Biomedical subjects
Publications and source records attributed to D Savage.
Strongyloidiasis in immunocompromised patients is typically associated with a fulminant clinical course and little eosinophilia. We describe an immunocompromised patient with strongyloidiasis in whom the infection was only minimally symptomatic in association with a dramatic increase in eosinophil count.
An 11 year old girl underwent successful transsphenoidal pituitary adenomectomy for pituitary-dependent Cushing's syndrome. Three months after operation, just after stopping glucocorticoid replacement therapy, she developed benign intracranial hypertension. This resolved when exogenous glucocorticoids were restarted but occurred again when they were later stopped. On restarting glucocorticoids again, this second episode of intracranial hypertension resolved. This complication may have been due to the large fall in endogenous cortisol production after removal of her adenoma and subsequent persistent mild endogenous hypocortisolism.
Ambulatory blood pressure measurements were obtained in 57 children and young adults selected by prior high or low casual blood pressure levels and parental history of hypertension. Considerable variation in blood pressure levels occurred over 24 hours, with generally higher levels occurring in those so selected. Parental history had a small influence on higher levels, although statistical significance was not shown. Persons with higher blood pressure levels did not reach levels as low during sleep, especially with regard to the systolic measurement, and a greater variability was noted in those selected for higher levels. Although differentiation of persons with high and low blood pressure levels can be obtained by noting average levels persisting above a cut point, for example, 140/85, in growing children an arbitrary 90th percentile based on age, height, and weight may be more appropriate. Ambulatory monitoring showed that young persons, selected by casual measurements as having high blood pressure, have a greater percentage of high levels persisting over a 24-hour period, comprising a greater blood pressure load. These observations also showed that even two series of casual measurements may misclassify a person as having hypertension. Ambulatory blood pressure monitoring will enhance understanding of the early natural history of hypertension and allow improved prevention of the disease.
Recipients (4076) and donors (3325) of kidney transplants performed at 110 transplant centers were typed for HLA-DRB by the DNA RFLP method. The discrepancy rate of replicate samples distributed among 8 participating laboratories was a low 2.6%. The discrepancy rate between RFLP-DRB and serological HLA-DR typings was 25.0% for organ donors and 27.6% for kidney recipients. Discrepancy rates at the different transplant centers ranged from 9.7% to 86.7%. The discrepancies consisted of antigens being incorrectly interpreted by serology (16.8%), and of serological "blanks" turning out to be definable alleles by the DNA method (10.8%). The alleles that were mainly affected by discrepancies were DR1, DR8, DR10, DR12, DR13, DR14, DR16, DR17.2, and DR18.
The effect of matching for HLA-DR antigens was analyzed retrospectively in 3455 cadaver kidney transplants that were typed by the DNA-RFLP method. HLA-DR matching improved the one-year graft survival rate significantly (P < 0.01). Importantly, in 718 first transplants in which the number of mismatches assigned by serological typing was different from that assigned by DNA typing, only the DNA results showed a significant impact of matching on graft outcome (P = 0.03). These results demonstrate that DNA typing is clinically relevant. We were unable to confirm that the HLA-DR6 specificity or the DR6-split DRB1*1302 are associated with poor graft survival.
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Acute myelogenous leukemia (AML) is a clonal disease that is heterogeneous with respect to the pattern of differentiative expression of the leukemic progenitors. In some patients, the involved stem cells manifest pluripotent differentiative expression, whereas in others, the involved progenitors manifest differentiative expression mainly restricted to the granulocytic pathway. This is in contrast to chronic myelogenous leukemia (CML) which is a clonal disease known to arise in a pluripotent stem cell. Therefore, we tested whether these leukemias could be distinguished with respect to their involvement of immature precursors by studying colony-forming cells (CFC) and their precursors from four glucose-6-phosphate dehydrogenase (G6PD) heterozygous patients with AML and five patients with CML. CFC were separated from their precursors by FACS for expression of CD33 and CD34 followed by growth in a long-term culture (LTC) system. The vast majority of CFC express both the CD33 and CD34 antigens, but their less mature precursors, detected by their ability to give rise to CFC in LTC, express only CD34. In three of the four patients with AML, the CD33-CD34+ cells produced CFC in LTC that appeared to be predominantly or completely normal (ie, nonclonal) in origin. In the fourth patient, a significant enrichment of nonclonal progenitors was obtained in the CD33-CD34+ population, but these cells may also have included significant numbers of clonal cells. In contrast, in four of five patients with CML, cultures of both the CD33-CD34+ and CD33+CD34+ populations produced CFC in LTC that were almost entirely clonal in origin, whereas in the fifth patient a substantial number originated from nonclonal stem cells. These data indicate that granulocyte/monocyte progenitors are predominantly clonally derived in CML and AML. In CML, their precursors are also predominantly clonal, but in some cases of AML they are not. These findings may have implications for understanding the success or failure of current therapies of AML and CML.
In a collaborative project which was supported by 96 transplant centers, DNA typing of HLA-DR antigens was carried out on over 7,000 transplant donors and recipients at 8 participating laboratories. Approximately 25% of the individuals were found to have been typed incorrectly by serological means. An analysis of over 2,500 first cadaver kidney transplants showed a significant correlation of matching for the HLA-DR antigens in transplants where the serological typing was confirmed by DNA typing. In transplants where the serological typing was found to be incorrect, the analysis of serological HLA-DR mismatches resulted in no correlation with graft outcome whereas a significant correlation was found when the corrected DNA typed HLA-DR antigens were analyzed. Transplants which had been reported to the Collaborative Transplant Study based on serological typing as matched for HLA-A, -B, -DR or HLA-B, -DR were found to have a superior graft survival rate only if HLA-DR compatibility was confirmed by DNA typing.
