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Ingenbleek Y.,University of Strasbourg | McCully K.S.,Pathology and Laboratory Medicine Service | McCully K.S.,Harvard University
Nutrition | Year: 2012

Objective: To explain why vegetarian subjects develop morbidity and mortality from cardiovascular diseases unrelated to vitamin B status and Framingham criteria. Methods: A study of 24 rural male subjects 18 to 30 y old and 15 urban male controls was conducted in the Sahel region of Chad. Food consumption was determined from a dietary questionnaire, and overall health status was assessed by body weight, body mass index, serum albumin, plasma transthyretin, urinary nitrogen, and creatinine. Plasma lipids, vitamins B6, B9 and B12, homocysteine, and related sulfur amino acids were measured as selected cardiovascular disease risk factors. Results: Body weight, body mass index, blood, and urinary markers of protein status were significantly lower, with an estimated 10% decrease of lean body mass in the study group compared withurban controls. Neither lipid fractions nor plasma levels of vitamins B6, B9, and B12 were significantly different between the two groups. Although the mean consumption of sulfur amino acids(10.4 mg·kg -1·d -1) by rural subjects was significantly below the recommended dietary allowances (13 mg·kg -1·d -1), plasma methionine values were similar in the two groups. In contrast, homocysteine concentration was significantly increased (18.6 μmol/L, P < 0.001), and the levels of cysteine and glutathione were significantly decreased in the study group, demonstrating inhibition of the trans-sulfuration pathway. The strong negative correlation (r = -0.71) between transthyretin and homocysteine implicated lean body mass as a critical determinant of hyperhomocysteinemia. Conclusion: The low dietary intake of protein and sulfur amino acids by a plant-eating population leads to subclinical protein malnutrition, explaining the origin of hyperhomocysteinemia and the increased vulnerability of these vegetarian subjects to cardiovascular diseases. © 2012.


Genzen J.R.,Cornell University | Tormey C.A.,Yale University | Tormey C.A.,Pathology and Laboratory Medicine Service
American Journal of Clinical Pathology | Year: 2011

Among the most important functions of a pathology or laboratory medicine service is the clear, accurate, and rapid communication of critical test results (critical values) to patient care providers. Pathologists and laboratory professionals are often confronted with many obstacles in the reporting of such critical values, including establishing clinically relevant criteria for critical values, resolving difficulties in locating an ordering provider when a critical value is obtained, and ensuring that the provider understands the severity and implications of a critical result when he or she has questions. This article presents a hypothetical (yet fairly common) clinical case scenario regarding critical values and then provides an up-to-date discussion and review of the literature on the reporting of critical results. © American Society for Clinical Pathology.


Ravnskov U.,Magle Stora Kyrkogata 9 | McCully K.S.,Pathology and Laboratory Medicine Service | McCully K.S.,Harvard University
American Journal of the Medical Sciences | Year: 2012

There is a universal lack of exposure response between degree of lipid lowering and the outcome in clinical and angiographic trials questioning the current view on atherogenesis. However, there are numerous observations and experiments suggesting that microorganisms may play a causal role. A clue is the fact that the lipoproteins constitute an innate immune system by binding and inactivating microorganisms and their toxic products through formation of circulating complexes. Their size may increase in the presence of hyperhomocysteinemia because homocysteine reacts with low-density lipoprotein (LDL) to form homocysteinylated LDL aggregates. Autoantibodies against homocysteinylated or oxidized LDL may also enhance the aggregation. Because of the high extracapillary pressure, such aggregates may obstruct arterial vasa vasorum producing ischemia and cell death within the arterial wall leading to the creation of a vulnerable plaque. The many epidemiological observations, clinical findings and laboratory experiments that conflict with the cholesterol hypothesis are in good accordance with ours. © 2012 Lippincott Williams & Wilkins.


McCully K.S.,Pathology and Laboratory Medicine Service | McCully K.S.,Harvard University
Expert Review of Clinical Pharmacology | Year: 2015

The homocysteine theory of arteriosclerosis was discovered by study of arteriosclerotic plaques occurring in homocystinuria, a disease caused by deficiencies of cystathionine synthase, methionine synthase or methylenetetrahydrofolate reductase. According to the homocysteine theory, metabolic and nutritional abnormalities leading to elevation of plasma homocysteine cause atherosclerosis in the general population without these rare enzymatic abnormalities. Through studies of metabolism of homocysteine thiolactone, the anhydride of homocysteine, in cell cultures from homocystinuric children, the pathway for synthesis of sulfate was found to be dependent upon thioretinamide, the amide formed from retinoic acid and homocysteine thiolactone. Two molecules of thioretinamide form the complex thioretinaco with cobalamin, and oxidative phosphorylation is catalyzed by reduction of oxygen, which is bound to thioretinaco ozonide, by electrons from electron transport particles. Atherogenesis is attributed to formation of aggregates of homocysteinylated lipoproteins with microorganisms, which obstruct the vasa vasorum during formation of arterial vulnerable plaques. © 2014 Informa UK, Ltd.


