, and metastasis. To investigate the incidence of VTE (venous thromboembolism), and DVT (deep venous thrombosis) in patients with hematology malignancies we have studied 22 patients: 7 with a myeloproliferative disorder (5 with polycythemia rubra vera, 2 with essential thrombocyhemia), 4 with lymphoma, and 11 with leukemia. No patients had suffered from venous or arterial thrombosis before diagnosis of cancer, 14 patients had a first symptomatic thrombosis occurring five months after diagnosis, 4 after starting cytoreductive treatment, 5 patients had a recurrent thrombosis during remission of their disease, no significant differences were found in the cumulative incidence of thrombosis after stratification of the patients respectiely to sex, age, and transient factors (surgery, immobilization, cateteri). For the diagnosis of DVT: CUS (compression ultrasonografy) was performed in all patients combined with D-Dimer levels. Besides we have studied the levels of TF and Heparanase (anti-heparanase antibodies IgG 2BK: HP3/17). The incidence of VTE/DVT has been demonstrated to be associated with the highest levels of TF and Heparanase.

6517 Background: Polycythemia rubra vera (PRV) is a myeloproliferative disorder characterized by panmyelosis. Increased mRNA for c-kit has been demonstrated in CD34+ stem cells in patients with pol...

I read with interest the editorial by Dr. Beutler entitled "Problems in the Diagnosis of the Hemoglobinopathies and of Polycythemia," which was published in the January issue of the Proceedings (pages 102 to 104). My viewpoint about the utility of red cell mass determination for the assessment of patients with erythrocytosis differs from his, however. Dr. Beutler indicated that he is "unaware of any firm evidence that this relatively complex and expensive procedure is of major value," and he discussed the lack of utility in the distinction of primary polycythemia from secondary polycythemia. I concur that the red cell mass and plasma volume determi­ nation are not useful in the differential diagnosis of estab­ lished erythrocytosis; however, the red cell mass does have utility in establishing the diagnosis of erythrocytosis. In work done through the Polycythemia Vera Study Group, Berlin I has shown that the red cell mass can be reliably predicted to be increased only when the hematocrit is 60% or more. Patients with hematocrits in the upper 50 percentiles may have an increased, normal, or, occasionally, low red cell volume with the hematocrit increased because of plasma volume contrac­ tion. This setting can be clarified by the measurement of a red cell mass and plasma volume determination. I agree that pitfalls can occur with use of this technology; thus, one certainly must interpret the results in concert with the other clinical data. In a patient with a hematocrit of 58% who has leukocytosis, thrombocytosis, and splenomegaly, the need for a red cell mass determination is minimal. Nonetheless, many cases of erythrocytosis are not this clear-cut, and the test can aid physicians in distinguishing between truepolycythemia and stress erythrocytosis.

Normal hemopoiesis is dependent upon the appropriate function of pluripotent stem cells. These primitive progenitors are characterized by their ability to proliferate extensively and to mature along the various pathways of hemopoietic differentiation. Their self-renewal capacity ensures the propagation of the system. In addition it is mandatory that these stem cells are responsive to regulatory mechanisms in order to adjust their activity to varying demands [22]. Pluripotent stem cells were first identified and quantitated by Till and McCulloch using their well established spleen colony assay (CFU-S) [34]. This method facilitated investigations that led to some understanding of mechanisms regulating the activity of stem ceils. When the assay was used to assess bone marrow of two strains of genetically anemic mice (W/W ~ and S1/S1 d) two defects could be identified leading to the development of anemia. In animals of the one strain (W/W v) the defect was found to be endogenous to the pluripotent stem cells and readily correctable by stem cell transplantation [24]. In animals of the other strain (S1/SF) a defective supporting environment could be identified which was only correctable by transplantation of whole spleens [23]. In man clinical conditions such as chronic myelogenous leukemia (CML), acute myelogenous leukemia (AML), and Polycythemia rubra vera (PV) are now considered to originate in defective stem cells. This information was essentially provided by studies carried out by Fialkow and his co-workers on such patients that were also heterozygous for the X-linked marker enzyme G-6-PD [2, 15, 19]. This method permitted the investigations to trace cells carrying the disease phenotype back to common ancestors, indicating the clonal nature of these disorders. In order to assess mechanisms leading to altered stem cell function stem cell populations have to be studied directly. Until recently investigations of such nature in man were limited to hemopoietic progenitor populations that were committed to either granulopoiesis (CFU-C) [33] erythropoiesis (BFU-E) [18], or megakaryopoesis [25, 36]. A culture system for murine multilineage hemopoietic cells was first described by Metcalf et al. [32]. "Ihese primitive cells could be identified in culture by their ability to produce

