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Michael N Fahiewilson - One of the best experts on this subject based on the ideXlab platform.
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determination of prolactin the Macroprolactin problem
Best Practice & Research Clinical Endocrinology & Metabolism, 2013Co-Authors: Michael N Fahiewilson, Thomas P SmithAbstract:Serum prolactin is frequently measured when investigating patients with reproductive disorders and elevated concentrations are found in up to 17% of such cases. Clinical laboratories rely predominantly on automated analysers to quantify prolactin levels using sandwich immunometric methodologies. Though generally robust and reliable, such immunoassays are susceptible to interference from a high molecular mass prolactin/IgG autoantibody complex termed Macroprolactin. While Macroprolactin remains reactive to varying degrees in all prolactin immunoassays, it exhibits little if any biological activity in vivo and consequently its presence is considered clinically irrelevant. Macroprolactinaemia, defined as hyperprolactinaemia due to excess Macroprolactin with normal concentrations of bioactive monomeric prolactin, may lead to misdiagnosis and mismanagement of hyperprolactinemic patients if not recognised. Current best practice recommends that all sera with elevated total prolactin concentrations are sub-fractionated using polyethylene glycol precipitation to provide a more meaningful clinical measurement of the bioactive monomeric prolactin content. Manufacturers of prolactin assays should strive to minimise interference from Macroprolactin in their assays. Clinical laboratories should introduce screening procedures to exclude Macroprolactinaemia in all patients identified as having hyperprolactinaemia. Clinicians should be aware of this potential diagnostic pit fall and insist on PEG screening of all hyperprolactinaemic sera.
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serum total prolactin and monomeric prolactin reference intervals determined by precipitation with polyethylene glycol evaluation and validation on common immunoassay platforms
Clinical Chemistry, 2008Co-Authors: Luisa Beltran, Michael N Fahiewilson, Joseph T Mckenna, Lucille Kavanagh, Thomas P SmithAbstract:BACKGROUND: Macroprolactin is an important source of immunoassay interference that commonly leads to misdiagnosisandmismanagementofhyperprolactinemic patients. We used the predominant immunoassay platforms for total prolactin and bioactive monomeric prolactin to assay serum samples treated with polyethylene glycol (PEG) and establish and validate reference intervals for Macroprolactin. METHODS: We used the Architect (Abbott), ADVIA Centaur and Immulite (Siemens Diagnostics), Access (Beckman Coulter), Elecsys (Roche Diagnostics), and AIA (Tosoh) analyzers with samples from healthy males (n 53) and females (n 93) to derive parametric reference intervals for total and post-PEG monomericprolactin.Concentrationsofimmunoreactive prolactin isoforms in serum samples from healthy individuals were established by gel filtration chromatography (GFC). We then used samples from 22 individuals whose hyperprolactinemia was entirely
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false positive polyethylene glycol precipitation tests for Macroprolactin due to increased serum globulins
Annals of Clinical Biochemistry, 2008Co-Authors: Sweta Ram, Beverley Harris, Joseph J R Fernando, Rousseau Gama, Michael N FahiewilsonAbstract:AbstractBackgroundThe polyethylene glycol (PEG) precipitation test is widely used to detect hyperprolactinaemia caused by Macroprolactin. We report two cases of hyperprolactinaemia in which a low recovery of serum prolactin (PRL) after PEG precipitation indicated the presence of Macroprolactin, but no Macroprolactin was detected by gel filtration chromatography (GFC). Both cases had elevated concentrations of serum globulin (IgG myeloma and polyclonal hypergammaglobulinaemia due to human immunodeficiency virus [HIV] infection), which prompted us to investigate further the effect of serum globulin on the specificity of the PEG precipitation procedure.MethodsThe effect of increasing concentrations of gamma globulin on the precipitation of PRL by PEG was studied by adding purified human gamma globulin to serum. Ten samples from HIV-infected patients, which showed a low recovery of PRL after PEG precipitation (<60%) were studied with GFC.ResultsAddition of gamma globulin decreased the recovery of PRL followin...
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false positive polyethylene glycol precipitation tests for Macroprolactin due to increased serum globulins
Annals of Clinical Biochemistry, 2008Co-Authors: Sweta Ram, Beverley Harris, Joseph J R Fernando, Rousseau Gama, Michael N FahiewilsonAbstract:AbstractBackgroundThe polyethylene glycol (PEG) precipitation test is widely used to detect hyperprolactinaemia caused by Macroprolactin. We report two cases of hyperprolactinaemia in which a low r...
