Excessive calcium ingestion leading to milk-alkali syndrome.

This report describes the presentation and clinical course of a 40-year-old woman who had an emergency admission for eclampsia. During routine investigations, she was found to have profound hypercalcaemia, the cause of which was identified as milk-alkali syndrome, caused by self-medication with antacid tablets for dyspepsia. Treatment with aggressive rehydration, bisphosphonates and discontinuation of antacid tablets restored normocalcaemia. The patient made a full recovery with no long-term side-effects. Her male infant was safely delivered with no deleterious effects of exposure to high calcium concentrations in utero.

Natriuretic peptides and the heart: current and future implications for clinical biochemistry.

The measurement of B-type natriuretic peptides in plasma is under intense promotion as a method of screening for heart failure. This article provides a historical context for this contention, and attempts to highlight what practical problems may be encountered in establishing a screening service from a clinical biochemistry standpoint. B-type natriuretic peptide measurements may also prove, in future, to have a significant role in the objective monitoring of treatment for heart failure, and to be a valuable prognostic indicator in patients suffering from acute coronary syndrome.

Familial ligand-defective apolipoprotein B-100: detection, biochemical features and haplotype analysis of the R3531C mutation in the UK.

Familial ligand-defective apolipoprotein (apo) B-100 (FDB) is an autosomal codominant disorder which may give rise to hypercholesterolaemia. It is caused by the substitution of glutamine for arginine at codon 3500 of the apo B gene (apo B R3500Q), resulting in decreased binding of low density lipoprotein (LDL) to the LDL receptor. In order to search for other mutations in this region of the apo B gene, we have screened genomic DNA, obtained from 412 hypercholesterolaemic individuals, using heteroduplex analysis. Additional heteroduplex bands were observed following analysis of DNA from 11 individuals, nine of whom were heterozygous for apo B R3500Q. The two remaining individuals, both of Celtic origin, were shown by DNA sequencing to be heterozygous for a C-->T transition at nucleotide 10800 of the apo B gene, resulting in the substitution of cysteine for arginine at codon 3531 (apo B R3531C). Both had a strong family history of atherosclerosis and family studies revealed a further four individuals heterozygous for the mutation, three of whom were hypercholesterolaemic. Individuals heterozygous for apo B R3531C and R3500Q had mean +/- S.E.M. cholesterol concentrations of 7.82 +/- 0.68 and 8.53 +/- 0.31 mmol/l, respectively. These values were significantly higher than the value of 5.51 +/- 0.23 mmol/l observed in their unaffected relatives. These findings suggest that apo B R3531C is both less common in the UK and gives rise to a less severe form of hypercholesterolaemia than the classical 3500 mutation. In one of the families, the R3531C mutation occurred on a haplotype, compatible with that previously assigned to the mutation in a North American family also of Celtic origin. This is consistent with the mutation having been inherited from a common distant ancestor in individuals of Celtic origin.

Arginine infusion blocks the action of parathyroid hormone but not arginine vasopressin on the renal tubule in man.

Six male volunteers were infused with arginine (0.5 g/kg body weight) over 30 min, after an overnight fast and water deprivation. There was a significant decrease in renal phosphate clearance (P less than 0.025) and urinary cyclic adenosine monophosphate (cAMP) output (P less than 0.025) during the 60- to 90-min period after the beginning of the infusion; both returned to the preinfusion basal levels within 150 min. The plasma levels of parathyroid hormone (PTH) were not affected by the infusion and remained unchanged during the subsequent 150 min. Plasma levels of arginine vasopressin (AVP) were also not significantly affected although plasma osmolality increased by 6-9 mmol/kg in all subjects. The infusion resulted in a diuresis, and a fall in urine osmolality but a decrease in free-water clearance; creatinine clearance was not affected. Six other subjects were given a bolus of 230 i.u. PTH intravenously, and 20 days later this was repeated during an infusion of arginine (0.5 g/kg body weight). There was a significant decrease in urinary phosphate (P less than 0.025) and cAMP excretion (P less than 0.05) when PTH was given with arginine. It is suggested that arginine blocks the action of PTH on the proximal renal tubule but not that of vasopressin on the distal nephron and collecting ducts.

Hyponatraemia in patients with head injury.

Three patients with head injury are described to illustrate certain features of the development, treatment and recovery of hyponatraemia. The hyponatraemia is initially due to water retention but true sodium depletion may develop because of an associated urine sodium loss. The mechanism of the latter is discussed.

The effect of lithium therapy on arginine vasopressin secretion and thirst in man.

Lithium therapy is known to reduce the renal responsiveness to arginine vasopressin (AVP: the antidiuretic hormone in man) and a proportion of treated patients develop polyuria and polydipsia. In this study seven nonpolyuric female patients receiving lithium treatment for an affective disorder (lithium group) were age-matched with seven healthy females (control group). The mean response of plasma AVP to osmotic stimulation was significantly enhanced in the lithium group but the mean osmotic threshold for AVP release was unchanged. Thirst appreciation in the lithium group commenced and increased overall at an osmotic stimulus 5 mmol/kg less than the control group. It is suggested that primary thirst does play a role in the expression of lithium-induced polyuria.

