Suspected collagen disorders in the bleeding disorder clinic: a case-control study.

Disorders of collagen are associated with a mild bleeding tendency because of the potential abnormal interaction of collagen, von Willebrand factor (VWF) and platelets required during primary haemostasis and due to generalized soft tissue fragility. Abnormal collagen may contribute to bleeding in existing mucocutaneous bleeding disorders, but the prevalence in this setting is unknown. Generalized symptomatic joint hypermobility (SJH) is common in collagen disorders and may be objectively measured. To assess the association between symptomatic joint hypermobility and mucocutaneous bleeding disorders, we performed a case-control study in which case subjects were 55 consecutive individuals who had visited our bleeding disorder clinic with a diagnosis of von Willebrand disease, low von Willebrand factor levels, mild platelet function disorder or undefined bleeding disorder. Controls were 50 subjects without a bleeding disorder, and were age and gender matched to the cases. All subjects were assessed with: (i) Beighton score for joint hypermobility, (ii) revised Brighton criteria, (iii) Condensed MCMDM1-VWD bleeding questionnaire, and (iv) haemostasis laboratory studies. The prevalence of SJH/suspected collagen disorder in the bleeding disorder clinic was 24% (13/55) compared with 2% (1/50) in the control population (OR 15, 95% CI 2-121). Seventy-seven per cent of bleeding disorder clinic SJH subjects (10/13) had a prior personal or family history of Ehlers-Danlos, Benign Joint Hypermobility Syndrome or Osteogenesis Imperfecta (OI). Symptomatic joint hypermobility was associated with increased odds of an underlying mucocutaneous bleeding disorder. These findings suggest that a collagen disorder is common and often unrecognized in the bleeding disorder clinic as a potential contributor to the bleeding symptoms.

Generational differences in factors influencing physicians to choose a work location.

INTRODUCTION: Canadian medical schools have increased enrolment and recruited more rural students in an effort to address general and rural physician shortages. The success of this approach depends on the recruitment of these newly trained physicians to under-serviced areas. Studies from North America suggest that the career expectations and practice patterns of younger, more recently graduated physicians differ from those of their older counterparts. This study explored the factors that influenced the work location choices of physicians of differing generations, who trained at universities in Saskatchewan, and Newfoundland and Labrador, two Canadian provinces with large rural populations and no community larger than 235 000 population. METHODS: Semi-structured, qualitative interviews were conducted with physicians who graduated from either the Memorial University of Newfoundland or the University of Saskatchewan. Generation definitions were based on the graduation year. Early-career physicians graduated between 1995 and 1999; mid-career physician graduated between 1985 and 1989; late-career physicians graduated between 1975 and 1979; and end-career physicians graduated between 1965 and 1969. Each physician was asked questions about the number and nature of work location changes over the course of their careers and the factors related to their decision to choose each location. Interview transcripts and notes were analyzed using a thematic analysis approach. Although the study focus was on generational differences, similarities and differences between universities, sexes and specialties (family physicians/GPs vs specialists) were also examined. Recruitment to the provinces was focused on as a whole, because the largest communities in the provinces are small compared with most urban communities. RESULTS: Forty-eight physicians were interviewed, five to nine physicians who graduated in each decade and from each university. The desire to be near family and friends was cited as the primary consideration when choosing a work location, regardless of generation. Likewise, residency training location, the ability to use their skills and knowledge fully, and the quality of recruitment efforts were important considerations in choosing a work location for all physicians. For some, remuneration was very influential in their work location decision; however, many physicians who chose to remain in their smaller 'home' provinces noted the lower cost of living in these provinces. Physicians who graduated in the 1980s and 1990s placed greater emphasis on work-life balance and spouse's employment opportunities than their older generation counterparts. In contrast, physicians who graduated in the 1960s and 1070s highlighted the medical need of the community, and the desire for adventure and to see new places as important. CONCLUSIONS: While many factors for choosing a work location appear to be stable over generations, a number of generational differences were found. Younger physicians placed greater emphasis on work-life balance and spouse's employment than older generation physicians. These differences may have important implications for small population regions which may not be able to support physician-spouse pairs or certain subspecialties. Although economic factors have largely been the focus of recruitment and retention initiatives in these provinces, the findings highlight the importance of addressing the needs and expectations of younger generation physicians in order to attract these physicians.

