Peter George
University of Otago, Pathology, Faculty Member
Familial dysalbuminaemic hyperthyroxinaemia (FDH) is an important cause of discordant thyroid function test (TFT) results (due to an inherited albumin variant) however, the diagnosis can be challenging. A 51 year-old man had persistently... more
Familial dysalbuminaemic hyperthyroxinaemia (FDH) is an important cause of discordant thyroid function test (TFT) results (due to an inherited albumin variant) however, the diagnosis can be challenging. A 51 year-old man had persistently elevated free thyroxine (T4), with discordant normal TSH and normal free triiodothyronine. He was clinically euthyroid and had a daughter with similar TFTs. We aimed to apply a whole protein mass spectrometry (MS) method to investigate this case of suspected FDH. Intact serum albumin was assessed directly using electrospray time-of-flight (TOF) MS. Results were confirmed using tryptic peptide m/z mapping and targeted DNA sequencing (exons 3 and 7 of the albumin gene). We also used this sequencing to screen 14 archived DNA samples that were negative for thyroid hormone receptor mutations (in suspected thyroid hormone resistance). MS analysis demonstrated heterozygosity for an albumin variant with a 19 Da decrease in mass, indicative of an Arg→His substitution. The FDH variant was confirmed with peptide mapping (showing the precise location of the substitution, 218Arg→His) and DNA sequencing (showing guanine to adenine transition at codon 218 of exon 7). The same FDH variant was identified in one additional screened sample. TOF MS is a novel procedure for diagnosing FDH. The test is rapid (<10 min), can be performed on <2 µL of serum and requires minimal sample preparation. KEY: TERMS: : familial dysalbuminaemic hyperthyroxaemia, mass spectrometry, albumin variant, discordant thyroid function tests.
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Objectives The aim of this study is to compare a new improved point of care cardiac troponin assay (new POC-cTnI) with 1. its predecessor (old POC-cTnI) and 2. a high sensitivity assay (hs-cTnI) for the diagnosis of acute myocardial... more
Objectives The aim of this study is to compare a new improved point of care cardiac troponin assay (new POC-cTnI) with 1. its predecessor (old POC-cTnI) and 2. a high sensitivity assay (hs-cTnI) for the diagnosis of acute myocardial infarction (AMI) and for major adverse cardiac events (MACE) by 30 days. Methods This is a single centre observational study, set in Christchurch Hospital, New Zealand. Patients presenting to the emergency department with non-traumatic chest pain underwent blood sampling at 0 h and 2 h post presentation for analysis with the 3 cTnI assays for the outcome of AMI and for analysis using an accelerated diagnostic protocol (ADP-normal 2 h troponins, normal electrocardiograms and Thrombolysis In Myocardial Infarction (TIMI) score of 0 or ≤ 1) for 30 day MACE. Results Of 962 patients, 220 (22.9%) had AMI. Old POC-cTnI was least sensitive at 70.0% (65.4–73.9%) by 2 h (p < 0.001). New POC-cTnI, sensitivity 93.6% (89.9–96.2%) had similar sensitivity to hs-cTnI,...
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Both congenital and acquired antithrombin-III (AT-III) deficiencies are amenable to replacement therapy. We describe two antithrombins produced by recombinant DNA techniques from human alpha 1-antitrypsin (alpha 1AT) cDNA in yeast.... more
Both congenital and acquired antithrombin-III (AT-III) deficiencies are amenable to replacement therapy. We describe two antithrombins produced by recombinant DNA techniques from human alpha 1-antitrypsin (alpha 1AT) cDNA in yeast. Alteration of the alpha 1AT active site, replacing methionine 358 with arginine, results in a thrombin inhibition rate similar to that of heparin-activated AT-III. Alteration of two further residues, to give a five-residue sequence identical to AT-III, does not increase this rate further. Neither antithrombin is activated by heparin; both are unglycosylated and have shorter in vivo half-lives (t1/2) than human alpha 1AT. These antithrombins should be suitable for therapeutic replacement of AT-III in cases of congenital deficiency and in conditions associated with acquired AT-III deficiency, such as disseminated intravascular coagulation.