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roche elecsys prolactin ii assay reactivity with Macroprolactin compared with eight commercial assays for prolactin and determination of monomeric prolactin by precipitation with polyethylene glycol
Clinical Laboratory, 2007Co-Authors: Michael N Fahiewilson, Christian Bieglmayer, Jurgen Kratzsch, Charly Nusbaumer, Heinz Jurgen Roth, Martina Zaninotto, Mario Plebani, Arnulf Hubbuch, Erich SchneiderAbstract:Hyperprolactinaemia due to Macroprolactin (MPRL) can lead to misdiagnosis and inappropriate treatment. We studied the new Roche Elecsys Prolactin assay (PRL II) which has been developed to reduce reactivity with MPRL. We investigated the performance of the PRL II assay at six laboratory sites to determine precision and establish reference intervals for total immunoreactive PRL and for monomeric PRL determined by precipitation with polyethylene glycol (PEG). We compared the reactivities with Macroprolactin of the PRL II, the PRL I and seven other PRL assays. The PRL II assay reacted less strongly than the PRL I assay and similarly to the ADVIA Centaur assay with Macroprolactin. PEG precipitation can be used with the PRL II assay to estimate the concentration of monomeric PRL.
Thomas P Smith - One of the best experts on this subject based on the ideXlab platform.
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TP. Specificity and clinical utility of methods for the detection of Macroprolactin. Clin Chem 2006;52:1366–72
2015Co-Authors: Lucille Kavanagh, James Gibney, Joseph T Mckenna, Michael N. Fahie-wilson, Thomas P SmithAbstract:prolactin are a relatively common cause of misdiagnosis and mismanagement of hyperprolactinemic patients. Methods: We studied sera from a cohort of 42 patients whose biochemical hyperprolactinemia was explained entirely by Macroprolactin. Using 5 pretreatments, poly-ethylene glycol (PEG), protein A (PA), protein G (PG), anti-human IgG (anti-hIgG), and ultrafiltration (UF), to deplete Macroprolactin from sera before immunoassay, we compared residual prolactin concentrations with monomer concentrations obtained by gel-filtration chro-matography (GFC). A monomeric prolactin standard was used to assess recovery and specificity of the pretreatment procedures. Results: Residual prolactin concentrations in all pre-treated sera differed significantly (P <0.001) from mo
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determination of prolactin the Macroprolactin problem
Best Practice & Research Clinical Endocrinology & Metabolism, 2013Co-Authors: Michael N Fahiewilson, Thomas P SmithAbstract:Serum prolactin is frequently measured when investigating patients with reproductive disorders and elevated concentrations are found in up to 17% of such cases. Clinical laboratories rely predominantly on automated analysers to quantify prolactin levels using sandwich immunometric methodologies. Though generally robust and reliable, such immunoassays are susceptible to interference from a high molecular mass prolactin/IgG autoantibody complex termed Macroprolactin. While Macroprolactin remains reactive to varying degrees in all prolactin immunoassays, it exhibits little if any biological activity in vivo and consequently its presence is considered clinically irrelevant. Macroprolactinaemia, defined as hyperprolactinaemia due to excess Macroprolactin with normal concentrations of bioactive monomeric prolactin, may lead to misdiagnosis and mismanagement of hyperprolactinemic patients if not recognised. Current best practice recommends that all sera with elevated total prolactin concentrations are sub-fractionated using polyethylene glycol precipitation to provide a more meaningful clinical measurement of the bioactive monomeric prolactin content. Manufacturers of prolactin assays should strive to minimise interference from Macroprolactin in their assays. Clinical laboratories should introduce screening procedures to exclude Macroprolactinaemia in all patients identified as having hyperprolactinaemia. Clinicians should be aware of this potential diagnostic pit fall and insist on PEG screening of all hyperprolactinaemic sera.