Successful pregnancy after high dose chemotherapy and marrow transplantation for treatment of aplastic anemia.

A 29-year-old woman with severe idiopathic aplastic anemia was given immunosuppressive therapy with procarbazine, 37.5 mg/kg, antithymocyte globulin, 36 mg IgG/kg, and cyclophosphamide, 200 mg/kg. This was followed by a marrow transplant from her HLA identical sister, immunosuppressive therapy with intermittent methotrexate for 3 months postgrafting and ultimate restoration of hematopoiesis. Two years after transplantation the patient delivered a healthy male infant. This is the first successful pregnancy after a high dose chemotherapy and marrow transplantation for treatment of aplastic anemia.

Chronic myelomonocytic leukemia: an ultrastructural study by transmission and scanning electron microscopy.

The hematologic findings in three cases of chronic myelomonocytic leukemia are presented, with results of ultrastructural studies by transmission and scanning electron microscopy on two of the cases. In the peripheral blood there was a dual, non-lymphocytic, markedly increased population of granulocytes and monocytes. The granulocytes showed marked nuclear abnormality and nuclear cytoplasmic organelle asynchrony. In the marrow the majority of the cells appeared granulocytic but atypical forms and intermediate difficult to distinguish from monocyte precursors were evident by electron microscopy. The ultrastructural findings lend some support to the concept that the neoplastic granulocytes and monocytes having a common precursor.

Red cell membrane changes during storage.

A great deal is known about the red cell membrane and its abnormalities in various pathologic states. During red cell storage there is a progressive development of spheroechniocytosis with eventual production of irreversibly nondeformable red cells. The loss of membrane function is most likely related to some abnormality in maintenance of the cytoskeleton of the red cell. These changes appear to occur independent of ATP levels. Despite the increasing knowledge of the structure and function of the red cell membrane very little as yet is known about the specific abnormality in the red cell membrane that occurs during storage in the blood bank. Recent evidence for abnormal spectrin-actin interaction and abnormal spectrin oxidation has been the most promising. Areas of interest for research include studies of the specific mechanisms by which the plasticizer DEHP interacts with the membrane, specific definition of the molecular defect in membrane proteins that occurs during storage, and means to prevent these. If such deterioration and membrane stiffening could be prevented then the quality of the red cells that are transfused would be improved both in their function and ability to survive in the microcirculation. A final need, while not of specific value to the red cell itself, is the development of media and additives that will allow for increased plasma and Factor VIII yields, one of the driving forces in the blood transfusion system.

Effect of splenectomy on slowing human immunodeficiency virus disease progression.

BACKGROUND: Lymphoreticular tissue is the most important site for human immunodeficiency virus (HIV) replication in HIV-infected individuals. OBJECTIVE: To compare the long-term effect of splenectomy on survival and time to development of acquired immunodeficiency syndrome in subjects who had undergone splenectomy with subjects who had not undergone splenectomy. DESIGN: A cohort study with a follow-up of up to 13.4 years. SETTING: Subjects were recruited from a hospital outpatient clinic population and a multicenter study of patients with hemophilia. PARTICIPANTS: Forty-five HIV-infected individuals were observed prospectively for up to 13.4 years (17 had undergone splenectomy and 28 had not undergone splenectomy). Five subjects underwent splenectomy before acquiring HIV infection and 12 underwent splenectomy during the asymptomatic phase of HIV infection. The group who did not undergo splenectomy consisted of HIV-infected individuals who were asymptomatic at study enrollment. MAIN OUTCOME MEASURES: A Cox proportional hazards model was used to test the effects of splenectomy on survival and time to development of acquired immunodeficiency syndrome when adjusting for potential confounders (age, initial CD4+ cell count, and treatment with antiretroviral drugs). Splenectomy was treated as a time-dependent covariate to account for the variation in its timing. RESULTS: During the average follow-up of 8.6 years, 9 (53%) of the 17 subjects who underwent splenectomy and 23 (82%) of the 28 subjects who did not undergo splenectomy died; acquired immunodeficiency syndrome developed in 6 (35%) of the subjects who underwent splenectomy and 23 (82%) of the subjects who did not undergo splenectomy. Splenectomy was associated with a significant reduction of risk of developing acquired immunodeficiency syndrome (adjusted relative risk [RR] <0.4, P<.05), whereas the effect on risk of mortality approached, although it did not reach, significance (adjusted RR approximately 0.5, P approximately .10). CONCLUSION: The absence of a spleen during the asymptomatic phase of HIV infection seems to have a beneficial effect on HIV disease progression.