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Research Interests: Folic acid, Lipids, Humans, Kidney, Fasting, and 23 moreEnd Stage Renal Disease, Female, Male, Risk factors, Randomised Controlled Trial, Homocysteine, Clinical Sciences, Aged, Chronic Renal Failure, Middle Aged, Peripheral Vascular Disease, Pyridoxine, Randomized Controlled Trial, Methionine, Combination drug therapy, Risk Factors, Sarcosine, Glycine Betaine, Chronic Kidney Failure, Cross-Over Studies, Renal disease, Serum lipids, and Betaine
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The performance of fructosamine assays in 35 laboratories was assessed over a six month period in 1987. While agreement between laboratories was poor in the range expected in diabetic patients, most laboratories were internally... more
The performance of fructosamine assays in 35 laboratories was assessed over a six month period in 1987. While agreement between laboratories was poor in the range expected in diabetic patients, most laboratories were internally consistent. The interlaboratory differences are largely attributed to the calibration methods used for this test. Fructosamine results from any one laboratory must not be interpreted by comparison with data from other laboratories or the literature. Other common biochemical tests were found to suffer from similar problems, but to a less serious extent.
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Classical Rett syndrome is a severe neurodevelopmental X-linked dominant disorder affecting 1/15,000 girls worldwide. MECP2 has been identified as the predominant gene associated with Rett syndrome. Approximately 65-85% of patients with... more
Classical Rett syndrome is a severe neurodevelopmental X-linked dominant disorder affecting 1/15,000 girls worldwide. MECP2 has been identified as the predominant gene associated with Rett syndrome. Approximately 65-85% of patients with classical Rett syndrome have identifiable MECP2 mutations. In comparison, up to 57% of patients with atypical Rett have mutations in the MECP2 gene. To investigate the spectrum and frequency of MECP2 mutations in New Zealand Rett syndrome patients and evaluate whether available clinical criteria were sufficient to direct molecular testing for Rett syndrome. and Methods MECP2 coding regions were analysed by direct automated DNA sequencing and multiplex ligation dependent probe assay (MLPA) in samples from 74 patients referred for investigation of possible Rett syndrome. Necessary clinical criteria were examined in detail in 18 patients, with 7/18 having identifiable MECP2 mutations. Fifteen patients (20%) carried MECP2 mutations, four of which were no...
Research Interests: Genetics, Polymorphism, Adolescent, Mental Retardation, Humans, and 18 moreChild, Mutation, Female, Male, New Zealand, DNA sequence design, Young Adult, Infant, Phenotype, Rett syndrome, Spectrum, Genotype, Adult, Neurodevelopmental Disorder Autism, Learning Disabled, Protein Binding, Cohort Studies, and DNA sequence
Patients with porphyria present in a diverse and unusual variety of ways and most clinicians will see only a few cases, if any, during their professional lives. Porphyria may present (1) with acute symptoms, which may be abdominal pain,... more
Patients with porphyria present in a diverse and unusual variety of ways and most clinicians will see only a few cases, if any, during their professional lives. Porphyria may present (1) with acute symptoms, which may be abdominal pain, neurological or psychiatric; (2) with skin rash or photosensitivity; or (3) with a putative family history. Screening for latent porphyria has been greatly facilitated by fluorescence emission scanning of plasma and by mutational analysis. Our reference laboratory has recently diagnosed several cases of the less common types of porphyria, which we postulate is due to the availability of these methods and to the changing population of New Zealand. Accurate screening and diagnosis of porphyria is important, as an acute porphyric attack is life-threatening and preventable. Retrospective diagnosis may be difficult.