From 1965 to 1972, 19 patients with the Budd-Chiari syndrome were investigated. An underlying diagnosis was made in 10 cases, polycythemia rubra vera being the commonest etiology. Percutaneous liver biopsy confirmed the diagnosis in 18 patients, and in 14 the site of hepatic vein obstruction was defined or its presence suggested by hepatic venography. Hepatic scintiscanning showed predominant central localization of radiocolloid in 7 patients. In another 8 patients this appearance was present in association with other less specific features. These findings were correlated with inferior vena cavography in 13 patients in whom a characteristic narrowing and distortion of the vein throughout its intrahepatic course was noted. In 3 other patients, the vein was found to be occluded. Autopsy evidence in 6 patients suggests that the central concentration of radiocolloid on scintiscanning and the narrowing and distortion of the inferior vena cava were due to disproportionate enlargement of the caudate lobe. Additional studies indicated that the separate venous drainage of the caudate lobe may be preserved when the main hepatic veins are occluded and that hypertrophy of the caudate lobe occurs because of its relatively more efficient perfusion. Demonstration of the enlarged caudate lobe by scintiscanning and inferior vena cavography provides valuable diagnostic support for the Budd-Chiari syndrome.

The cause of stroke in a young adult can usually be ascertained with proper workup. One of the most common causes is atherosclerotic cerebrovascular disease, and cigarette smoking is an important risk factor in young adults. Several types of nonatherosclerotic cerebral vasculopathy can also result in premature cerebral infarction; these include cervicocephalic arterial dissection, nonpenetrating traumatic arterial disease, moyamoya disease, fibromuscular dysplasia, vasculitis, and migraine. Cardiac embolism may play a more important role than was previously thought, and hematologic disorders (eg, sickle cell disease, polycythemia rubra vera, coagulation problems) are known to predispose patients to stroke. A careful history of risk factors and a thorough neurologic and cardiovascular examination followed by adequate testing, including angiography, are essential to diagnosis.

Article, 信州医学雑誌 24(2): 163-168(1976)

A method, based on the differing capacities of cells to adhere to a column of polyester fibres, has been described for separating human bone marrow cells into a nonadherent and an adherent fraction. The effect of this cell separation procedure on colony formation by erythroid progenitor cells was investigated. In contrast to the unseparated population, it was found that erythropoietin-dependent erythroid colony formation by nonadherent cells could be considerably enhanced by the addition of leukocyte conditioned medium to the cultures. Similar erythroid enhancing activity was also detected in a partially purified preparation of granulocytic colony stimulating activity obtained from human embryo kidney culture supernatants. Erythroid colony formation in the absence of added erythropoietin, by non-adherent bone marrow cells from patients with polycythemia rubra vera, were also enhanced by the addition of LCM to the cultures. This finding suggests that the enhancing factor in LCM may not be dependent on the presence of erythropoietin in the cultures for its activity. While the cellular mechanisms by which leukocyte conditioned medium enhances erythroid growth remain to be determined, the data presented provides strong evidence for the view that the plating efficiency of erythroid progenitor cells is determined not only be the concentration of erythropoietin, but also by the presence of leukocyte conditioned medium in the cultures.