Growth of malignant histiocytic cells induced by phorbol myristate acetate.

Cells from the spleen of a patient with malignant histiocytosis were cultured in methyl cellulose with and without 100 ng/mL of phorbol myristate acetate (PMA). Colony growth occurred only with PMA; comparing surface marker studies of the cells before and after culture, it was evident that proliferation had occurred among the histiocytic cells as well as the lymphocytes. After exposure to PMA in organ culture for ten days, the histiocytes appeared to be differentiated and showed evidence of continuing phagocytosis by electron microscopy. This suggests that PMA is a mitogen for the histiocytes in this condition and maintains differentiation of the cells.

Effects of blood and crystalloid cardioplegia on cardiac function at organ and cellular levels during hypothermic cardiac arrest.

The present investigation was undertaken to compare the effects of cold crystalloid and blood cardioplegia on the functional recovery of the heart; on Ca++ binding and uptake, Ca++-ATPase of the sarcoplasmic reticulum (SR), and sarcolemmal (SL) ATPase; and on serum MB fraction of creatine kinase (MBCK) after one and half hours of reperfusion following one hour of ischemic cardiac arrest in dog. This study was made also to determine if the functional changes are related to the changes in biochemistry at the molecular level. The dogs were divided into three groups: sham bypass (SB), cold crystalloid cardioplegia (CC), and pump blood cardioplegia (PB). There was a decrease in the cardiac index (CI), left ventricular work index (LVWI), and mean aortic pressure (MAP) in all three groups. The index of myocardial contractility [dp/dt)/IIP) and CI were lower in the CC group as compared with the SB and PB groups. All the hemodynamic values for the PB group were similar to those of the SB group except total systemic vascular resistance (TSVR) and left ventricular end-diastolic pressure (LVEDP) which were lower in the PB group. The index of myocardial contractility and cardiac index appeared to be greater in the PB group than in the CC group. There was a decrease in the Ca++ uptake by SR from both the CC and PB groups. Ca++ binding and Ca++,-ATPase of SR from the PB group were depressed. The sarcolemmal ATPase was unaffected in both groups. The serum MBCK increased in both PB and CC groups, though the increase was smaller in the PB group. These results indicate that the functional recovery of the heart was slightly better with pump blood cardioplegia than with cold crystalloid cardioplegia. The depressed myocardial contractility and cardiac function in the CC group were associated with a decrease in the Ca++ uptake by SR. However, the decreases in the Ca++ binding, Ca++ uptake, and Ca++ ATPase by SR from the pump blood cardioplegic group were not accompanied by decreases in the cardiac contractility and cardiac function. Myocardial damage as assessed by serum MBCK was smaller in the PB group than in the CC group.

High 2,3-DPG blood cardioplegia and myocardial preservation during cardiopulmonary bypass.

Blood may provide superior cardioplegia compared with crystalloid cardioplegic solution. However, the results are controversial. This may be due to a leftward shift of the hemoglobin (Hb)-O2 dissociation curve induced by hypothermia, increasing the oxygen affinity for Hb. This effect may negate the potential benefit of blood cardioplegia. The oxygen affinity for Hb can be decreased by increasing the red cell 2,3-diphosphoglycerate (2,3-DPG), and hence, more oxygen can be delivered to the myocardium. The present investigation was undertaken to study the effects of 2,3-DPG-enriched blood cardioplegia on the functional recovery of the myocardium and changes in the coronary sinus red blood cell (RBC) adenosine-triphosphate (ATP), lactate, and RBC DPG after one and a half hours of reperfusion following one hour of ischemic cardiac arrest in dogs. The dogs were divided into three groups: crystalloid (CR); stored blood (SB), and high 2,3-DPG blood (HDPG) cardioplegic groups. Incubation of canine RBC in phosphoenal pyruvate (PEP) led to a 36% increase in DPG and a rightward shift in the Hb-O2 dissociation curve. There was a 4 mm Hg shift in the P50. When compared with the CR group, there was a significant decrease in the cardiac index (CI) and left ventricular work index (LVWI) and a significant increase in the total systemic vascular resistance (TSVR) in the SB group. The CI and LVWI of the HDPG group were similar to those of the CR group, but the TSVR was significantly greater in the former group. The LVWI was significantly greater and the TSVR smaller in the HDPG group as compared with those in the SB group.(ABSTRACT TRUNCATED AT 250 WORDS)

Portal hypertension complicating myelofibrosis: reversal following splenectomy.