Research Interests: Porphyrins, Humans, Female, Male, Heme, and 4 moreMiddle Aged, Adult, Biological markers, and Porphyrias
To determine the frequency of HLA-H gene mutations in New Zealand patients with haemochromatosis. The Cys282Tyr and His63Asp mutations in the HLA-H gene were analyzed by polymerase chain reaction, restriction enzyme digestion and... more
To determine the frequency of HLA-H gene mutations in New Zealand patients with haemochromatosis. The Cys282Tyr and His63Asp mutations in the HLA-H gene were analyzed by polymerase chain reaction, restriction enzyme digestion and electrophoresis in two separate patient groups. The first was a group of 20 Christchurch patients with a definite clinical diagnosis of haemochromatosis. The second group consisted of 33 patients, with a provisional diagnosis of haemochromatosis, attending Dunedin Hospital for therapeutic venesection. All 20 Christchurch patients and 25 of the 33 (76%) Dunedin patients were homozygous for the Cys282Tyr mutation. After review of the clinical data, histology and response to venesection a diagnosis of haemochromatosis could be confidently excluded in six of the remaining eight patients. Despite atypical features, a diagnosis of haemochromatosis could not be excluded in the final two patients, one of whom was a compound heterozygote for the two mutations. Homoz...
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Trace elements are commonly measured by inductively coupled mass spectrometry (ICP-MS). A 30-year-old man had a plasma selenium (Se) concentration on ICP-MS of 66 µmol/L (reference interval 0.45-1.40), a potentially lethal level, despite... more
Trace elements are commonly measured by inductively coupled mass spectrometry (ICP-MS). A 30-year-old man had a plasma selenium (Se) concentration on ICP-MS of 66 µmol/L (reference interval 0.45-1.40), a potentially lethal level, despite no history of Se exposure or toxicity symptoms. He had earlier undergone magnetic resonance imaging with a gadolinium (Gd) contrast agent, which is known to interfere with Se on ICP-MS. We aimed to adjust our method by monitoring a second Se isotope that is unaffected by Gd to detect this preanalytical interference. Plasma samples referred for trace metal testing had Se measured on ICP-MS (monitoring (78)Se), which we modified to also monitor a second isotope ((82)Se). The modified method was then applied to a specimen with known Gd contamination. Plasma Se results (n = 41) derived from monitoring the two different Se isotopes were similar with a good correlation (R (2 )= 0.991) over a range of 0.23-2.21 µmol/L. On repeat analysis, our patient had a...
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Extraction followed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis is the method of choice when it comes to the accurate quantification of 25-OH-vitamin D in blood samples. It is generally assumed that the addition... more
Extraction followed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis is the method of choice when it comes to the accurate quantification of 25-OH-vitamin D in blood samples. It is generally assumed that the addition of exogenous internal standard allows for the determination of the endogenous analyte concentration. In this study we investigated the extraction properties of endogenous and exogenous 25-OH-vitamin D. Eight samples were used for the evaluation of the extraction procedure and 59 patients' samples for a method comparison. The methanol-to-sample ratio (v/v) and the sample-to-hexane ratio (v/v) were varied and the LC-MS/MS signals of endogenous 25-OH-vitamin D3, spiked 25-OH-vitamin D2 and internal standard of the extracts recorded. The optimized 'in-house' LC-MS/MS assay was compared to two automated chemiluminescence immunoassays from DiaSorin and Abbott. Mathematical analysis of the data revealed a differential extraction of endogenous 2...