Forty three children with diabetes were recruited to evaluate home blood pressure monitoring using an electronic oscillometric sphygmomanometer (Philips HP5330). This device was found to be simple to use and reliable. It fulfilled the accuracy criteria of the American Association for the Advancement of Medical Instrumentation for both systolic and diastolic blood pressure and those of the British Hypertension Society for systolic blood pressure. Thirty eight children successfully measured their own blood pressure at home and taught other family members to do the same. The results indicate that home blood pressure monitoring is of value in the management of diabetic children.
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The clinical value of serological HLA matching for cadaver kidney transplantation remains uncertain because the success rate for HLA-matched cadaver transplants is lower than that of HLA-matched sibling grafts. Up to 25% of serological HLA-DR typings may be incorrect when compared with a more accurate DNA-RFLP method, and we have now examined whether incorrect HLA-DR typings account for the lower than expected success rates of HLA-matched cadaver transplants. 58 transplant centres took part in this study and DNA was extracted from over 4000 samples of frozen tissue at the study centre. 8 laboratories then completed blind RFLP typing for HLA-DR. Serological typing data were reported by individual transplant laboratories. 29 of 107 transplants (27%) that were reported as HLA A, B, DR compatible and 76 of 273 (28%) transplants that were reported as HLA B, DR compatible according to serological typing were found to be HLA-DR mismatched by DNA typing. The one-year transplant success rate for DNA-matched HLA, A, B, DR grafts was 87% compared with 69% for mismatched grafts (p less than 0.02); the corresponding success rate for DNA-matched HLA B, DR grafts was 85% compared with 72% for mismatched grafts (p less than 0.01). Many transplants that were previously thought to be HLA matched are mismatched, and this finding may account for previously unexplained graft failures.
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Electrocardiographic left ventricular hypertrophy (increased left ventricular mass) is a known risk predictor of stroke independent of blood pressure level. However, electrocardiography is an insensitive index of such hypertrophy. To assess the potential risk associated with increased left ventricular mass via continuous measurement (as is becoming available with echocardiography), published longitudinal data from the Framingham study were used to estimate risk of stroke associated with various levels of increased left ventricular mass. This model predicts that left ventricular mass is at least as powerful as, if not more powerful than, systolic blood pressure levels for predicting risk of stroke.
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Two women are described in whom, on the basis of prior therapy for breast cancer and the presence of painful, lytic bone lesions, an initial diagnosis of metastatic breast cancer was made. Further evaluation established the diagnosis of multiple myeloma in both patients. Neither had evidence of recurrent breast cancer. These cases indicate that women with a history of breast cancer in whom lytic bone lesions develop without evidence of extraskeletal metastases should have the diagnosis of multiple myeloma excluded.
In order to develop a diagnostic approach to the common problem of anemia associated with alcoholism, 121 chronic alcoholics admitted to a general medical service with a low hematocrit were evaluated. Multiple contributing causes of anemia were present in most patients. Megaloblastic marrow change was found in 33.9% of patients, sideroblastic change in 23.1%, absent iron stores in 13.2%, aggregated macrophage iron in 81.0%, and acute blood loss in 24.8%. The MCV was of little value in predicting the presence of megaloblastic change unless markedly elevated (greater than 110 fl). In 15 of 41 patients with megaloblastic marrow morphology (36.6%) the MCV was normal or low. Among 40 patients with MCV values between 100 and 110 fl, megaloblastic change was not present in the bone marrow smears of 24 (60.0%). Neutrophil hypersegmentation was 95% specific but only 78% sensitive for megaloblastic change; in contrast, the presence of macroovalocytosis was 90% sensitive but only 68% specific. Serum lactic dehydrogenase, plasma folate, and erythrocyte folate levels had such low sensitivities and specificities for megaloblastic change as to be of little predictive value. Hematologic responses to folic acid were often inadequate in patients with megaloblastic morphologic changes, apparently because of associated acute and chronic illness. Our findings are consistent with the hypothesis that 2 mechanisms account for the development of megaloblastic hematopoiesis in alcoholics: induction of folate deficiency and a direct toxic effect of alcohol on erythroid precursors independent of folate depletion, as reflected by the presence of normal plasma and erythrocyte folate levels in several patients with megaloblastic change. In no patient was sideroblastic change the sole apparent cause of anemia. Megaloblastic hematopoiesis and aggregated macrophage iron frequently accompanied sideroblastic change. Examination of the blood smear revealed siderocytes in one-third of patients with sideroblastic marrows and dimorphic erythrocyte morphology in the majority. Dimorphic blood smears, however, were neither sensitive nor specific for sideroblastic change. Serum iron concentrations were usually not elevated in the group with sideroblastic abnormalities. In predicting marrow iron stores, serum iron and iron-binding capacity concentrations were often non-diagnostic or misleading. Serum ferritin levels less than 100 ng/ml, however, showed 100% sensitivity and 95% specificity for absent marrow iron stores despite the frequent presence of abnormal liver function. On the basis of our findings, practical guidelines have been formulated for the evaluation and therapy of anemia in alcohol