Portal hypertension occurs in approximately 10% of patients with myelofibrosis. Increased portal blood flow secondary to splenomegaly has been proposed to explain its development. In a 60-year-old woman with proven myelofibrosis of 10 years' duration and gross splenomegaly, portal hypertension developed with esophageal varices and ascites. There was no demonstrable obstruction to portal blood flow. Following splenectomy the ascites and esophageal varices disappeared. Despite the presence of splenic myeloid metaplasia, splenectomy did not impair the patient's hematologic status. Portal hypertension complicating myelofibrosis has a poor prognosis, so careful attention should be given to its detection. Splenectomy may be preferable to portal-systemic shunting in the management of this complication.

The effect of the plasticizer di(2-ethylhexyl)phthalate on red cell deformability.

Red cell concentrates (RCC) are stored for 35 to 42 days in plastic containers manufactured with the liquid plasticizer di(2-ethylhexyl)phthalate (DEHP). DEHP leaches from the polyvinylchloride (PVC) plastic bag, then binds to and stabilizes the RC membrane. This study was undertaken to determine the deformability of the RC membrane using an osmotic gradient ektacytometer and to relate these measurements to the concentration of DEHP in the stored RCC. Pooled RCC was aliquoted into PL146 (PVC), PL732 (polyolefin), and PL732 (with added DEHP) bags with samples removed weekly for analysis of osmotic fragility, deformability, and DEHP concentration. The adenosine triphosphate (ATP) content was also measured. The increase in osmotic fragility during storage was greater when RCC was stored without DEHP. In addition, there was a decrease in the maximum elongation index (El max) when there was decreased DEHP in the storage bag. The osmolarity (Omax) at which El max occurred, as well as the Omin, the osmolarity at which minimum elongation (El min) occurred was higher in the PL732 container than in the PL146 or in the PL732 to which DEHP had been added. These changes could be reversed by addition of DEHP at the beginning of the storage period, showing a direct correlation between DEHP concentration during storage and RC membrane flexibility. By a better understanding of the mechanism of DEHP protection, it might be possible to substitute a less toxic stabilizing compound.

Waldenström macroglobulinemia terminating in acute leukemia: a report of three cases.

Acute leukemia was observed to develop in three patients with Waldenstöm macroglobulinemia. Each patient had been treated with cytotoxic drug therapy. Pancytopenia preceded the onset of the terminal leukemia in two of the three cases. The acute leukemias were all of acute myelogenous type. All of the patients died soon after the development of the terminal leukemia. A number of recent reports have documented acute terminal leukemia in patients with macroglobulinemias and multiple myeloma, as well as other malignant and nonmalignant diseases. The role of the cytotoxic drugs, especially chlorambucil, cyclophosphamide, and melphalan, in leukemogenesis has been raised by these recent reports.

Coagulation factor therapy for hemophilia: relation to hepatitis B and to liver function.

Therapy with concentrated coagulation factors has greatly improved the management of hemophilia, but the consequence of repeated infusion of these blood products are unknown. Hepatic dysfunction is frequent in patients with hemophilia, and the use of these products may be responsible. The relation between liver function and both the frequency and type of therapy with coagulation factors was studied in a group of patients with hemophilia. Of the 36 patients studied, 75% were found to have antibody to hepatitis B surface antigen in their serum and 44% had high levels of serum glutamic oxaloacetic transaminase (SGOT). The infusion of concentrated coagulation factor more than once per year was significantly associated with the presence of antibody to hepatitis B surface antigen and with a high SGOT level. The patients treated with concentrates prepared from blood obtained from large donor pools were significantly more likely to have antibody to hepatitis B surface antigen in their serum but no more likely to have a high H-SGOT level than the patients treated exclusively with cryoprecipitate, plasma or whole blood. These findings suggest that in patients with hemophilia the frequency of coagulation factor treatment may be a more important determinant of hepatic dysfunction than the type of treatment.

Alterations in red cell metabolism during and following cardiac bypass surgery.