Disturbance of peripheral microvascular fluid permeability by the onset of atrioventricular asynchrony in patients with programmable pacemakers.

BACKGROUND: In vitro and in vivo evidence suggests that atrial natriuretic peptide can enhance fluid flux from intravascular to extravascular compartments. The relevance of this to human pathophysiology remains unclear. OBJECTIVES: To determine whether a central haemodynamic change associated with increased plasma concentrations of atrial natriuretic peptide produces detectable change in the capillary filtration coefficient in a peripheral microvascular bed. PATIENTS: 12 patients with programmable dual chamber permanent pacemakers. METHODS: Calf capillary filtration coefficient (using a modified plethysmographic technique) and plasma atrial natriuretic peptide concentrations were measured during atrioventricular synchronous and ventricular pacing. RESULTS: Atrioventricular asynchrony was associated with higher mean (SD) concentrations of atrial natriuretic peptide (231.9 (123.1) v 53.5 (38.8) pg/ml) and an increased mean (SD) calf capillary filtration coefficient (4.2 (1.1) v 3.6 (1.1) ml/min.mm Hg.100 ml x 10(-3)), but there was no correlation between the magnitude of the change in these variables in individual patients. CONCLUSIONS: The peripheral capillary filtration coefficient may change in response to altered central haemodynamics. Atrial natriuretic peptide remains one potential candidate mechanism, but other factors are also likely to be involved.

Biochemical diagnosis of myocardial infarction within the thrombolytic time window.

A demonstrated temporal change in the total activity of creatine kinase or mass measurement of the cardio-specific isoenzyme creatine kinase MB is currently used as the biochemical diagnosis of myocardial infarction. The isoforms of creatine kinase MB may provide an earlier diagnostic marker of myocardial infarction than the currently available biochemical markers. We compare the sensitivity and specificity of total creatine kinase activity, creatine kinase MB mass measurement and the muscle and heart specific isoforms of creatine kinase in the early diagnosis of myocardial infarction. Using current methodologies, neither CK isoform offered any advantage over CK mass measurement as an early marker of ischaemic myocardial damage.

The mathematical basis of multivariate risk screening: with special reference to screening for Down's syndrome associated pregnancy.

The underlying mathematical techniques behind the multivariate normal distribution are explained in principle and expanded in detail for up to three variables. The application of multivariate distributions to screening programs is described with particular reference to the calculation of risk ratios for the detection of Down's syndrome between 15 and 19 weeks of gestation.

Creatine kinase isoforms: investigation of inhibitors of in vitro degradation and establishment of a reference range.

The in vitro stability of creatine kinase isoforms was examined by separation with high voltage electrophoresis. The effect of inhibitors of carboxypeptidase was evaluated. Preservation of samples is essential to inhibit in vitro changes in isoform pattern. EDTA at a final concentration of 15 mmol/L is recommended. Using appropriately preserved samples, normal reference intervals for the MM isoforms have been established.

The effect of weight correction on risk calculations for Down's syndrome screening.

Recent advances in prenatal screening have led to the possibility that the risk of Down's syndrome associated pregnancy may be assessed by blood tests for maternal serum alphafetoprotein, human chorionic gonadotrophin (and possibly unconjugated oestriol) taken at 15-18 weeks of gestation. In neural tube defect screening correction of maternal serum alphafetoprotein for maternal weight has been recommended, although the precise method for weight correction is still under debate. We report an assessment of weight correction for maternal serum alphafetoprotein and human chorionic gonadotrophin based on 1408 singleton pregnancies and for unconjugated oestriol based on 197 singleton pregnancies. We demonstrate that weight correction of maternal serum alphafetoprotein and human chorionic gonadotrophin is statistically valid but that correction of unconjugated oestriol is not.

Familial defective apolipoprotein B-100: a study of patients from lipid clinics in Scotland and Wales.

Familial defective apolipoprotein (apo) B-100 (FDB) is an autosomal codominant disorder, which may be associated with hypercholesterolaemia. The defect is caused by the substitution of glutamine for arginine at amino acid residue 3500 of apo B-100. A total of 357 hypercholesterolaemic patients, 48 with a clinical diagnosis of familial hypercholesterolaemia attending lipid clinics in Scotland and Wales, were screened for the presence of FDB. Seven unrelated individuals, five of whom had a family history of coronary heart disease, and a further 11 first-degree relatives, were shown to be heterozygous for the mutation. Pedigree analysis demonstrated the mutation to be present on a single haplotype, suggesting that in Britain it is inherited from a common ancestor. Treatment of 11 heterozygous individuals with lipid-lowering medication showed falls in total and low density lipoprotein cholesterol ranging from 11.6 to 38.8% and 5.3 to 49.5%, respectively. In view of the condition's association with coronary heart disease and hypercholester-olaemia, it may be worthwhile identifying carriers attending lipid clinics, so that affected siblings can be offered cholesterol-lowering treatment where necessary.