Joshi M.,University of Arkansas for Medical Sciences | Monson T.P.,CAVHS and Infection Control | Joshi A.,University of Arkansas for Medical Sciences | Woods G.L.,Pathology and Laboratory Medicine Service
Annals of the American Thoracic Society | Year: 2014

Rationale: IFN-γ release assays (IGRAs) including the QuantiFERON-TB gold in-tube test (QFT-GIT) are increasingly used in place of the tuberculin skin test (TST) in surveillance programs for Mycobacterium tuberculosis infection in the United States. However, data on conversions, reversions, and predictive value of QFT in such programs for health care workers (HCWs) are limited. Objectives: The purpose of this study is to assess long-term reproducibility and conversion and reversion rates of QFT-GIT among HCWs who underwent serial testing at a tertiary care center in the United States. Methods: Retrospective chart review of HCWs at the Central Arkansas Veterans Healthcare System (CAVHS) who underwent serial testing with QFT-GIT as a part of their employee screening between November 1, 2008 and January 31, 2011. Measurements and Main Results: A total of 2,303 HCWs had at least 2 QFT-GITs 1 year apart. The initial QFT-GIT was positive for 69 and 2 were indeterminate. Of these 69 HCWs, 31 (45%) reverted on repeat testing, and 25 of 31 (80.6%) HCWs who reverted had a negative look-back TST. Of the 2,232 HCWs with an initial negative QFT-GIT, 71 (3.2%) converted on repeat testing. A third QFT-GIT assay was performed in 41 of the 71 converters and 90% (37 of 41) reverted back to negative. Only two HCWs had TST and QFT-GIT conversion. Conclusions: Poor IGRA reproducibility and a low predictive value of QFT-GIT conversions indicate that QFT-GIT with current interpretation criteria should not be used for serial screening of U.S. HCWs. Negative TSTs have higher reproducibility than QFT-GIT for serial testing of HCWs in low tuberculosis incidence settings.


Gehrie E.A.,Yale University | Tormey C.A.,Yale University | Tormey C.A.,Pathology and Laboratory Medicine Service
Transfusion Medicine and Hemotherapy | Year: 2014

In the context of transfusion medicine, alloimmunization most often refers to the development of antibodies to non-ABO red blood cell (RBC) antigens following pregnancy, transfusion, or transplantation. The development of RBC alloantibodies can have important clinical consequences, particularly in patients who require chronic transfusions. It has been suggested that alloimmunization is more common in some clinical circumstances and patient populations than in others. As such, individuals that develop alloantibodies are frequently referred to as 'responders' in the medical literature. In contrast, individuals that do not develop alloantibodies despite repeated exposures to non-self blood group antigens have been referred to as 'non-responders'. The purpose of this article is to review the phenomenon of RBC alloimmunization in the context of responders and non-responders to: i) establish a basic framework for alloimmunization as reported across several diverse patient populations; ii) more fully explore literature reports which support the concept of responders/non-responders regarding blood group antigen alloimmunization; iii) summarize the mechanisms that have been shown to predispose an individual to alloimmunization to determine how these factors may differentiate 'responders' from 'non-responders'; and iv) briefly discuss some practical approaches to prevent alloimmunization in patients who may be prone to alloantibody development. © 2014 S. Karger GmbH, Freiburg.


Unni N.,Pathology and Laboratory Medicine Service | Peddinghaus M.,Yale University | Tormey C.A.,Yale University | Stack G.,Pathology and Laboratory Medicine Service
Transfusion | Year: 2014

Background Patients transfused at more than one health care facility face safety risks, because their transfusion record is fragmented. Blood group antibodies documented at one facility may be unknown to others. Because many antibodies are evanescent, access to prior antibody records is important for preventing incompatible transfusions and delayed hemolytic reactions. The study goal was to quantify multisite transfusion activity and its impact on antibody record accuracy. Study Design and Methods Patients (n = 100) undergoing hospital transfusion testing were surveyed to determine the locations and dates of any prior transfusions. Also, transfusion records were examined to determine whether patients (n = 200) known to be alloimmunized at one hospital had antibody testing done at another nearby hospital and, if so, how often the results were discrepant. Results Twenty-three percent (23/100) of patients undergoing type-and-screen testing reported receiving transfusions at 24 other facilities. Locations of transfusions that occurred elsewhere were 54.2% (13/24) at eight other in-state hospitals, 12.5% in bordering states, 20.8% in more distant states, and 12.5% during military service. Twenty-one percent (42/200) of patients known to be alloimmunized at one hospital had antibody test results on record at another nearby hospital. Antibody discrepancies were noted in 64.3% (27/42) of cases. The most common discrepancy was the failure of one facility to detect an antibody. Conclusion Multisite transfusions were common. For patients seen at both of two nearby hospitals, antibody records were frequently discrepant. The findings support the need for interfacility sharing of transfusion records, particularly at the regional level. © Published 2013. This article is a U.S. Government work and is in the public domain in the USA.