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characterization of Macroprolactin and assessment of markers of autoimmunity in Macroprolactinaemic patients
Clinical Endocrinology, 2009Co-Authors: Lucille Kavanaghwright, Thomas P Smith, James Gibney, Joseph T MckennaAbstract:Summary Objective It has been reported that Macroprolactin is a complex of PRL and an immunoglobulin G (IgG). This study further characterizes Macroprolactin and evaluates for other markers of autoimmunity using a cohort of Macroprolactinaemic sera. Patients and normal subjects Following treatment of hyperprolactinaemic sera (n = 58) with polyethylene glycol (PEG), PRL values fell from 524–13 546 mU/l (Range) to 452–8455 mU/l, while in Macroprolactinaemic sera (n = 41), PRL concentration fell from 525–5747 to 98–378 mU/l (PEG treated normoprolactinaemic reference range, 68–230 mU/l in males, 70–390 mU/l in females). Design PRL was measured in sera prior to and following gel filtration chromatography, ultrafiltration, treatment with protein A-sepharose, protein G-sepharose, antihuman IgG-agarose and sodium thiocyanate (NaSCN). The binding of radio-labelled PRL in Macroprolactinaemic sera was also measured. Sera were assayed for antithyroid and antinuclear antibodies. C-reactive protein (CRP) and CD5 positive B cells were also measured. Comparisons were made between values obtained in normal, hyperprolactinaemic and Macroprolactinaemic sera. Results Macroprolactinaemic sera indicated the presence of an IgG molecule and/or IgG fragments with one or more molecules of PRL. In 97% of the sera Macroprolactin had a molecular weight of 204 kDa. Treatment of Macroprolactinaemic sera with NaSCN caused dissociation of Macroprolactin, releasing monomeric PRL. Macroprolactinaemic sera did not yield evidence of an increase in markers of autoimmunity when compared with hyperprolactinaemic or normal sera. Conclusions Comprehensive analysis of Macroprolactin confirmed its composition as an IgG molecule or fragment with a PRL molecule. The occurrence of Macroprolactin does not appear to be associated with autoimmunity.
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serum total prolactin and monomeric prolactin reference intervals determined by precipitation with polyethylene glycol evaluation and validation on common immunoassay platforms
Clinical Chemistry, 2008Co-Authors: Luisa Beltran, Michael N Fahiewilson, Joseph T Mckenna, Lucille Kavanagh, Thomas P SmithAbstract:BACKGROUND: Macroprolactin is an important source of immunoassay interference that commonly leads to misdiagnosisandmismanagementofhyperprolactinemic patients. We used the predominant immunoassay platforms for total prolactin and bioactive monomeric prolactin to assay serum samples treated with polyethylene glycol (PEG) and establish and validate reference intervals for Macroprolactin. METHODS: We used the Architect (Abbott), ADVIA Centaur and Immulite (Siemens Diagnostics), Access (Beckman Coulter), Elecsys (Roche Diagnostics), and AIA (Tosoh) analyzers with samples from healthy males (n 53) and females (n 93) to derive parametric reference intervals for total and post-PEG monomericprolactin.Concentrationsofimmunoreactive prolactin isoforms in serum samples from healthy individuals were established by gel filtration chromatography (GFC). We then used samples from 22 individuals whose hyperprolactinemia was entirely
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hyperprolactinemia due to Macroprolactin a commonly unrecognized phenomenon causing misdiagnosis and mismanagement
Endocrinologist, 2008Co-Authors: Joseph T Mckenna, Thomas P SmithAbstract:Abstract: Macroprolactin is a frequently unrecognized phenomenon giving rise to inaccurate diagnosis in an estimated 10% of cases of hyperprolactinemia in the United States. This has been associated with unnecessary investigation and inappropriate treatment including pituitary exploration. Simple laboratory procedures can be adapted to routinely screen hyperprolactinemic sera for Macroprolactin. Therefore, it is timely to alert endocrinologists, gynecologists, and all those involved in the management of hyperprolactinemia to Macroprolactin, its frequent occurrence and its ready recognition. Demand by clinicians to establish routine screening of hyperprolactinemic sera for the presence of Macroprolactin will be useful in leading to adoption of routine screening procedures necessary for the appropriate recognition of the phenomenon.
Joseph T Mckenna - One of the best experts on this subject based on the ideXlab platform.