Victims of atherothrombotic infarction of the brain, the most common variety of stroke, frequently have recurrent strokes. Risk factors believed to accelerate such events include hypertension, diabetes mellitus, hyperlipidemia, atherosclerotic disease (of heart, aortocervical and intracranial vessels), erythrocythemia, stress, tobacco smoking, hyperuricemia, and perhaps obesity. Most prior studies indicate average anticipated 5 year mortality of 35 to 65 percent and stroke recurrence rate of 20 to 40 percent. A consistent effort to control risk factors in 88 survivors of a first cerebral infarction yielded 17 percent mortality and 16 percent stroke recurrence rates during the 5 years following first stroke. This sustained and systematic approach to risk factor management seemed beneficial to these stroke victims.

Osler's disease is characterized by the triangular features of teleangiectatic lesions, hemorrhagic tendency and inheritance.Recently we experienced a case of this disease. The patient was a 50 year old woman who complained of oral bleeding, and we found other 6 patients in her family. We treated her surgically and she now has a good prognosis. We detected the relationship between Osler's disease and HLA (Human Leukocyte Antigen) locus. HLA typing was carried out by microcytotoxicity test. The haplotype A2 and B5 were found in 3 of 4 patients in this family.

6-thioguanine, an antimetabolite not potentiated by allopurinol, has been used in the treatment of 29 patients with polycythemia vera. All but two of the patients had been treated previously by venesection and/or radioactive phosphorus (32p) and/or alkylating agents. The usual dose was 40-160 mg daily alternate weeks according to individual response. The treatment period varied from 6-66 months (mean, 31 months). Of 27 evaluable patients 24 (89%) responded to treatment and at one year there was a significant fall in all blood count parameters. Seven patients relapsed while on treatment and four were withdrawn because of side effects. 6-thioguanine merits further evaluation in the management of polycythemia vera, particularly in those patients who have received large cumulative doses of 32p and/or alkylating agents and in whom an alternative mode of therapy is desirable.

Bone marrow sections from posterior iliac crest aspiration and/or trephine specimens have been examined in 39 patients with true polycythaemia, along with a variety of other clinical and laboratory data. The emphasis has been on objective assessment of cellularity and megakaryocyte concentration in a prospective four year study. In patients with untreated primary polycythaemia mean cellularity was 87.0% and 86.4% for aspirate and trephine specimens compared with 55.5% and 48.7% for secondary cases and 48.3% and 45.5% for controls. Eighty per cent of primary polycythaemia patients had moderate to marked megakaryocytic hyperplasia. We conclude that, in the presence of an elevated red cell volume, marrow cellularity of >75%, particularly when accompanied by megakaryocytic hyperplasia, of iliac crest aspirate or trephine specimens is sufficient per se to establish a diagnosis of polycythaemia rubra vera.

Although cases of hepatic vein thrombosis (Budd Chiari Syndrome) in oral contraceptive (OC) users have been reported in the literature, the association has not been definitively established. Hepatic vein thrombosis, an uncommon disorder, presents with right upper quadrant abdominal pain, hepatomegaly, and ascites. Diagnostic procedures include hepatic scintiscans, ultrasonography, computerized tomography and magnetic resonance imaging, determination of intrahepatic pressure, liver biopsy, and inferior vena cava and hepatic venography. Hepatic vein thrombosis may develop without an apparent underlying cause or as a complication of an illness known to be associated with vascular thromboses such as polycythemia rubra vera or paroxysmal nocturnal hemoglobinuria. In relation to the large numbers of women taking OCs, there have been very few cases of hepatic vein thrombosis. Evidence linking OC use to the development of hepatic adenomas is far more convincing. In a multicenter case-control study of 33 cases of hepatic vein thrombosis in women 15-45 years of age, each of whom was matched to 3-4 controls, the relative risk of hepatic vein thrombosis in OC users compared with nonusers was 2.37 (p 0.02). It was noted that the 1 patient with paroxysmal nocturnal hemoglobinuria, 5 of 12 patients with overt primary myeloproliferative disorder, and 7 of 8 patients with a forme fruste of a myeloproliferative disorder were OC users, suggesting that OCs--through their thrombogenic action--augmented the thrombotic tendency of the underlying condition. The objectives of therapy in hepatic vein thrombosis are to relieve the hepatic congestion and prevent further clot formation. The majority of patients die within 3 years of diagnosis.

