Distal renal tubular acidosis in multiple myeloma.

A patient with early multiple myeloma was initially seen with a severe hyperchloremic metabolic acidosis with a normal anion gap and a urine pH of 6.3. The patient did not have glucosuria, aminoaciduria, of phosphaturia. A bicarbonate loading test showed that the fractional excretion of bicarbonate was less than 5% and confirmed the hypothesis that the patient had a distal renal tubular acidification defect. The pathophysiologic mechanism that caused this defect is unknown, but it is associated with the presence of a serum M component (IgG-lambda) and a urine M component (lambda light chains). Multiple myeloma should be considered in the differential diagnosis of conditions of patients who have a renal tubular acidification defect.

A sensitive screening method of detecting anti-granulocyte antibodies employing radiolabeled staphylococcal protein A.

We describe an improved method of detecting anti-granulocyte antibodies utilizing radiolabeled staphylococcal protein A (SPA). The results of this SPA assay were compared to data obtained with leukoagglutination tests and granulocyte indirect immunofluorescence techniques. We have shown that the SPA assay is highly sensitive and reproducible. In addition, absorption studies confirmed that the assay is specific for granulocytes. The SPA assay is performed in microtiter plates, and requires significantly fewer granulocytes and less test sera than previously described techniques. Also, we have shown that granulocytes prepared for this assay can be separated and stored for up to 48 h. Therefore, the SPA assay described herein is particularly useful for screening of sera and is one of the most sensitive assays available for detecting anti-granulocyte antibodies.

Cutaneous extramedullary hematopoiesis following splenectomy for idiopathic myelofibrosis.

A 50-year-old man with idiopathic myelofibrosis had development of extensive cutaneous extramedullary hematopoiesis after undergoing splenectomy. Treatment with hydroxyurea was not effective, but electron-beam irradiation controlled the cutaneous infiltration. This rare clinical manifestation of idiopathic myelofibrosis can be confused with cellulitis, and diagnosis depends upon biopsy.

Visual detection of granulocyte surface antigens using the avidin-biotin complex.

A visual test for detection of granulocyte surface markers using the avidin-biotin complex (ABC) has been developed. That this assay is highly specific, reproducible, and sensitive was determined by studying the expression of HLA antigens on granulocytes with monoclonal antibodies. Further, using granulocyte specific alloantisera, the results of the ABC test compared well to data from leukoagglutination assays and indirect immunofluorescence tests. The assay is particularly advantageous in that granulocytes can be stored, only small amounts of cells and sera are needed, and heterogeneous cell populations can easily be studied.

Babesiosis: problems in diagnosis using autoanalyzers.

A 76-year-old white man previous diagnosed as having Waldenstrom's macroglobulinemia continued with persistent fevers and sweats for two and a half years. Recently, repeated automated differentials during 11 days of hospitalization failed to note any intracellular inclusions in the RBCs. Blood sent to the Microbiology Laboratory was noted to contain Babesia species. A review of the hematology slides revealed that Babesia species was present on all the slides the analyzer had screened. This failure to note infected RBCs may pose serious diagnostic problems.

Cobalamin binding and uptake in vitro in the human central nervous system.

Little information exists about the CNS transport of cobalamin. Therefore we undertook to characterize the cobalamin-binding proteins of CSF and to examine uptake of the vitamin by homogenates of CNS tissue. CSF from 24 patients had a mean unsaturated cobalamin-binding capacity of 335 +/- 282 pg/ml. The vast majority of this was TC II (302 +/- 276 pg/ml). The remainder consisted of R binder and a binder eluting with the void volume on Sephadex G-200 gel chromatography. CSF TC II was identical to serum TC II immunologically, functionally, in molecular size, and in electrophoretic mobility, but the levels of the two did not correlate. CSF TC II levels may correlate best with CSF protein levels and tended to be higher in abnormal fluids. Unlike serum TC II, CSF TC II tended to adhere to glass surfaces; uncorrected, this may be a source of artifact in studying various fluids. CSF contains little cobalamin, but most of the endogenous cobalamin was carried by TC II instead of by R binder. Thus CSF appears to have a much higher total TC II: R binder ratio than does plasma. TC II enhanced 57CoB12 uptake by neonatal and adult human brain homogenate and by mouse brain homogenate. The primary phase of TC II-57CoB12 uptake in vitro by human brain cortex homogenate occurred mostly within 30 min and was maximal at 22 degrees C. Uptake was specific, but apo-and holo-TC II appeared to have equal affinity for the receptors. Spinal cord homogenate took up less TC II-57CoB12 per wet weight of tissue than did brain homogenate. R binders did not enhance cobalamin uptake; in fact, they inhibited it. We conclude that uptake of cobalamin by CNS tissue is dependent on TC II and that TC II may be even more prominent in cobalamin transport in the CSF than it is in plasma.