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TP. Specificity and clinical utility of methods for the detection of Macroprolactin. Clin Chem 2006;52:1366–72
2015Co-Authors: Lucille Kavanagh, James Gibney, Joseph T Mckenna, Michael N. Fahie-wilson, Thomas P SmithAbstract:prolactin are a relatively common cause of misdiagnosis and mismanagement of hyperprolactinemic patients. Methods: We studied sera from a cohort of 42 patients whose biochemical hyperprolactinemia was explained entirely by Macroprolactin. Using 5 pretreatments, poly-ethylene glycol (PEG), protein A (PA), protein G (PG), anti-human IgG (anti-hIgG), and ultrafiltration (UF), to deplete Macroprolactin from sera before immunoassay, we compared residual prolactin concentrations with monomer concentrations obtained by gel-filtration chro-matography (GFC). A monomeric prolactin standard was used to assess recovery and specificity of the pretreatment procedures. Results: Residual prolactin concentrations in all pre-treated sera differed significantly (P <0.001) from mo
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should Macroprolactin be measured in all hyperprolactinaemic sera
Clinical Endocrinology, 2009Co-Authors: Joseph T MckennaAbstract:Macroprolactin is a nonbioactive prolactin isoform usually composed of a monomer of prolactin and a IgG molecule which has a prolonged clearance rate similar to that of the immunoglobulins. Macroprolactinaemia, hyperprolactinaemia entirely accounted for by the presence of Macroprolactin, is estimated to account for approximately 10% of all hyperprolactinaemia coming to clinical attention in the United Kingdom and the United States. Failure to recognize that Macroprolactinaemia can explain hyperprolactinaemia, leads to unnecessary investigation, incorrect diagnosis and inappropriate treatment. Screening of hyperprolactinaemic sera for the presence of misleading concentrations of Macroprolactin is readily performed in biochemistry laboratories although the procedures have not been automated. The most widely employed method is to treat the hyperprolactinaemic sera with polyethylene glycol which precipitates out high-molecular weight constituents including immunoglobulins. Re-assay of the sera for prolactin will then identify those sera which yield values within the relevant normal range indicative of Macroprolactinaemia and not true hyperprolactinaemia. The case for the routine screening of all hyperprolactinaemic sera for Macroprolactin is compelling. The consequences of failure to recognize Macroprolactinaemia are significant, the problem is frequently encountered, the means of addressing it are immediately available and it is cost effective.
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characterization of Macroprolactin and assessment of markers of autoimmunity in Macroprolactinaemic patients
Clinical Endocrinology, 2009Co-Authors: Lucille Kavanaghwright, Thomas P Smith, James Gibney, Joseph T MckennaAbstract:Summary Objective It has been reported that Macroprolactin is a complex of PRL and an immunoglobulin G (IgG). This study further characterizes Macroprolactin and evaluates for other markers of autoimmunity using a cohort of Macroprolactinaemic sera. Patients and normal subjects Following treatment of hyperprolactinaemic sera (n = 58) with polyethylene glycol (PEG), PRL values fell from 524–13 546 mU/l (Range) to 452–8455 mU/l, while in Macroprolactinaemic sera (n = 41), PRL concentration fell from 525–5747 to 98–378 mU/l (PEG treated normoprolactinaemic reference range, 68–230 mU/l in males, 70–390 mU/l in females). Design PRL was measured in sera prior to and following gel filtration chromatography, ultrafiltration, treatment with protein A-sepharose, protein G-sepharose, antihuman IgG-agarose and sodium thiocyanate (NaSCN). The binding of radio-labelled PRL in Macroprolactinaemic sera was also measured. Sera were assayed for antithyroid and antinuclear antibodies. C-reactive protein (CRP) and CD5 positive B cells were also measured. Comparisons were made between values obtained in normal, hyperprolactinaemic and Macroprolactinaemic sera. Results Macroprolactinaemic sera indicated the presence of an IgG molecule and/or IgG fragments with one or more molecules of PRL. In 97% of the sera Macroprolactin had a molecular weight of 204 kDa. Treatment of Macroprolactinaemic sera with NaSCN caused dissociation of Macroprolactin, releasing monomeric PRL. Macroprolactinaemic sera did not yield evidence of an increase in markers of autoimmunity when compared with hyperprolactinaemic or normal sera. Conclusions Comprehensive analysis of Macroprolactin confirmed its composition as an IgG molecule or fragment with a PRL molecule. The occurrence of Macroprolactin does not appear to be associated with autoimmunity.