症例は65才,主婦.鼻出血,心窩部痛を主訴に入院した.父に鼻出血,娘に鼻出血および毛細血管拡張病変を認めた. 14才頃より鼻出血が時々あり, 57才頃より毛細血管拡張と口腔内出血が著しくなつた.入院時,皮膚,口腔・鼻腔粘膜の著しい毛細血管拡張,眼瞼結膜に強度の貧血を認めた.肺には異常血管雑音を聴取せず,肝は約4cm触知したが,脾腫は認めなかつた.検査所見では便潜血陽性,ヘモグロビン6.5g/dl,血清鉄, UIBCは鉄欠乏型であつた.肝機能障害を認め,超音波検査は肝硬変に一致した.凝固系検査は正常であつた.胃・十二指腸造影検査,内視鏡検査にて胃および十二指腸潰瘍を認め,潰瘍底部とその周辺部に毛細血管拡張病変を認めたこと,胃液検査にて胃酸が分泌過多であつたことから,本症における消化性潰瘍の発生機序について考察を加えた.

The effect of simulated altitude erythrocythemia on hemoglobin flow rate and maximal O2 uptake (VO2max) was determined for nine women sea-level residents. Test conditions included normoxia and normobaric hypoxia (16% O2-84% N2). Cycle tests were performed under normoxia (T1-N) and hypoxia (T1-H) at prereinfusion control and under hypoxia 48 h after a placebo infusion (T2-H) and 48 h after autologous infusion of 334 ml of erythrocytes (T3-H). Hematocrit (38.1-44.9%) and hemoglobin concentration (12.7-14.7 g.dl-1) increased from control to postreinfusion. At peak exercise, VO2max decreased from T1-N (2.40 l.min-1) to T1-H (2.15 l.min-1) then increased at T3-H (2.37 l.min-1). Maximal arterial-mixed venous O2 difference decreased from T1-N to T1-H and increased at T3-H. Cardiac output (Q), stroke volume, heart rate, and total peripheral resistance during maximal exercise were unchanged from T1-N through T3-H. Hemoglobin flow rate (Hb flow) at maximum did not change from T1-N to T1-H but increased at T3-H. When compared with submaximal values for T1-N, VO2 was unchanged at T1-H and T3-H; Q increased at T1-H and decreased at T3-H; arterial-mixed venous O2 difference decreased at T1-H and increased at T3-H; Hb flow did not change at T1-N but increased at T3-H. For young women, simulated altitude erythrocythemia increased peak Hb flow and decreased physiological altitude (227.8 m) but did not affect maximum cardiac output (Qmax).

The distribution of ABO and Rhesus (D) blood groups was studied retrospectively in 40 patients with primary myelofibrosis (PMF). Only patients with a leukoerythroblastic peripheral blood, splenomegaly and marrow fibrosis in whom chronic myeloid leukemia and secondary myelofibrosis was absent were included in the study. In 14 patients (35%), PMF was preceded by another myeloproliferative disorder (polycythemia rubra vera, essential thrombocythemia or unclassified myeloproliferative disorder), while 26 patients (65%) represented agnogenic myeloid metaplasia (AMM). Comparison with Hospital and Irish blood group distribution showed a significant increase in blood group B (p less than 0.01) in PMF. This increase remained statistically significant for both the AMM and the non-AMM subgroup of PMF when each subgroup was considered separately. This finding supports previous suggestions that the various myeloproliferative disorders which proceed to myelofibrosis are a closely related group rather than a heterogeneous collection of diseases.

