Biomedical subjects
J T Hindmarsh
Publications and source records attributed to J T Hindmarsh.
Biochemical differentiation of the porphyrias.
OBJECTIVES: To differentiate the porphyrias by clinical and biochemical methods. DESIGN AND METHODS: We describe levels of blood, urine, and fecal porphyrins and their precursors in the porphyrias and present an algorithm for their biochemical differentiation. Diagnoses were established using clinical and biochemical data. Porphyrin analyses were performed by high performance liquid chromatography. RESULTS AND CONCLUSIONS: Plasma and urine porphyrin patterns were useful for diagnosis of porphyria cutanea tarda, but not the acute porphyrias. Erythropoietic protoporphyria was confirmed by erythrocyte protoporphyrin assay and erythrocyte fluorescence. Acute intermittent porphyria was diagnosed by increases in urine delta-aminolevulinic acid and porphobilinogen and confirmed by reduced erythrocyte porphobilinogen deaminase activity and normal or near-normal stool porphyrins. Variegate porphyria and hereditary coproporphyria were diagnosed by their characteristic stool porphyrin patterns. This appears to be the most convenient diagnostic approach until molecular abnormalities become more extensively defined and more widely available.
Plasma porphyrins in the porphyrias.
BACKGROUND: As an aid in the diagnosis and management of porphyria we have developed a method to fractionate and quantify plasma porphyrins and have evaluated its use in various porphyrias. METHODS: We used HPLC with fluorometric detection to measure plasma concentrations of uroporphyrin I and III, heptacarboxyl III, hexacarboxyl III, pentacarboxyl III, and coproporphyrin I and III. We studied 245 healthy subjects, 32 patients with classical porphyria cutanea tarda (PCT), 12 patients with PCT of renal failure, 13 patients with renal failure, 8 patients with pseudoporphyria of renal failure, 3 patients with acute intermittent porphyria, 5 patients with variegate porphyria, 5 patients with hereditary coproporphyria, and 4 patients with erythropoietic protoporphyria. RESULTS: Between-run CVs were 5.4-13%. The recoveries of porphyrins added to plasma were 71-114% except for protoporphyrin, which could not be reliably measured with this technique. Plasma porphyrin patterns clearly identified PCT, and its clinical sensitivity equaled that of urine porphyrin fractionation. The patterns also allowed differentiation of PCT of renal failure from pseudoporphyria of renal failure. CONCLUSIONS: The assay of plasma porphyrins identifies patients with PCT and appears particularly useful for differentiating PCT of renal failure from pseudoporphyria of renal failure.
The death of Napoleon Bonaparte: a critical review of the cause.
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King George III and acute porphyria.
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Strategies to promote rational clinical chemistry test utilization.
OBJECTIVE: To critically review the elements of laboratory services that result in inappropriate ordering of clinical chemistry tests and the efficacy of corrective interventions. METHODS AND RESULTS: In our experience, inappropriate use of laboratory services derives from multiple factors, including the use of multitest profiles, organ- or disease-specific test panels, indiscriminate ordering, standing orders, excessive reporting delays, poor audit trails of test requests, rigid group test ordering, failure to eliminate obsolete tests, and some features of computer software design. Educational strategies can be effective in modifying test-ordering patterns, provided there is sustained feedback to physicians. Careful design of requisitions and the use of disease-specific algorithms have also proven effective. CONCLUSION: Limited resources must be directed to where they are most effective by optimizing laboratory work-flow from test ordering to reporting, to avoid practices that promote inappropriate laboratory use.
Reference interval for whole blood ionized magnesium in a healthy population and the stability of ionized magnesium under varied laboratory conditions.
OBJECTIVE: To establish a reference interval for ionized magnesium (iMg), to evaluate the stability of whole blood iMg under varied laboratory storage conditions, and to study the correlation between total and iMg in healthy volunteers and in an intensive care unit (ICU) population. METHODS: Blood specimens were collected anaerobically from 125 healthy volunteers and 200 ICU patients into tubes containing lithium heparin, transported to the laboratory on ice, stored at 4 degrees C and analyzed within 2 h on a NOVA 8 Electrolyte Analyzer. Additional specimens were stored under different conditions before analysis to assess the stability of iMg. RESULTS: In healthy volunteers, the mean whole blood iMg level was 0.52 mmol/L with a range of 0.44 to 0.59 mmol/L. The iMg/total serum Mg ratio was at 0.60 (0.50-0.69). Regression analysis of iMg vs total Mg produced a correlation coefficient (r) of 0.48 (p < 0.0001). Ionized Mg levels were comparable between males and females (0.52 +/- 0.04 vs 0.51 +/- 0.03, p = 0.38). In the ICU group, a wider range of iMg results was observed (0.35-0.78 mmol/L) and the correlation between iMg and total Mg was r = 0.71 (p < 0.0001). Storage of whole blood specimens in uncapped tubes at room temperature resulted in a small, but significant, decrease in iMg over a 6-h period. Little change was seen in capped tubes stored either at room temperature or at 4 degrees C. over 6 h, or at 4 degrees C. over 5 days. CONCLUSIONS: Using the NOVA 8 Electrolyte Analyzer, we established a reference interval for whole blood iMg in a healthy Canadian population. The correlation between ionized Mg and total Mg was weak, but statistically significant. Ionized Mg levels in lithium heparin tubes were stable over 5 days when specimens were stored at 4 degrees C, suggesting that specimens may be stored at least overnight prior to processing.