Radioimmunoassays of arginine vasopressin and atrial natriuretic peptide: application of a common protocol for plasma extraction using Sep-Pak C18 cartridges.

A rapid vacuum-driven procedure, using pre-treated Sep-Pak C18 cartridges, has been developed for the simultaneous extraction of arginine vasopressin (AVP) and atrial natriuretic peptide (ANP) from plasma. Non-specific interference was removed by fractional elution with an aqueous methanol/trifluoroacetic acid (TFA) mixture. AVP and ANP were coeluted under positive pressure with a methanol/TFA mixture and the eluates air-dried before measurement using separate radioimmunoassays. Assay ranges for AVP and ANP were 0.12-29.5 pmol/L and 0.65-162 pmol/L, respectively, with mean recoveries (standard deviation in parentheses) for AVP of 96.4% (5.5%) at a level of 11.8 pmol/L and for ANP of 94.8% (5.9%) at a level of 32.4 pmol/L. The extraction and assay procedures were validated by observing the changes in plasma AVP and ANP concentrations in normal subjects at different stages of hydration and in elderly patients during treatment for congestive cardiac failure.

Simplified detection of a mutation causing familial hypercholesterolaemia throughout Britain: evidence for an origin in a common distant ancestor.

Familial hypercholesterolaemia (FH) is an inherited autosomal codominant disorder caused by many different mutations in the low-density lipoprotein receptor (LDLR) gene. The one described most frequently in patients with FH from England, arises from a G-->A transition at the first nucleotide of codon 80, resulting in the substitution of lysine for glutamic acid at residue 80 of the mature protein, FH E80K. We describe a simple method to detect this mutation in genomic DNA using the polymerase chain reaction (PCR). A 69 base pair (bp) fragment of exon 3 of the LDLR gene is amplified using a mutagenic upstream PCR primer. This substitutes a T for an A residue in the amplified product, 2 bp upstream from the mutant site, generating a restriction site for the endonuclease Taq I, in normal, but not in mutant DNA. Following digestion of amplified DNA with Taq I, normal but not mutant DNA is cut into two fragments of 29 and 40 bp, which are readily identified by polyacrylamide gel electrophoresis. Using this method, 410 patients with clinically diagnosed FH, attending lipid clinics in Edinburgh (72), Newport (158), Walsall (30) and Southampton (150), were screened for the mutation. Five individuals tested positive as heterozygotes, one from Edinburgh, three from Newport and one from Southampton. This finding was confirmed by DNA sequence analysis. We conclude that FH due to this mutation occurs in individuals throughout Great Britain and that it can be detected accurately using this simple technique. DNA from these and other individuals previously identified to be heterozygous for FH E80K, was then studied using PCR of highly informative microsatellite markers flanking the LDLR gene. Sixteen of 17 apparently unrelated individuals heterozygous for FH E80K also were heterozygous for an identical size (239 nucleotide) allele, of polymorphic microsatellite D19S394, located approximately 250 kb away from the LDLR gene. This supports the hypothesis that FH E80K in these 16 individuals arose from a single ancestor less than 1000 years ago.

Can serum prostate-specific antigen replace bone scintigraphy in the follow-up of metastatic prostatic cancer?

Bone scintigraphy is the most sensitive imaging technique for the initial detection of bone metastases and is widely used in the staging of prostatic cancer. This study was performed to assess whether the development of further bone metastases can be detected by serial measurements of the serum glycoprotein prostate-specific antigen (PSA) as an alternative to follow-up scintigraphy. The bone scintigrams and PSA levels of 101 patients with metastatic prostate cancer entered into two therapeutic trials have been reviewed. Serial results of both investigations were available in 59 cases. In three cases new bone deposits were observed without a corresponding rise in PSA. In two other cases the scintigrams were considered to be suspicious of progression with no change in PSA levels; however, further follow-up indicated that these changes were not due to metastases. In 13 cases PSA levels were rising in advance of new deposits on the scintigrams. In the remaining 41 cases the PSA levels and scintigraphic findings paralleled each other. We conclude that serial estimation of PSA levels is a simpler marker for disease progression than bone scintigraphy in metastatic prostatic cancer, but that neither technique in isolation gives complete accuracy.

Pulsatile release of arginine vasopressin (AVP) and it's effect on response to desmopressin in enuresis.

A response to desmopressin spray is only seen in a proportion of children with enuresis. To investigate whether response is related to nocturnal levels of arginine vasopressin (AVP) 35 children with enuresis, aged 8 to 14 years, had plasma AVP measurements overnight before entering a double blind randomised, placebo controlled crossover study to assess their response to evening treatment with desmopressin spray. There was no significant difference seen between nocturnal AVP levels obtained from children who responded to desmopressin and those who did not. Frequent sampling in six children demonstrated a pulsatile pattern of secretion for AVP. This has implications for studies of nocturnal AVP levels, and questions the validity of using infrequent measurements of AVP to assess it's secretion.