Nine patients with Budd-Chiari syndrome (BCS) were treated by a portal systemic shunt. One had thrombosis of the superior mesenteric vein (SMV) and another had complete obstruction of the retrohepatic inferior vena cava (IVC). All other patients had a marked stenosis of the retrohepatic IVC with caval pressure ranging from 12 to 24 mmHg (mean: 17 mmHg). Seven patients had an interposition mesocaval shunt using an autologous jugular vein. The patient with a thrombosed SMV had a portoatrial shunt. The patient with an obstructed IVC had a cavoatrial shunt after an erroneous portacaval shunt had failed to relieve ascites. There were no operative deaths and no major postoperative complications. One patient died 19 months after operation of acute leukemia complicating polycythemia rubra vera. All other patients were alive and well 8 months to 6 years after operation. None of them had encephalopathy. These results suggest several comments: Portal systemic shunts are a good treatment for BCS and have a low operative risk. The mesocaval shunt is an efficient procedure, even when there is stenosis of the IVC with high caval pressure; shunts to the right atrium should be performed only in the case of complete obstruction or inaccessibility of the IVC. The long-term prognosis is excellent, except in patients with potential malignancies. Therefore, portal systemic shunts should be indicated early in patients with symptomatic BCS.

Summary Fibrinolytic potential, a quantitative measurement of available plasminogen and active plasmin, was studied in four patients with Polycythemia vera. The patients in this study were free of clinical evidence of hemorrhage or thrombosis. Fibrinolytic potential was measured using a new fibrin plate method (Hyland) consisting of fibrin, free of plasminogen and factor XIII, suspended in agarose gel. Two of the four patients demonstrated fibrinolytic potential which was grossly subnormal, 22% and 38% of normal, respectively. The other two patients were normal. The two patients with defective fibrinolytic potential had WBC counts > 20,000/mm 3 , while those with normal activity had WBC counts 3 . These results support earlier findings of an antifibrinolytic activity of granulocytes. It is suggested that although hyperviscosity and thrombocytosis are also involved, impaired fibrinolysis might also contribute to the thrombotic tendency of this disease, and the bleeding or thrombosis associated with polycythemia very probably represents a summation of these defects.

The effects of graded induced erythrocythemia on cardiovascular and metabolic responses to intense treadmill running were studied in four highly trained endurance runners. Three autologous infusions of 1 unit (U) whole blood (450 ml/U) were administered sequentially 2–7 days apart. Maximal O2 consumption (VO2max) increased from 5.04 l/min at control (C) to 5.24 l/min after 2 U (R2) and 5.38 l/min after 3 U (R3). Cardiac output during treadmill running at 91% control VO2max was 28.2 l/min at C, 29.8 l/min at R2, and 33.1 l/min at R3. Corresponding heart rates were unchanged, and stroke volume was increased at R3. Peak lactate concentration was reduced, and arterial acid-base status improved at R2 and R3 after standardized bouts of intense exercise. Arterial blood pressures and electrocardiograms during exercise were not affected by erythrocythemia. We conclude that the reinfusion of up to 3 U of autologous blood into highly trained endurance runners who have normal hematology does not adversely affect their cardiovascular response to maximal exercise. In addition, the increases in VO2max following reinfusion of 2 U, and again after 3 U, suggest that the aerobic power of the working muscles was not surpassed at these levels of erythrocythemia.

SummaryAdministration of anagrelide, an antiplatelet agent, to ten normal male subjects was accompanied by an asymptomatic fall in platelet count. The drop was gradual and usually occurred within two weeks. Only a slight shortening of platelet survival was seen. Bone marrow morphology appeared normal. Measurement of platelet production rates showed a reduced response to thrombocytopenia. A substantial increase in the percentage of large platelets was observed in drug treated subjects. These observations are compatible with a selective inhibition of platelet production. Based upon these findings, the use of anagrelide will probably be best limited to short-term applications or to conditions where selective lowering of platelet count may be desired such as in polycythemia rubra vera or idiopathic thrombocytosis.