Performance measurement in cancer care: uses and challenges.

Unnecessary, inappropriate, and futile care are given in all areas of health care including cancer care. Not only does such care increase costs and waste precious resources, but patients may have adverse outcomes when the wrong care is given. One of the ways to address this issue is to measure performance with the use of administrative data sets. Through performance measurement, the best providers can be chosen, providers can be rewarded on the basis of the quality of their performance, opportunities for improvement can be identified, and variation in practice can be minimized. Purchasers should take leadership role in creating data sets that will enhance, clinical performance. Specifically, purchasers should require the following from payers: 1) staging information; 2) requirements and/or incentives for proper International Classification of Diseases coding, including other important (comorbid) conditions; 3) incentives or requirements for proper data collection if the payer is using a reimbursement strategy that places the risk on the provider; and 4) a willingness to collect and report information to providers of care, with a view toward increasing quality and decreasing the costs of cancer care. Demanding better clinical performance can lead to better outcomes. Once good data is presented to patients and providers, better clinical behavior and improved cancer care systems will quickly follow.

A gene-controlling response of bone marrow progenitor cells to granulocyte-macrophage colony stimulating factors.

The production of granulocytes and macrophages from progenitor cells in the bone marrow is controlled, in part, by a family of humoral regulators, termed colony stimulating factors (CSF). We have examined genetic factors controlling this process using in vitro cloning techniques. The inbred mouse strain LP/J showed elevated colony formation (CFU-C) in response to one subtype of CSF (G,M-CSF) compared to other strains of mice examined including the strain C57BL/6J. This variation resulted in a shift to the left of the CFU-C dose-response curve for LP/J. No difference between LP/J and C57BL/6J was seen with another subtype of CSF (CSF-1). Maximal CFU-C response was similar in the two mouse strains with both types of CSF, and mixing experiments with both types of CSF gave the same maximal level of colony formation as the individual CSF. (C57BL/6J X LP/J)F1 progeny exhibited a CFU-C dose-response curve to CSF-2 that was intermediate between the parental types, indicating additive inheritance. Genetic analysis of backcross progeny suggested that the variation in CFU-C response is probably determined by a single primary gene, although the variability of the colony formation assay has complicated interpretation of genetic studies. These results suggest that CSF-1 and G,M-CSF act independently on a single bone marrow progenitor cell population. The properties of the genetic variation for G,M-CSF response are consistent with an alteration in cellular receptors for G,M-CSF.

Human granulocytes lack red cell Kx antigen.

We have investigated the presence or absence of the red cell Kx antigen on human granulocytes by measuring specific uptake of anti-Kx using three techniques: direct measurement by 125I-staphylococcal protein A (125I-SPA) and avidin-biotin-complex (ABC) immunoperoxidase staining and also, an indirect measurement using granulocyte adsorption of anti-Kx. Our results with all three methods indicate that the Kx antigen is not present on normal human granulocytes. Prior to adsorption of the anti-Kx serum with purified, pooled, normal human granulocytes, 11 of 21 (53%) of normal granulocytes were non-reactive by 125I-SPA and 16 of 20 (80%) by ABC. This pattern of reactivity was shown to be due to contamination of our anti-Kx serum with an antibody to a granulocyte-specific antigen unrelated to the Kx antigen. After adsorption, there was no diminution in the reactivity of the adsorbed anti-Kx compared to the unadsorbed antiserum against red cells which express strong Kx antigen, i.e. Ko and DTT-modified normal human red cells, by either serologic or 125I-SPA techniques. Likewise, reactivity with McLeod red cells, which have weak expression of the Kx antigen, was not changed using either the unadsorbed or adsorbed anti-Kx. The adsorbed anti-Kx was nonreactive with all 12 normal donors' granulocytes tested by 125I-SPA and with 10 normal donors' granulocytes tested by ABC. Furthermore, granulocytes from a Ko individual were nonreactive using either unadsorbed or adsorbed anti-Kx. These studies indicate that Kx antigen is not present on normal human granulocytes. Further, additional adsorption studies using granulocytes from a boy with X-linked chronic granulomatous disease (CGD) indicated that these granulocytes also do not possess the Kx antigen. In contrast to previous reports, these data suggest that Kx antigen is most probably a red cell-specific antigen and that the red cell Kx antigen has no direct relationship to the biochemical defect in CGD.

