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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.

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.

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.

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.

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.

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