Environmental aspects of arsenic toxicity.
The toxicity of arsenic and its long history of use in human culture has resulted in widespread concern about the natural and anthropogenic levels of arsenic in our environment. In this article, an overview of the current environmental status of arsenic is presented. A brief history of the usage of this element is followed by a discussion of the current applications. Both natural as well as anthropogenic sources of input are described and discussed in terms of their relative impact on the Earth's environment. Numerous control mechanisms for arsenic exist in the environment, and the major processes involved (physical, chemical, and biological) are highlighted. Natural cycling of this element through the various environmental compartments (air, water, soil, and biota) are described as well as some current methods for the removal of arsenic from natural and industrial waters. Finally, a brief overview of the most common methods for the analysis of arsenic in environmental samples is presented.
A strategy to promote rational clinical chemistry test utilization.
There is abundant evidence that clinical chemistry laboratory tests are over-ordered in North America, but there does not seem to be an effective corrective strategy that has a prolonged effect. The goal of this study was to design one that had a prolonged effect. Using a pre- and post-intervention survey study design, the authors observed the effect of physician education followed by a ban on test-panel ordering of common clinical chemistry tests, reinforced by written reminders to physicians not heeding the ban, on ordering patterns (tests per specimen), and total numbers of these tests ordered. Panels of > 16 common biochemistry tests per specimen were reduced from 15% to 6% of orders for inpatients and from 44% to 11% for outpatients 1 year after the implementation of the ban on test-panel ordering. However, the ban had little effect on the ordering rates for panels of 7 common tests. Educational exercises (newsletters and lectures) had no effect. The authors conclude that a ban on test-panel (profile) ordering reinforced by continuing reminders to nonconforming physicians is an effective means of reducing clinical chemistry test usage over the long term. A 38% reduction of common biochemistry tests ordered was achieved. However, overall costs savings were modest. Nevertheless, the authors conclude that the cost-effective use of the clinical pathology laboratory by careful selection of tests in an essential part of a medical trainee's education.
Variable phenotypic expression of genotypic abnormalities in the porphyrias.
The inherited porphyrias are the consequence of inherited deficiencies of enzymes in the heme synthesis pathway; they exhibit classical Mendelian inheritance patterns. The acute porphyrias (acute intermittent, porphyria variegata, hereditary coproporphyria) result from 50% (approx.) deficiencies of specific enzymes, which demonstrate autosomal dominant inheritance. However, only approx. 10% of subjects who inherit a porphyrin enzyme deficiency develop the corresponding acute porphyria and in most instances there is no obvious reason why one patient with an enzyme deficiency is symptomatic whereas another is not. Control of heme synthesis is achieved by the repressor effect of heme on the enzyme ALA synthase. Acute attacks of porphyria can be precipitated in susceptible persons by drugs, ethanol, starvation, hormones, stress and infection. The mechanism is usually by induction of ALA synthase activity. The molecular biology of porphyria variegata and hereditary coproporphyria is large unexplored. Acute intermittent porphyria is due to a partial deficiency of the enzyme porphobilinogen deaminase in the liver. The location of the gene for this enzyme has been identified on the long arm of chromosome 11. Acute intermittent porphyria is a genetically heterogenous disease with the abnormality frequently being a point mutation affecting synthesis of the enzyme.
Creatine kinase isoenzyme band mimicking CK MB on agarose gel electrophoresis.
The authors report the case of an 80-year-old man with prostatic disease whose serum contained an aberrant band in the MB position on agarose gel electrophoresis of creatine kinase (CK) isoenzymes. The authors demonstrated that the band probably was CK BB; the patient had no evidence of myocardial infarction. Contrary to most previous reports of such cases, the aberrant enzyme did not appear to be linked with IgG, IgA, or IgM; it also did not behave as if attached to a chelatable cation. Care must be taken to avoid mistaking such bands for CK MB.