The red cell antigens A, B, D, U, Ge, Jk3 and Yta are not detected on human granulocytes.

We report the inability to detect the following red blood cell antigens on human granulocytes: A, B, D, U, Gerbich (Ge), JkaJkb (Jk3) and Cartwright (Yta). To study each antigen, granulocytes were purified on density gradients, fixed in glutaraldehyde, and the uptake of specific antisera measured using two direct immunological techniques: 125I-staphylococcal protein A (125I-SPA) binding and avidin-biotin-complex (ABC) immunoperoxidase staining. Glutaraldehyde fixation was shown not to affect the antigenicity when the antisera were tested using red blood cells. Using three anti-A, three anti-B and three anti-A,B antisera, our 125I-SPA results of 47 tests with granulocytes from group A individuals and 39 tests with granulocytes from group B individuals indicate that A or B antigens are not expressed on human granulocytes. Tests using ABC were also negative with 37 and 36 granulocytes from group A or B individuals, respectively. In addition, no positive results using 125I-SPA were obtained with granulocytes from individuals having antigen positive red cells when tested with two anti-D (number of tests performed (n = 22), three anti-Ge (n = 22), three anti-U (n = 20), two anti-Jk3 (n = 17), and three anti-Yta (n = 25); control anti-NA1 or -NB1 antisera were invariably positive. Also, using these antisera, no positive results were obtained by ABC except with one anti-Yta antiserum which was positive with one of seven granulocytes tested. This anti-Yta was also positive with three of 10 granulocytes by 125I-SPA. This activity was shown to be due to a granulocyte-specific antibody; adsorption of the antiserum with human granulocytes removed all activity against granulocytes but did not reduce the activity against red cells. Thus, our results are in agreement with recent reports which demonstrated the absence of the A, B and D antigens on human granulocytes. However, we have been unable to confirm previous reports which indicated the presence of the U, Ge and Jk3 antigens on human granulocytes. Also, we have been unable to detect the Yta antigen on human granulocytes.

Delphi-panel analysis of appropriateness of high-dose chemotherapy and blood cell or bone marrow autotransplants in women with breast cancer.

BACKGROUND: There is controversy whether high-dose chemotherapy and a blood cell or bone marrow autotransplant is a better treatment than conventional-dose chemotherapy for women with local/regional or metastatic breast cancer. Subject selection and time-to-treatment biases make definitive comparison impossible. Recent results of randomized trials are contradictory. OBJECTIVE: Determine appropriateness of high-dose chemotherapy and a blood cell or bone marrow autotransplant in women with breast cancer. PANELISTS: Nine breast cancer experts from diverse geographic sites and practice settings. EVIDENCE: Boolean MEDLINE searches of 'breast cancer' and 'chemotherapy' and/or 'blood cell' or 'bone marrow transplants'. PROCESS: We used a modified Delphi-panel group judgement process. Clinical variables were permuted to define 2058 clinical settings. Each panelist rated appropriateness of high-dose therapy and an autotransplant versus conventional therapy on a 9-point ordinal scale (1: most inappropriate, 9: most appropriate). An appropriateness index was developed based on median rating and amount of disagreement. The relationship of appropriateness indices to the permuted clinical variables was considered by analysis of variance and recursive partitioning. CONCLUSIONS: In women with local/regional breast cancer autotransplants were rated: 1) appropriate in those with > or = 10 cancer-involved lymph nodes; 2) uncertain in those with 4-9 cancer-involved nodes; and 3) inappropriate in women with < or = 3 cancer-involved lymph nodes. In women with metastatic breast cancer autotransplants were rated: 1) appropriate in those with metastases to 'favorable' sites (skin, lymph node, pleura) and a complete or partial response to chemotherapy; 2) uncertain in women with metastases to 'unfavorable' sites (lung, liver, or central nervous system) and a complete response to chemotherapy or those with bone metastases and a complete or partial response or stable disease after chemotherapy; and 3) inappropriate in other settings.