Chuanyi M. Lu

Epinephrine Is Required for Normal Cardiovascular Responses to Stress in the Phenylethanolamine N-Methyltransferase Knockout Mouse

Background— Epinephrine (EPI) is an important neurotransmitter and hormone. Its role in regulating cardiovascular function at rest and with stress is unclear, however. Methods and Results— An epinephrine-deficient mouse model was generated in which the epinephrine-synthesizing enzyme phenylethanolamine N-methyltransferase was knocked out (KO). Blood pressure and heart rate were monitored by telemetry at rest and during graded treadmill exercise. Cardiac structure and function were evaluated by echocardiography in mice under 1 of 2 conditions: unstressed and lightly anesthetized or restrained and awake. In KO mice, resting cardiovascular function, including blood pressure, heart rate, and cardiac output, was the same as that in wild-type mice, and the basal norepinephrine plasma level was normal. However, inhibition of sympathetic innervation with the ganglion blocker hexamethonium caused a 54% smaller decrease in blood pressure in KO mice, and treadmill exercise caused an 11% higher increase in blood pressure, both suggesting impaired vasodilation in KO mice. Interestingly, phenylethanolamine N-methyltransferase KO did not change the heart rate response to ganglionic blockade and exercise. By echocardiography, KO mice had an increased ratio of left ventricular posterior wall thickness to internal dimensions but did not have cardiac hypertrophy, suggesting concentric remodeling in the KO heart. Finally, in restrained, awake KO mice, heart rate and ejection fraction remained normal, but cardiac output was significantly reduced because of diminished end-diastolic volume. Conclusion— Our data suggest that epinephrine is required for normal blood pressure and cardiac filling responses to stress but is not required for tachycardia during stress or normal cardiovascular function at rest.

Diagnostic and Clinical Considerations in Concomitant Bone Marrow Involvement by Plasma Cell Myeloma and Chronic Lymphocytic Leukemia/Monoclonal B-Cell Lymphocytosis: A Series of 15 Cases and Review of Literature

CONTEXT Plasma cell myeloma and chronic lymphocytic leukemia are both common hematologic malignancies, sharing many epidemiologic features. Concomitant detection of the 2 conditions poses special diagnostic challenges for the pathologist. OBJECTIVE To describe the pathologic findings in cases of concomitant bone marrow involvement by myeloma and CD5(+) monoclonal B cells and to outline the differential diagnostic possibilities, suggest a workup for correct diagnosis, and examine clinical outcome. DESIGN Fifteen cases that met the diagnostic criteria were identified from pathology databases at 4 participating institutions. Morphologic findings were reviewed, additional immunohistochemical stains performed, and flow cytometric, cytogenetic, and relevant laboratory and clinical information was summarized. Previously published cases were searched from electronic databases and cross-references. RESULTS Most patients (13 of 15) were older males. Often (11 of 15) they presented clinically with myeloma, yet had both monotypic plasma cells and B cells in the diagnostic marrow. In 4 patients, myeloma developed 24 months or later after chronic lymphocytic leukemia. In 7 patients, myeloma and CD5(+) B cells showed identical immunoglobulin light-chain restriction. Primary differential diagnoses include lymphoplasmacytic lymphoma, marginal zone lymphoma, and chronic lymphocytic leukemia with plasmacytoid differentiation. CD56 and/or cyclin D1 expression by plasma cells was helpful for correct diagnosis. Most patients in our cohort and published reports were treated for plasma cell myeloma. CONCLUSIONS Concomitant detection of myeloma and chronic lymphocytic leukemia in the bone marrow is a rare event, which must be carefully differentiated from lymphomas with lymphoplasmacytic differentiation for correct treatment.

Pathology Consultation on Anticoagulation Monitoring Factor X-Related Assays

OBJECTIVES To review various anticoagulation therapies and related laboratory monitoring issues, with a focus on factor X-related chromogenic assays. METHODS A case-based approach is used to review pertinent published literatures and product inserts of anticoagulation drugs and to look back on clinical use of factor X-related chromogenic assays. RESULTS The number of anticoagulants available to clinicians has increased greatly in the past decade. Whether and how these anticoagulants should be monitored are areas of uncertainty for clinicians, which can lead to misuse of laboratory assays and suboptimal patient management. Factor X-related assays are of particular concern because of the similar and often confusing test names. Based on a common clinical case scenario and literature review regarding anticoagulant monitoring, an up-to-date discussion and review of the various factor X-related assays are provided, focusing on the differences in test designs and clinical utilities between the chromogenic anti-Xa and chromogenic factor X activity assays. CONCLUSIONS Anticoagulation therapy and related laboratory monitoring are rapidly evolving areas of clinical practices. A good knowledge of relevant laboratory assays and their clinical applications is necessary to help optimize patient care.

