Loma Linda University

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R. Bruce Wilcox, PhD
Professor, Basic Sciences
School of Medicine
Publications    Book Review - Scholarly Journals--Published
  • R. Bruce Wilcox, Jerald E. Nelson. Counterpoint: Legitimate and Illegitimate Tests of Free-analyte Assay function: We Need to identify the Factors that Influence Free-analyte Assay Results. Clinical Chemistry 55/442-444/2009

    ( 10/2009 )
  Scholarly Journals--Published
  • Kristofer S. Fritz, Alastair J.S. McKean, Jerald C. Nelson and R. Bruce Wilcox. 2008. Analog-based Free Testosterone Test Results linked to Total Testosterone Concentrations, Not Free Testosterone Concentrations. Clinical chemistry 54, 512-516.

    ( 0/2008 )

    BACKGROUND: Analog-based free testosterone test results, sex hormone binding globulin (SHBG) concentrations, and total testosterone concentrations are somehow related. This study used new experiments to clarify these relationships.

    CONCLUSION: An analog-based free testosterone immunoassay reported free testosterone test results that were related to total testosterone concentrations under varied experimental conditions. This alleged free testosterone assay did not detect serum free testosterone (the test results it reported were nonspecific) and should not be used for this purpose.

    © 2008 American Association for Clinical Chemistry

  • Kristofer S. Fritz, Rene M. Weiss, Jerald C. Nelson, R. Bruce Wilcox. "Unequal Concentrations of Free T3 and Free T4 after Ultrafiltration." Clinical Chemistry 53.7 (2007): 1384-1385.

    ( 7/2007 ) Link...

    Ultrafiltration is a standard method for separating free T3 and free T4 from serum proteins and protein bound hormone (1, 2). It is expected that free T3 and free T4 in aqueous solutions will accompany water as water moves across semipermeable membranes, a process that results in equal concentrations of free T3 and free T4 in the aqueous solutions on opposite sides of semipermeable membranes after ultrafiltration. The movements of free thyroid hormones through semipermeable membranes
    have not been compared to the movement of water, nor have the concentrations of free hormones on opposite sides been determined in the absence of hormone-binding proteins. We report experiments with 4 different ultrafiltration devices to determine
    the movements of 3H2O, 125IT3, and 125I-T4 across semipermeable membranes in a biologically relevant protein-free aqueous solution.

    A recent study by the authors documented inconsistency in the retention of serum proteins by these same devices. The present study confirms the findings of the previous study; ultrafiltration is complex, poorly characterized, and incompletely understood. The movement of water, T3, and T4 across semipermeable membranes could not be predicted based on the reported MWCO. These inconsistencies complicate the interpretation of previous free thyroid hormone measurements involving uncharacterized ultrafiltration.