A patient with acquired von Willebrand's syndrome associated with polycythemia rubra vera is described. Ristocetin cofactor activity was decreased, while the levels of vWF:Ag and VIII:C were normal. Crossed immunoelectrophoretic analysis showed that vWF:Ag was composed of much more anodic component. The mixture study using pooled normal plasma and the patient IgG fractions showed the inhibition of ristocetin cofactor and the decrease of less anodic parts of vWF:Ag in normal plasma. After 1-deamino-8-arginine vasopressin (DDAVP) infusion the marked increases of vWF:Ag, VIII:C and ristocetin cofactor and a rapid return of ristocetin cofactor to the baseline were observed. Transient increase of vWF:Ag after DDAVP infusion showed less anodic forms and in the relative proportion as normal plasma. The present study showed that the patient IgG fractions had the specific inhibitory activity against the antigenic sites on the active subfractions of von Willebrand's factor.

We present a 6-generation kindred of over 221 members, 43 of whom were affected with von Hippel-Lindau (vHL) disease. Through a simple screening protocol, we diagnosed vHL retrospectively in 15 cases, and for the first time in 28, 11 of whom were presymptomatic. We found many complications of vHL in previously diagnosed relatives and in new cases. This study has demonstrated the utility and benefit of preventive surveillance in those known to have vHL, and of presymptomatic screening for affected relatives in families with vHL. The features of vHL were reviewed in our 43 cases and 511 cases from the medical literature. The patterns, frequencies, and ages of onset for each lesion were compared. Renal malignancies caused almost as much mortality in vHL as CNS malignancies. This family was exceptional for absence of pheochromocytoma and erythrocythemia, for more renal and pancreatic cysts and malignancies, and for slightly fewer eye or CNS lesions. Bilateral renal adenocarcinomata were found presymptomatically in five young subjects, who had bilateral nephrectomy and hemodialysis. Three survived long-term after renal transplants. Five relatives had pancreatic malignancies, which are definite although uncommon manifestations of vHL. Recommendations are made for family screening, which was economical and effective. Bayesian calculations help to predict risks for genetic counseling. The molecular basis of vHL may soon be found, since it has been linked to DNA markers on the short arm of chromosome 3.

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I. Clinical Observations 1. The "IJ value, "JM value and "JM/"IJ ratio have been measured as the quantitative expression of ultralow-frequency displacement ballistocardiograms in 259 hypertensive pa-tients and in 124 healthy persons. 2. In cases with arterial hypertension including three cases of polycythemia rubra vera, were observed the ascending dominant waves with a remarkably small "IJ and a tall "JM. 3. In normal adults, "JM/ "IJ ratio was proved to be 2.2-2.3 in all ages, however, a tendency to decrease was observed in "IJ, and "JM values. 4. In experimental hypertension (induced by noradrenaline injection) too, there was seen a decrease of "IJ value and an increase of "JM/ "IJ ratio. Among the hypertensive cases with an exceptronally low "JM/"IJ ratio, a dilatation of the ascending aorta and aortic arch was detected in most cases. 5. The main factor increasing "JM/"IJ ratio was a decrease of "IJ, which was especially influenced by arteriosclerosis and by an increase of systolic blood pressure. 6. No definite correlation was noted, among ECG, serum cholesterol level and eye-ground findings. 7. An obvious positive correlation was observed between the "JM/"IJ ratio and the low-/ high-frequency component ratio in the harmonic analysis of the pulse waves. 8. On the ultralow frequency ballistocardiogram, was noticed a largezr headward deflection in displacement of the body in each heart beat. The damping of this displacement might be considered to be a precipitating factor of the cerebral vascular lesions. II. Model Experiments 1. An experimental ultralow-frequency ballistocardiograph was designed and constructed. The apparatus consisted of the hammock-shaped bed, weighing 1.2 Kg and the natural frequency of the system being 0.23 cps, the damping being 4.1 per cent of the critical value, when the bed was loaded with 8Kg weight. 2. In order to search for the component of displacement wave and factors influencing the waves, a hydraulic circulatory model, was constructed, consisting from a glass flask as the heart and a rubber tube as the aorta. 3. Displacement wave was proved to be influenced by cardiac force, features of the blood vessel wall and blood pressure etc., and an especially close relationship was noticed between the shape of displacement wave and the elasticity of the aorta. 4. The ascending aorta and the aortic arch were proved to be the very parts which affected the displacement curves.