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serum total prolactin and monomeric prolactin reference intervals determined by precipitation with polyethylene glycol evaluation and validation on common immunoassay platforms
Clinical Chemistry, 2008Co-Authors: Luisa Beltran, Michael N Fahiewilson, Joseph T Mckenna, Lucille Kavanagh, Thomas P SmithAbstract:BACKGROUND: Macroprolactin is an important source of immunoassay interference that commonly leads to misdiagnosisandmismanagementofhyperprolactinemic patients. We used the predominant immunoassay platforms for total prolactin and bioactive monomeric prolactin to assay serum samples treated with polyethylene glycol (PEG) and establish and validate reference intervals for Macroprolactin. METHODS: We used the Architect (Abbott), ADVIA Centaur and Immulite (Siemens Diagnostics), Access (Beckman Coulter), Elecsys (Roche Diagnostics), and AIA (Tosoh) analyzers with samples from healthy males (n 53) and females (n 93) to derive parametric reference intervals for total and post-PEG monomericprolactin.Concentrationsofimmunoreactive prolactin isoforms in serum samples from healthy individuals were established by gel filtration chromatography (GFC). We then used samples from 22 individuals whose hyperprolactinemia was entirely
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hyperprolactinemia due to Macroprolactin a commonly unrecognized phenomenon causing misdiagnosis and mismanagement
Endocrinologist, 2008Co-Authors: Joseph T Mckenna, Thomas P SmithAbstract:Abstract: Macroprolactin is a frequently unrecognized phenomenon giving rise to inaccurate diagnosis in an estimated 10% of cases of hyperprolactinemia in the United States. This has been associated with unnecessary investigation and inappropriate treatment including pituitary exploration. Simple laboratory procedures can be adapted to routinely screen hyperprolactinemic sera for Macroprolactin. Therefore, it is timely to alert endocrinologists, gynecologists, and all those involved in the management of hyperprolactinemia to Macroprolactin, its frequent occurrence and its ready recognition. Demand by clinicians to establish routine screening of hyperprolactinemic sera for the presence of Macroprolactin will be useful in leading to adoption of routine screening procedures necessary for the appropriate recognition of the phenomenon.
A.r. Ellis - One of the best experts on this subject based on the ideXlab platform.
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Macroprolactin s composition and reactivity in immunoassays and laboratory interpretation of results of an unusual patient serum
Annals of Clinical Biochemistry, 2006Co-Authors: A.r. Ellis, M Fahiewilson, M Axcell, K Sands, R P HillAbstract:Background Macroprolactin is a high molecular mass complex of prolactin that may be the cause of elevated serum prolactin as determined by immunoassay. The composition of Macroprolactin and its reactivity in immunoassays are variable but the complex has minimal bioactivity in vivo. Hyperprolactinaemia due to unrecognized Macroprolactinaemia can lead to misdiagnosis and mistreatment. Methods Serum from a patient with an unusual pattern of immunoreactivity was distributed to three users of each of the most popular immunoassays represented in the UK National External Quality Assessment Scheme (NEQAS) for prolactin. Clinical details were provided and participating centres were invited to investigate the prolactin content of the specimen according to their local protocol, and to comment on their results. The nature of the Macroprolactin in the specimen was investigated in detail by gel filtration chromatography of the native serum and of the serum after adsorption of IgG with protein A, and by affinity chromatography with concanavalin A. Results Gel filtration studies revealed two peaks of Macroprolactin in this serum. These Macroprolactins were shown to be different in their IgG content and degree of glycosylation. All eight immunoassays reacted strongly with the Macroprolactin present. The majority (78%) of centres that interpreted their results either demonstrated the presence of Macroprolactin in the specimen, or suggested it as a likely cause of the hyperprolactinaemia. However, two centres inappropriately excluded Macroprolactinaemia as the cause of the elevated prolactin, and a further two did not consider it at all. Data from previous UK NEQAS distributions (between 1996 and 2003) of Macroprolactin containing sera are presented which suggest that the frequency of recognition of Macroprolactin as a possible cause of hyperprolactinaemia has increased over time. Conclusions Very high molecular mass forms of prolactin and the presence of multiple molecular mass forms, as detected in the case presented here, are uncommon. Also, the pattern of immunoreactivity reported in this specimen was unusual as most Macroprolactins studied previously react less strongly in, for example, the Bayer ADVIA Centaur assay compared to the Roche E170 assay. Both peaks of Macroprolactin in this serum reacted in all assays tested. This case highlights the variable nature and immunoreactive behaviour of Macroprolactin species.