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We recruited nondiabetic subjects (n = 158) attending a lipid disorders clinic, a subset of whom (n = 46) had established cardiovascular disease. Glycine betaine, N,N-dimethylglycine, and carnitine were measured in fasting plasma and... more
We recruited nondiabetic subjects (n = 158) attending a lipid disorders clinic, a subset of whom (n = 46) had established cardiovascular disease. Glycine betaine, N,N-dimethylglycine, and carnitine were measured in fasting plasma and urine samples. The concentrations and excretions were related to known cardiovascular risk factors in multivariate regression models. The relationships between homocysteine and plasma and urinary glycine betaine were highly significant (P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; .002), comparable with the known relationships with folate and plasma creatinine. The regression coefficient for plasma glycine betaine was consistently approximately -0.1 in 5 different regression models (3 best-subsets and forward and backward stepwise regression models) for predicting homocysteine using 23 variables. Plasma glycine betaine was higher in males than in females, and the difference was associated with a difference in percentage of body fat. Its concentration included a constant factor of approximately 20 micromol/L that was independent of any of the variables investigated here. In the total group, body fat, homocysteine, and carnitine were significant predictors of plasma glycine betaine. Carnitine, an important betaine that is involved in lipid metabolism positively correlated with both homocysteine and glycine betaine. In our sample, the urinary excretion of glycine betaine was outside the reference range in 14 of the 158 subjects and the betaine fractional clearances were above the reference range in 23 subjects. Fractional clearance correlated strongly with plasma homocysteine (r = 0.50), and this relationship may be stronger in patients with known vascular disease. Urinary loss of glycine betaine may contribute to hyperhomocysteinemia and the development of cardiovascular disease.
Research Interests: Metabolism, Adolescent, Cardiovascular disease, Humans, Female, and 21 moreMale, Regression Analysis, Decode-And-Forward, Decode and Forward, Lipid metabolism, Homocysteine, Clinical Sciences, Aged, Middle Aged, L-carnitine, Peripheral Vascular Disease, Adult, Regression Model, Cardiovascular Risk Factor, Multivariate Regression, Body Fat, Sarcosine, Glycine Betaine, Stepwise Regression, Creatinine, and Betaine
Aim To establish an assay service for thiopurine methyl transferase (TPMT) activity in order to facilitate dose initiation of thiopurine drug therapy and to define appropriate reference intervals and optimal cut-offs for the New Zealand... more
Aim To establish an assay service for thiopurine methyl transferase (TPMT) activity in order to facilitate dose initiation of thiopurine drug therapy and to define appropriate reference intervals and optimal cut-offs for the New Zealand population. Methods 407 patients underwent radio-enzymatic assay testing of TPMT activity prior to initiation of thiopurine drug therapy. Those with low activity also underwent genotyping
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Research Interests: Vitamins, Humans, Female, Male, Middle Aged, and 5 morePilot Projects, Simvastatin, Coenzyme Q, Drug Tolerance, and The American
Research Interests: Overweight, Humans, Female, Male, Aged, and 7 moreMiddle Aged, Time Factors, Taurine, Sarcosine, Type 2 Diabetes Mellitus, Choline, and Betaine
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A man presented with elevated plasma triglycerides and was commenced on fibrate treatment. The triglycerides did not fall and compliance was questioned. The triglyceride elevation was inconsistent with the observed lack of turbidity in... more
A man presented with elevated plasma triglycerides and was commenced on fibrate treatment. The triglycerides did not fall and compliance was questioned. The triglyceride elevation was inconsistent with the observed lack of turbidity in the plasma sample. Triglyceride elevation was not confirmed by a different analytical method and lipoprotein electrophoresis showed a normal very low density lipoprotein (VLDL) band pattern. Glycerol kinase deficiency was suspected and was supported by elevated urine glycerol, and confirmed by reduced leucocyte enzyme activity and mutational analysis of the GK gene which showed a novel three base pair deletion. Demonstration of a point mutation also excludes a contiguous gene deletion syndrome.