A method for the estimation of vitamin B12 in erythrocytes using E. gracilis is described. In 29 normal subjects the mean value was 158 pg./ml. (S.D. 31 pg.) packed cells. Five of 14 patients with untreated primary polycythemia had very low erythrocyte vitamin B12 levels, and in the group as a whole the value was significantly less than normal. In eight patients with secondary polycythemia the erythrocyte vitamin B12 did not differ from normal, though two patients had values below the normal range. In 19 cases of pernicious anemia the mean erythrocyte vitamin B12 level was 53 pg./ml. (S.D. 32 pg.) packed cells which was significantly reduced. There was no constant relation between the erythrocyte and plasma levels. In eight cases of folate deficiency the erythrocyte vitamin B12 level was significantly reduced, with a mean value of 95 pg./ml. (S.D. 57 pg.) packed cells.

Hereditary hemorrhagic telangiectasia is a rare disease, probably due to mesenchymal dysplasia. It is characterized by the presence of multiple acquired angiomas or telangiectases of varying distribution and number with a marked tendency to bleed spontaneously or from slight trauma. The disease is not sex bound. It is transmitted as a dominant characteristic. The initial symptom usually consists of abnormally profuse epistaxis beginning about puberty. This is followed by the development of multiple telangiectasia of the skin and mucous membranes from the age of 25 to 35. Hemorrhage from the nasal mucosa is most frequent, and all symptoms tend to reach their greatest severity during the fourth decade. The average mortality rate is 4 per cent. The lesions are most commonly found in the nasal mucosa, the skin of the face, the buccal mucosa, the lips, the tongue, the floor of the mouth, the scalp, the ears, the conjunctivas and

Injections were made of a sterile 0.4 per cent solution of germanium dioxide into four lots of mature male and female albino rats. Exact conditions of control were maintained. To two lots there was administered in four doses at intervals of 4 days a total of 6.6 mg. of the oxide per kilo of body weight. To two lots there was given in three doses at like intervals a total of 45 mg. of the compound per kilo of body weight. In each lot there was one rat which served as a control and which did not receive any germanium. A preliminary period of observation was maintained as a further control during which two determinations of the erythrocyte and leucocyte counts of the blood were made 7 days apart on all the rats. Weekly counts were made on all the rats during the progress of the investigation which lasted for 4 weeks, during 3 of which the treated animals were under the influence of germanium. In the first group 11 days elapsed between the last injection and the last count. In the second group the interval was 14 days. It was found that without exception all of the test rats responded to the germanium dioxide by a marked and sustained rise in the number of erythrocytes in the blood which ranged from 1 to nearly 5 millions. These results are statistically valid. There was an apparent tendency for the degree of effect to be related to the initial erythrocyte number, in that with a lower initial count there seemed to take place a greater rise, and vice versa. There was no indication that the larger doses of germanium dioxide exerted a greater stimulating effect on the production of the resultant erythrocythemia than the smaller doses. There is evidence that the effect is quick in making its appearance. The rise in the red cell count was found to occur within a week, and after but two injections of the oxide. Indications were obtained that germanium dioxide tends to increase the coagulability of the blood. Autopsy findings showed color changes in the liver and bone marrow. We believe that germanium dioxide is an erythrocytogenic agent and we hope that fruitful results will come from its therapeutic application.

Two sisters with severe pulmonary hypertension and Osler's disease are described. Heart disease also occurred in other family members affected with hereditary hemorrhagic telangiectasia. Multiple abnormalities of large systemic vessels, severe intrahepatic arteriovenous fistulas and systemic-pulmonary arterial anastomoses were demonstrated in one of the patients, and we conclude that analogous manifestations may have been present in her sister and presumably in other members of the family too. The patients are discussed in relation to similar cases reported earlier and to various types of pulmonary hypertension.