Myeloid neoplasms secondary to plasma cell myeloma: an intrinsic predisposition or therapy-related phenomenon? A clinicopathologic study of 41 cases and correlation of cytogenetic features with treatment regimens.

We describe 41 cases of myeloid neoplasms (MNs) secondary to plasma cell myeloma (PCM). The types of MN included myelodysplastic syndrome (MDS) in 34 (82.9%), acute myeloid leukemia (AML) in 4 (9.8%), and myeloproliferative neoplasm (MPN) or MDS/MPN in 3 (7.3%) cases. The latency from treatment to diagnosis of MN ranged from 9 to 384 months, with a median of 60 months. Of 37 cases with cytogenetic studies, complex abnormalities were detected in 22 (59.5%), -5(q)/-7(q) in 4 (10.8%), other abnormalities in 8 (21.6%), and normal karyotype in 3 (8.1%) cases. Complex abnormalities and -5(q)/-7(q) correlated directly with multiple chemotherapeutic regimens, particularly with combined melphalan/cyclophosphamide. Moreover, the features of cytogenetic abnormalities in our series were significantly different from those with concomitant PCM/MN who had significantly lower complex abnormalities. The latency, skewed proportion of MDS, and bias toward complex cytogenetic abnormalities/unbalanced aberrations of chromosomes 5/7 suggested an alkylating mutagenic effect on pathogenesis of secondary MN. Kaplan-Meier survival analysis demonstrated a median survival of 19 months, which was better than that for therapy-related (t)-MDS/AML. In contrast to t-MDS, the survival in our patients appeared to depend on subtypes of MDS as seen in de novo diseases.

Measurement of Microalbuminuria Using Protein Chip Electrophoresis

Microalbuminuria reflects the progression of nephropathy and cardiovascular disease in diabetic and hypertensive patients. Most commercially available tests currently used to measure microalbuminuria are immunoassays. We developed a microfluidics-based assay using the P200 protein chip (Caliper Life Sciences, Mountain View, CA, and Agilent Technologies, Santa Clara, CA) and 2100 Bioanalyzer (Agilent Technologies) to detect microalbuminuria. The method integrates and automates the electrophoretic separation and fluorescent detection of proteins from 14 to 200 kd. The assay was linear up to 750 mg/L and demonstrated good sensitivity with a lower detection limit of 7.5 mg/L. Intrachip and interchip coefficients of variation ranged from 0% to 4% and 4.9% to 13.5%, respectively. When albumin was measured by chip and immunoturbidimetry in diabetic urine samples, the chip consistently showed higher albumin concentrations. The discrepancy may be due to the chips ability to detect immunounreactive albumin. Overall, this simple, cost-effective assay offers a sensitive and accurate measurement of microalbuminuria that can be easily implemented in a clinical laboratory.

Pathology consultation on vitamin D testing: clinical indications for 25(OH) vitamin D measurement.

To the Editor I read with great interest the recent article by Krasowski1 on the timely topic of vitamin D testing. In this review, Krasowski1 presented a common clinical case scenario about vitamin D and provided an excellent discussion on causes of vitamin D deficiency and the challenges faced by pathologists related to 25-hydroxyvitamin D [25(OH)D] testing, including controversy about optimal and target serum 25(OH)D concentrations, variable and confusing reference intervals, various 25(OH)D assays, and misordering of 1,25-dihydroxyvitamin D [1,25(OH)2D] testing. Although Krasowski1 mentioned the dramatic increases in 25(OH)D testing volume, the article did not discuss the clinical indications for vitamin D testing, which, in my view, are even more important for pathologists in their clinical consultation on test utilization. During the past few years, the idea that nearly everyone needs extra vitamin D has gained significant attention in the general public and lay media, thanks to the speculated health benefits of vitamin D from epidemiologic association studies. More and more people are being tested for 25(OH)D, even as part of screening during routine physical examinations. As a result, the 25(OH)D assay has become one of the most ordered, if not the most ordered, esoteric test and is associated with an increasing cost burden to the often strained laboratory testing budget. Despite continued debate on the optimal 25(OH)D concentration and the cutoff values for vitamin D deficiency and insufficiency,2 according to the …

Impaired Chronotropic Response to Exercise in Mice Lacking Catecholamines in Adrenergic Cells

To define the in vivo role of adrenergic catecholamines (CAs), we generated a mouse model whereby tyrosine hydroxylase (TH) was knocked out (KO) in phenylethanolamine N‐methyltransferase–expressing cells. These adrenergic specific TH‐KO mice were viable and grossly normal. Their resting heart rate and blood pressure, as monitored by telemetry, were unchanged. However, when challenged with treadmill exercise, their chronotropic responses were significantly reduced by 14% compared to wild‐type mice. Thus, our data suggest that adrenergic CA is required for normal chronotropic responses to stress, but not required for prenatal and postnatal development or normal cardiovascular function at rest.