Winkler A.M.,Emory University | Tormey C.A.,Pathology and Laboratory Medicine Service | Tormey C.A.,Yale University
American Journal of Clinical Pathology | Year: 2013

Objectives: Direct thrombin inhibitors (DTIs), a relatively new class of anticoagulants, present several challenges regarding monitoring of their anticoagulant effects and overcoming bleeding associated with their use. The aim of this article is to (1) briefly present the pharmacologic properties of currently available DTIs, (2) discuss approaches to laboratory assessment of these drugs, and (3) review management of bleeding associated with their use. Methods: Published literature on DTIs, including clinical trials, case reports, and experimental animal models, was reviewed. The primary authors also reviewed their first-hand experiences with DTI anticoagulation. Results: Based on the literature review and the practical experiences of the authors, suggestions for the monitoring of DTIs and algorithmic approaches for the management of DTI-associated bleeding were developed. Conclusions: Routine coagulation assays (eg, the prothrombin time) show a relatively poor correlation with the degree of anticoagulation and DTI drug concentrations. Newer assays, such as the ecarin clotting time and dilute thrombin time, may be more useful in assessing DTI anticoagulation, but these assays are not yet widely available. Low-grade DTI-associated bleeds are best managed with cessation of the drug and supportive care, while higher-grade and/or life-threatening bleeds may best be reversed by active drug removal (eg, via the administration of activated charcoal or hemodialysis). At present there is little evidence to suggest that transfusion products such as factor concentrates or thawed plasma are of any particular benefit in DTI reversal; however, these products may play a supportive role in the management of bleeding. © American Society for Clinical Pathology.


Lum G.,Pathology and Laboratory Medicine Service
Laboratory Medicine | Year: 2011

Humoral hypercalcemia of malignancy (HHM) is the cause of hypercalcemia in the majority of patients with hypercalcemia and cancer. Parathyroid hormone-related protein (PTH-RP) has been identified as the circulating factor that mediates HHM. An N-terminal and a C-terminal PTH-RP are clinically useful assays for screening patients for HHM, and both assays are elevated in such patients. C-terminal PTH-RP depends on glomerular filtration and accumulates in patients with renal failure without malignancy, resulting in falsely-elevated levels, whereas N-terminal PTH-RP is low or undetectable in such patients. We present a case of a patient with renal failure and hypercalcemia who did not have an obvious malignancy and who presented with an elevated C-terminal PTH-RP level and a normal N-terminal PTH-RP. In patients with renal failure and hypercalcemia without cancer, C-terminal PTH-RP may be falsely elevated, especially if the eGFR is <20 mL/minute, and in such patients, N-terminal PTH-RP, because it is less affected by renal function, is the preferred test.


Tormey C.A.,Pathology and Laboratory Medicine Service | Stack G.,Pathology and Laboratory Medicine Service
Archives of Pathology and Laboratory Medicine | Year: 2014

Context. - The extent to which changes in secretory function contribute to the storage lesion of platelets (PLTs) prepared for transfusion is not well described. Objective. - To develop a cytokine-release assay for the assessment of PLT secretory capacity during the preparation and storage of PLTs. Design. - Small volumes of PLT-rich plasma and PLT concentrate (PC) were prepared from whole blood (WB; N = 4 donors). Aliquots of WB, PLT-rich plasma, and PC were treated with 20 μM adenosine diphosphate or saline (control). Samples of WB-derived PCs obtained from a regional blood center were similarly stimulated at various storage times (N = 10 units). Plasma levels of RANTES (chemokine ligand 5; regulated on activation, normal T cell expressed and secreted) and PLT aggregation were measured following agonist addition. Results. - Adenosine diphosphate stimulated RANTES release from PLTs in fresh WB on average by 4.1-fold (P < .001), in PLT-rich plasma by 4.7-fold (P = .002), and in PC by 1.3-fold (P < .001). For blood center PCs, adenosine diphosphate failed to stimulate RANTES release at day 2 of storage or later (P ≥ .31). Baseline RANTES levels in the plasma/supernatant increased 660% during PC preparation (P = .02) and an additional 30% during subsequent storage (P < .001). Mean PLT aggregation decreased during processing from WB (95.6%) to PC (60.5%; P = .04). For blood center PCs, mean PLT aggregation decreased substantially from days 2 (41.0%) to 7 (2.3%; P < .001). Conclusions. - A cytokine-release assay revealed a diminution in PLT secretory capacity during PC processing and storage, with complete elimination by day 2 of storage. Loss of PLT aggregability occurred more slowly. The cytokine-release assay may be a useful endpoint for optimizing PLT preparation and storage. © 2014, College of American Pathologists. All rights reserved.

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