Reduced concentrations of red cell organic phosphates and increased hemoglobin--oxygen affinity have been reported during and following cardiac bypass surgery. Some have related these changes to low concentrations of ATP and 2,3-diphosphoglycerate (DPG) in stored blood while others have related them to use of the pump oxygenator. There was a 10% decrease in DPG concentration in seven dogs on cardiac bypass although the animals received no transfusions. In 16 patients who received 0 to 7 units of blood during cardiac bypass there was a decrease of 10% in the red cell DPG concentration from the preoperative value, but it did not relate to the concentration of DPG in the transfused blood bags. The magnitude of the decrease was not sufficient to impair oxygen delivery severely. The results suggest that a re-evaluation of indications for the use of fresh red cells in cardiac surgery is necessary.

Felty's syndrome in a child.

The occurrence of the triad of leukopenia, splenomegaly and rheumatoid arthritis (RA) (Felty's syndrome) during childhood has not been reported previously. We describe an adolescent with onset during childhood of seropositive, nodular, erosive, polyarticular RA in whom both leukopenia and splenomegaly were accompanying features. Neither nonsteroidal antiinflammatory agents nor plasmapheresis were therapeutically beneficial, but low dose oral prednisone therapy resulted in both clinical and hematological improvement.

Prehemolytic erythrocyte deformability changes caused by trichothecene T-2 toxin: an ektacytometer study.

The trichothecene mycotoxin, T-2, is responsible for a wide range of human diseases and animal toxicoses and is known to cause hemolysis of erythrocytes, over time. In order to determine the initial, prehemolytic effect of T-2 toxin on the red cell, we analysed the osmotic deformability pattern using the ektacytometer. After a lag period of 10-60 minutes, hemolysis of T-2 treated red cells is associated with a loss of deformability. During this lag phase there is echinocytosis but no hemolysis. Concurrent with production of echinocytosis there is an initial left shift of the osmotic deformability profile so that the points of maximum and minimum deformability occur in solutions of lower osmolality than normal. The elongation index is also increased. This pattern, one of increased surface area and/or reduced volume (cellular dehydration), represents the initial effect of T-2 toxin on the red cell and is transient. Very quickly, the deformability profile returns to normal, then shifts to the right with a subsequent decrease in elongation index as hemolysis ensues. These changes are independent of the presence of Ca++ and Mg++ and reduced cellular levels of ATP. The findings are consistent with T-2 toxin interacting directly with the cell membrane.

Chronic immune thrombocytopenic purpura in hemophilia A.

Chronic immune thrombocytopenic purpura resistant to steroid therapy occurred in a 30-year-old patient with severe hemophilia A. This association has recently been reported in other patients, and a possible relation to the acquired immune deficiency syndrome (AIDS) has been suggested. Although this patient had been treated with factor VIII concentrate for 4 years, the proportions of helper and suppressor T cells were normal, and there was no evidence of AIDS. An uncomplicated splenectomy gave excellent results. All patients with hemophilia should have their platelet counts monitored closely and should report any unusual pattern of bleeding.

Determination of hemoglobin-oxygen affinity on micro samples.

The spectrophotometric determination of hemoglobin-oxygen dissociation on dilute red cell suspensions has been modified by the use of a bicarbonate buffer containing bovine serum albumin. The red cell suspension is equillibrated with known ratios of air and nitrogen and 5 per cent carbon dioxide at atmospheric pressure using two gas pumps. The method enables the hemoglobin-oxygen dissociation curve to be measured on 10 to 20 mul of whole blood, and has given values for the P50 (the oxygen tension at 50 per cent hemoglobin-oxygen saturation) of 25.9 plus or minus 1.5 S. D. which are comparable to the value of 26.0 plus or minus 1.0 S. D. obtained by the mixing technique and by other methods. The addition of bovine albumin (35 mg. per cent or greater) increased the P50 by 3 mm. Hg above that obtained with buffer alone. The P50 value has been compared in bis-Tris and phosphate buffers with and without albumin, and in bicarbonate buffers with the addition of approximately equimolar concentrations of either human or bovine serum albumin or polyvinyl-pyrrolidone (PVP), and buffer alone. The effect of albumin on the P50 value was most marked in bicarbonate buffer, and was statistically significantly greater in the presence of human or bovine albumin than in buffer alone or buffer plus PVP. The addition of albumin could not be explained through an alteration of cell shape or volume, but may be an influence on intracellular pH.