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Thiopurine methyltransferase genotyping and thiopurine metabolite testing has been established as an adjunct to monitoring patients taking thiopurine drugs. This special report describes the clinical implications for this type of testing... more
Thiopurine methyltransferase genotyping and thiopurine metabolite testing has been established as an adjunct to monitoring patients taking thiopurine drugs. This special report describes the clinical implications for this type of testing for patients with inflammatory bowel disease who are taking thiopurine drugs. A total of 10% of patients were found to be intermediate metabolizers and the mean dosage (in mg/kg equivalent) was lower in intermediate metabolizers than extensive metabolizers. The metabolite levels did not correlate with scores measuring clinical severity but levels of 6-methylmercaptopurine were related to the dosage of the drugs. Despite considerable study of thiopurine methyltransferase testing in the literature, it is still not widely used in many geographical areas. This study adds to the evidence about using such testing as well as expanding the role of simultaneously measuring thiopurine metabolites. Further work is planned to evaluate the uptake when such testing becomes available locally as a clinical service.
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Research Interests: Folic acid, Lipids, Humans, Kidney, Fasting, and 23 moreEnd Stage Renal Disease, Female, Male, Risk factors, Randomised Controlled Trial, Homocysteine, Clinical Sciences, Aged, Chronic Renal Failure, Middle Aged, Peripheral Vascular Disease, Pyridoxine, Randomized Controlled Trial, Methionine, Combination drug therapy, Risk Factors, Sarcosine, Glycine Betaine, Chronic Kidney Failure, Cross-Over Studies, Renal disease, Serum lipids, and Betaine
... Despite a lack of evidence from past research on volcanoes, it is likely that exposure routes exist for trace elements in volcanic ... was, however, a pilot study which was necessarily constrained by what is possible and practical... more
... Despite a lack of evidence from past research on volcanoes, it is likely that exposure routes exist for trace elements in volcanic ... was, however, a pilot study which was necessarily constrained by what is possible and practical when using human subjects on an active volcano. ...
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Research Interests: Twins, Pregnancy, Humans, Genetic Testing, Female, and 20 moreMale, Polymerase Chain Reaction, Haemostasis and Thrombosis, Pedigree, Embryo Transfer, Phenotype, Clinical Sciences, Preimplantation genetic diagnosis, Introns, Genotype, Hemophilia A, Linkage Disequilibrium, Thrombosis, Reproducibility of Results, Fertilization in Vitro, factor VIII, Mosaicism, Predictive value of tests, Linkage Analysis, and Live birth
Research Interests: Risk assessment, Electrocardiography, Prospective studies, Humans, Female, and 13 moreMale, New Zealand, Differential Diagnosis, Middle Aged, Acute Coronary Syndrome, Public health systems and services research, Time Factors, Biological markers, Risk Assessment, Sensitivity and Specificity, Chest Pain, Troponin T, and The American
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Research Interests: Risk assessment, Electrocardiography, Prospective studies, Humans, Triage, and 19 moreFemale, Asia, Male, Myocardial Revascularization, Lancet, Clinical Sciences, Myoglobin, Middle Aged, Acute Coronary Syndrome, Cardiac Arrhythmias, Validation Studies, Myocardial Infarction, Biological markers, Risk Assessment, Troponin, Sensitivity and Specificity, Clinical Protocols, Chest Pain, and Predictive value of tests
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We performed a double-blind placebo-controlled trial to study whether early treatment with erythropoietin could prevent the development of acute kidney injury in patients in two general intensive care units. As a guide for choosing the... more
We performed a double-blind placebo-controlled trial to study whether early treatment with erythropoietin could prevent the development of acute kidney injury in patients in two general intensive care units. As a guide for choosing the patients for treatment we measured urinary levels of two biomarkers, the proximal tubular brush border enzymes gamma-glutamyl transpeptidase and alkaline phosphatase. Randomization to either placebo or two doses of erythropoietin was triggered by an increase in the biomarker concentration product to levels above 46.3, with a primary outcome of relative average plasma creatinine increase from baseline over 4 to 7 days. Of 529 patients, 162 were randomized within an average of 3.5 h of a positive sample. There was no difference in the incidence of erythropoietin-specific adverse events or in the primary outcome between the placebo and treatment groups. The triggering biomarker concentration product selected patients with more severe illness and at great...