Enzyme heterogeneity in the porphyrias.
The use of immunological methods for measuring enzyme mass has identified several varieties of porphyria in which the reduction of porphyrin enzyme activity is not accompanied by a corresponding change in the enzyme mass. Currently, acute intermittent porphyria and hepatoerythropoietic porphyria have exhibited this phenomenon. In porphyria cutanea tarda, it has recently been shown that the pattern of enzyme deficiency in erythrocytic and nonerythrocytic tissues does not strictly follow the inheritance pattern (familial and sporadic) previously described. Also, contrary to previous dogma, some cases of type 1 porphyria cutanea tarda appear to be positive for cross reactive immunological material (CRIM).
Comparison of methods for the measurement of apoproteins A1 and B in serum.
We evaluated four currently available commercial methods for measuring the concentration of apoproteins A1 and B in human serum (a radioimmunoassay, an immunonephelometric assay, and two electroimmunoassays). We found that the immunonephelometric assay provided the best between-run precision, whereas the two electroimmunoassays gave the poorest. Only the immunoephelometric assay achieved a between-run coefficient of variation of less than 5%, which we believe is a desirable target for this parameter. Comparison with other laboratories was assessed using a reference serum obtained from the Centers for Disease Control, Atlanta, Georgia, USA; we are currently using this as a reference serum employing a range of +/- 15% of its assigned values as acceptable. Linearity of the immunonephelometric assay was satisfactory throughout the ranges of 0.5-2.0 g/L for apoprotein A1, and 0.3-1.8 g/L for apoprotein B.
Microalbuminuria.
Nephropathy progressing to end-stage renal failure is a common complication of diabetes mellitus. The development of diabetic nephropathy is preceded for many years by minor increases in urine albumin excretion (microalbuminuria), and some diabetologists believe that by reducing or reversing this early abnormality, possibly by more rigorous control of hyperglycemia or by correcting glomerular hemodynamic abnormalities, the later development of frank nephropathy might be delayed or prevented. Once frank nephropathy has developed, its progress to renal failure is little, if at all, influenced by therapy. The early detection of microalbuminuria is therefore important for the management of diabetic patients, and its measurement should be available to all diabetologists. Sensitive, precise, and accurate methods are readily available to most laboratories. The preferred specimen is a 24-hour collection of urine or a timed overnight collection. A quantitation corrected for creatinine on a first-morning specimen may be a sufficiently sensitive test to detect those patients who should be subjected to a more extensive collection. Whether random samples taken at other times of the day are also suitable for screening remains to be proved.
Further comments on chronic arsenic poisoning.
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Change in composition of high density lipoprotein during gemfibrozil therapy.
We investigated the high density lipoprotein cholesterol (HDL-C) response in 20 middle-aged males during a 12-week course of gemfibrozil. Three aspects of the increase in HDL-C (25%) were studied and our observations are as follows: (1) subfraction analysis showed that HDL3-C rose earlier and to a larger extent (28%) than HDL2-C (15%), (2) analysis of variance group--time interaction effect and correlation studies of HDL-C and total triglycerides suggest the increase in HDL-C was due to a direct effect of gemfibrozil on HDL metabolism, and (3) HDL-C was the only one of 4 HDL components to increase. Apoprotein A-I (apo A-I) and HDL-phospholipid (HDL-PL) did not change, and HDL-triglyceride (HDL-TG) decreased. This pattern is consistent with a change in composition of HDL, i.e. cholesterol enrichment and triglyceride depletion.
Presence of unsedimented precipitate in visually non-turbid supernates in the heparin-manganese method for HDL-cholesterol quantitation.
An inherent problem with the heparin-manganese precipitation procedure for high density lipoprotein-cholesterol (HDL-C) quantitation is the inability to sediment all the precipitated lipoproteins, especially in hypertriglyceridemic samples. This results in overestimation of HDL-C. Thus ultrafiltration has been recommended for turbid supernates. We have investigated 47 non-turbid supernates for possible presence of unsedimented precipitate. Optical turbidity in these samples was found to correlate with the serum triglyceride level. With ultrafiltration of the supernates, there was a significant decrease in cholesterol, optical turbidity and apoprotein A-I. The percent change in turbidity correlated with the percent change in cholesterol. There was also correlation between percent change in cholesterol and the prefiltration supernate turbidity. These results indicate that visually clear supernates may show optical turbidity; the turbidity is likely due to triglyceride-rich particles, which contain cholesterol; the fall in cholesterol with ultrafiltration is due to removal of these floating particles and some adsorbance of HDL particles to the filters.