  • Kristofer S. Fritz, R. Bruce Wilcox, Jerald C. Nelson. "A Direct Free Thyroxine (T4) Immunoassay with the Characteristics f a Tota T4 Immunoassay." Clinical Chemistry 53.5 (2007): 911-915. ( 5/2007 ) Link...
    Background: Direct free thyroxine (T4) measurements have been linked to both T4-binding serum protein concentrations and protein-bound T4 concentrations. Whether this is evidence of a relationship to total T4 concentrations has not been reported. Methods: We compared an analog-based direct free T4 immunoassay and a total T4 immunoassay. Each assay was applied to the fractions of serum T4 obtained by ultrafiltration and equilibrium dialysis. Both were applied to serum-based solutions in which free T4, T4-binding proteins, protein-bound T4, and total T4 were systematically varied, held constant, or excluded. Results: Neither the free T4 assay nor the total T4 assay detected dialyzable or ultrafilterable serum T4. Both assays detected and reported the T4 retained with serum proteins. Both free and total T4 results were related to the same total T4 concentrations in the presence and absence of T4-binding proteins. Both results were similarly related to total T4 concentrations when free T4 was held constant while total T4 was varied. Both were similarly related to a total T4 concentration that was held constant while free T4 progressively replaced protein-bound T4. These free T4 results, like total T4 results, were unresponsive to a 500-fold variation in dialyzable T4 concentrations. Conclusion: New experiments extend the characterization of a longstanding and incompletely characterized analog-based free T4 immunoassay. These free T4 measurements relate to total T4 concentrations in the same way that total T4 measurements do.
  • Kristofer S. Fritz, R. Bruce Wilcox, Jerald C. Nelson. "Quantifying Spurious Free T4 Results Attributable to Thyroxine-Binding Proteins in Serum Dialysates and Ultrafiltrates." Clinical Chemistry 53.5 (2007): 985-988. ( 5/2007 ) Link...
    Abstract Background: Direct equilibrium dialysis and direct ultrafiltration free thyroxine (T4) assays rely on semipermeable membranes to exclude T4-binding serum proteins from dialysates and ultrafiltrates. The presence of these proteins in dialysates or ultrafiltrates will yield spuriously high free T4 values when free T4 is quantified by RIA. Methods: We used a nonanalog free T4 RIA that detects and quantifies dialyzable and ultrafilterable serum free T4 to detect T4-binding serum proteins. Two equilibrium dialysis devices and 3 ultrafiltration devices were used to illustrate this application. Displacements of [125I]T4 from anti-T4 by various concentrations of T4-depleted thyroxine-binding globulin, albumin, and serum total protein were compared to displacements by various concentrations of free T4. Results: Both dialysis devices excluded detectable T4-binding serum proteins from dialysates. Two of 3 ultrafiltration devices excluded detectable T4-binding serum proteins from ultrafiltrates. One did not, and its ultrafiltrate yielded spurious free T4 values that correlated directly with serum protein concentrations. Conclusion: The presence or absence of T4-binding proteins in dialysates and ultrafiltrates and the spurious free T4 values that these proteins cause can be documented using a nonanalog free T4 RIA.
  • Jerald C Nelson, Rong Wang, David T Asher, R Bruce Wilcox . "Underestimates and overestimates of total T4 concentrations due to unwanted T4 binding protein effects." Thyroid 15. (2005): 12-15. ( 1/2005 )
    The first evidence of unwanted serum protein effects on analog-based total T4 determinations came from a study that varied serum protein concentrations while total T4 concentrations were constant (4). The present study approached this issue by varying total T4 concentrations while protein concentrations were constant. Four analog-based total T4 immunoassays were applied to solutions that contained either free T4 without binding protein, a T4 binding protein without T4, or protein bound T4. When total T4 concentrations were 3-12 g/dL, the assays reported total T4 determinations that ranged from none detected to 23 g/dL. These T4 determinations reflected the protein to which T4 was bound, in addition to the level of T4. Total T4 was under-represented when T4 was unbound, or TBG bound. Total T4 was over-represented when T4 was albumin bound, or transthyretin bound. There were substantial disparities among assays applied to the same total T4 solutions. These assays reported no detectable T4 when applied to T4 binding protein solutions without protein bound T4. Nonetheless, T4 binding proteins contributed to the underestimates and overestimates of protein bound T4. Different forms of protein bound T4 were quantified differently, evidence that protein-T4 complexes persist during quantification. We attribute the unexpected total T4 values to a combination of incomplete protein bound T4 release from T4 binding proteins during quantification, and variably inaccurate quantifications of the protein bound T4 that remained.
  • Jerald C Nelson, Rong Wang, David T Asher, R Bruce Wilcox2. "The nature of analog-based free T4 estimates ." Thyroid 14. (2004): 1030-1036. ( 2/2004 )
    Clinical laboratories often use analog-based immunoassays to estimate serum free T4 concentrations. These assays yield free T4 estimates that correlate closely with T4 binding protein concentrations (1-11). This correlation implies that either T4 binding proteins or protein bound T4 contribute to analog-based free T4 values. To further study the contributions made by T4 binding proteins to these free T4 estimates, four analog-based free T4 assays were applied to: 1) free T4 solutions without T4 binding proteins, 2) to T4 binding protein solutions without T4, and 3) to total T4 solutions containing T4 binding protein, free T4, and protein bound T4. The free T4 estimates obtained with these solutions ranged from 0.2-8.6 ng/dL, when free T4 concentrations ranged from