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Macroprolactin high molecular mass forms of circulating prolactin
Annals of Clinical Biochemistry, 2005Co-Authors: M N Fahiewilson, R. John, A.r. EllisAbstract:Two high molecular mass forms of prolactin (PRL) in serum have been identified by gel filtration chromatography (GFC): Macroprolactin (big-big PRL, > 100 kDa) and big PRL (40-60 kDa). Macroprolacti...
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Macroprolactin high molecular mass forms of circulating prolactin
Annals of Clinical Biochemistry, 2005Co-Authors: M N Fahiewilson, R. John, A.r. EllisAbstract:Two high molecular mass forms of prolactin (PRL) in serum have been identified by gel filtration chromatography (GFC): Macroprolactin (big-big PRL, > 100 kDa) and big PRL (40-60 kDa). Macroprolactin has a variable composition and structure, but is most frequently a complex of PRL and IgG, with a molecular mass of 150-170 kDa. It is formed in the circulation following pituitary secretion of monomeric PRL but has a longer half-life, and the PRL in the complex remains reactive to a variable extent in immunoassays. In the majority of subjects little or no Macroprolactin can be detected in serum, but in some individuals it may be the predominant immunoreactive component of circulating PRL and the cause of apparent hyperprolactinaemia. Owing to its high molecular mass, Macroprolactin appears to be confined to the intravascular compartment and much evidence indicates that it has minimal bioactivity in vivo and is not of pathological significance. Nevertheless, hyperprolactinaemia due to Macroprolactin can lead to diagnostic confusion and unnecessary further investigation and treatment if it is not recognized as such. Macroprolactin is a common cause of apparent hyperprolactinaemia with some assays and it is essential that laboratories introduce screening programmes to examine samples with elevated total immunoreactive PRL for the presence of Macroprolactin and determine the monomeric PRL component which is known to be bioactive in vivo. A number of screening tests have been described; that based on the precipitation of Macroprolactin with polyethylene glycol has been the most widely validated and applied. The reference technique of GFC should be available for confirmation and further investigation of samples, giving equivocal results in screening tests. In comparison with Macroprolactin, little is known about big PRL. It is a more consistent component of total serum PRL but rarely, if ever, the cause of hyperprolactinaemia. Further research is required into the nature of Macroprolactin and big PRL, the relationships between high molecular mass forms of PRL, and their clinical significance.
Rousseau Gama - One of the best experts on this subject based on the ideXlab platform.
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false positive polyethylene glycol precipitation tests for Macroprolactin due to increased serum globulins
Annals of Clinical Biochemistry, 2008Co-Authors: Sweta Ram, Beverley Harris, Joseph J R Fernando, Rousseau Gama, Michael N FahiewilsonAbstract:AbstractBackgroundThe polyethylene glycol (PEG) precipitation test is widely used to detect hyperprolactinaemia caused by Macroprolactin. We report two cases of hyperprolactinaemia in which a low recovery of serum prolactin (PRL) after PEG precipitation indicated the presence of Macroprolactin, but no Macroprolactin was detected by gel filtration chromatography (GFC). Both cases had elevated concentrations of serum globulin (IgG myeloma and polyclonal hypergammaglobulinaemia due to human immunodeficiency virus [HIV] infection), which prompted us to investigate further the effect of serum globulin on the specificity of the PEG precipitation procedure.MethodsThe effect of increasing concentrations of gamma globulin on the precipitation of PRL by PEG was studied by adding purified human gamma globulin to serum. Ten samples from HIV-infected patients, which showed a low recovery of PRL after PEG precipitation (<60%) were studied with GFC.ResultsAddition of gamma globulin decreased the recovery of PRL followin...
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false positive polyethylene glycol precipitation tests for Macroprolactin due to increased serum globulins
Annals of Clinical Biochemistry, 2008Co-Authors: Sweta Ram, Beverley Harris, Joseph J R Fernando, Rousseau Gama, Michael N FahiewilsonAbstract:AbstractBackgroundThe polyethylene glycol (PEG) precipitation test is widely used to detect hyperprolactinaemia caused by Macroprolactin. We report two cases of hyperprolactinaemia in which a low r...