Ten patients with polycythemia and renal carcinoma are presented and twelve previously documented cases from the literature summarized. The syndrome occurred in some 4.4 per cent of 205 patients with polycythemia and 2.6 per cent of 350 patients with renal carcinoma seen in the Presbyterian Hospital. The renal tumors, as well as adjacent parenchymal tissues, were not histologically unique in the six specimens studied. The polycythemia was, for the most part, a simple erythrocytosis without marked splenomegaly, leukocytosis or thrombocytosis. It thus resembled "secondary" rather than primary polycythemia except that it was not dependent upon arterial oxygen unsaturation. Two of our patients had complete hematologic remission following nephrectomy, one for two years and the other for eleven years. Two others from the literature had similar remissions for fourteen months and three years. Of the twenty-two patients thus far described, all eight who underwent nephrectomy had subsequent hematologic remission, whether or not other factors may have played a part. The polycythemia can therefore be regarded as secondary to the renal tumor, as maintained by previous authors. A similar erythropoietic effect has been described for uterine myoma and cerebellar hemangioblastoma, as well as benign renal adenoma and several varieties of carcinoma. The mechanism for the erythrocytosis is unknown, but probably an erythropoietic substance is produced, perhaps in the tumor or in the neighboring renal parenchyma. Whatever the mechanism and its site of action, the appreciable coincidence of polycythemia and renal carcinoma makes mandatory the urologic investigation of hematuria in polycythemia.

A patient with polycythemia rubra vera developed symptoms and signs of pernicious anemia three years after institution of therapy for the polycythemia. This is the first satisfactorily documented report of this sequence. Strict criteria utilized make both diagnoses unequivocal. Autoantibody studies, the first performed in such a patient, show the presence of parietal cell and intrinsic factor autoantibodies but no antibodies to other tissues. Vitamin B12 requirements have been excessive despite high or high normal serum levels and extreme marrow sensitivity to withdrawal of the Vitamin is evident in the presence of these high serum levels. Studies on Vitamin B12 binding proteins showed an elevation in α binding globulin with reversal of the α to β ratio. It is suggested that this protein is physiologically abnormal. The literature is briefly reviewed regarding the pathogenesis of the two disorders with the conclusion that their appearance in the one patient represents purely a chance phenomenon.

A histological comparison of the liver, spleen, bone marrow, circulating young erythrocytes, and differential count in mature male and female albino rats receiving germanium dioxide with their litter controls not receiving this compound was made. It was found that the livers of the test animals in most cases showed a condition of capillary dilatation and that more erythrocytes were in these capillaries than were in those of the controls. There was no evidence of any red cell formation by the liver. The spleens of the test rats gave the impression of being slightly more congested and of having a slightly more dense concentration of cells in the Malpighian corpuscles than those of the controls. There was no evidence of an increased red cell destruction nor was there any evidence of splenic erythropoiesis. In the bone marrow of the rats which had received the germanium dioxide injections there was evidence of a marked stimulation in formation of nucleated erythrocytes, in that many more of these cells were found here than in the marrow sections of the controls. The circulating blood of the test rats contained more young red cells as demonstrated by the increased number of erythrocytes taking the polychromatic stain than did the blood of the controls. No noteworthy differences in the values for the various types of white cells in the circulation determined by the differential count could be found between the two groups. Using, then, as an acceptable criterion of erythropoiesis an increase in the number of erythrocytes in the circulation which is accompanied by an increase in the number of young red cells, and an increased number of nucleated erythrocytes in the bone marrow, we consider ourselves justified in concluding that germanium dioxide is a potent erythropoietic agent and the source of the erythrocythemia produced by this compound is the increased production of red cell precursors by the bone marrow stimulated to increased activity by the compound used.