Terence J. Wilkin

Poor growth in school entrants as an index of organic disease: the Wessex growth study.

OBJECTIVE--To establish whether poor height or height velocity, assessed during the year of school entry, might identify children with previously undiagnosed organic disease. DESIGN--Observation of a total population and their case controls. SETTING--Community base. SUBJECTS--All 14,346 children in two health districts entering school during two consecutive years were screened for height by school nurses, and those whose height lay below the 3rd centile according to Tanner and Whitehouse standards (n = 180) were identified. After excluding 32 with known organic disease, five from ethnic minorities, and three who refused to take part, the remaining 140 short normal children were matched with 140 age and sex matched controls of average height (10th-90th centile) and their height velocities over 12 months measured. MAIN OUTCOME MEASURES--Height, height velocity, previously diagnosed organic disease, and organic disease diagnosed as a result of blood tests and specialist examination. RESULTS--Twenty five of the 180 short children (14%) were already known to have chronic organic disease which could explain their poor growth. Blood tests and specialist examination revealed a further seven with organic disease, which was acquired rather than congenital in three, and a second cause of short stature in one with known organic disease. These eight conditions had been missed at the school entry medical examination. The shorter the child, the more likely an underlying organic disorder, with seven of the 12 children whose heights were more than 3 standard deviations below the mean having some organic disease. Height velocity measured over 12 months, however, did not distinguish short normal children from those with disease or from their matched controls. CONCLUSIONS--Height, but not height velocity, is a useful index for identifying unrecognised organic disease at school entry. The shorter the stature the greater the prevalence of organic disease. The frequency of newly diagnosed remediable disease in this study (1 in 3-4000) is similar to that of neonatal hypothyroidism, which is routinely screened for. Routine investigation of all very short school entrants is recommended.

A comparison of spleen and lymph node cells as fusion partners for the raising of monoclonal antibodies after different routes of immunisation

Administration of antigen (human insulin) via the rear footpads of BALB/c mice with subsequent fusion of popliteal and inguinal lymph node lymphocytes induced a higher frequency of hybridomas (100%) secreting specific antibody than either intradermal immunisation and lymph node cell fusion (53%) or conventional subcutaneous immunisation and intraperitoneal boost followed by splenic lymphocyte fusion (8%). The rank order of serum antibody titres was found to correlate with the order of fusion efficiencies. Lymph node cell fusions also produced a greater spectrum of antibody specificities. Such differences in fusion efficiencies were also observed using bovine intestinal alkaline phosphatase.

Comparison of an enzyme-linked immunosorbent assay (ELISA) with a radioimmunoassay (RIA) for the measurement of rat insulin

A recently developed competitive enzyme-linked immunosorbent assay (ELISA) was compared with a conventional competitive radioimmunoassay (RIA) for the measurement of rat insulin in culture medium. Fifty-six samples were analysed by both assays. There was a correlation coefficient of r = 0.783 between results obtained using the two assay systems. The binding curves of the two assays were differently shaped, so that the ELISA gave good reproducibility over the concentration range 5-50 microU/ml insulin with inter- and intra-assay coefficients of variation less than 14%, but poor reproducibility at higher concentrations. Conversely, the RIA showed excellent reproducibility at concentrations greater than 50 microU/ml insulin, but poor sensitivity and high coefficients of variation below this level. The ELISA procedure offers practical advantages over the RIA, and performs well when measuring physiological concentrations of insulin.

Autoimmunity: Attack, or Defence? (The Case for a Primary Lesion Theory)

Most current theories to explain autoimmunity either implicate dysregulation within the immune system as the cause, and regard the diseased tissue as the victim,1,2 or speculate on idiotype anti-idiotype cross-reactions.3,4 There are objections to both views. The hypothesis presented here argues that autoimmunity is not itself an entity, but a physiological response to sustained excess antigen turnover in diseased tissues (the primary lesion) and fundamentally no different from the response to foreign antigen. Those who develop clinical disease are viewed as high responders to critical antigens. High responder status is determined by immune response (HL-linked) genotype, not immune dysregulation.

A microenzyme-linked immunosorbent assay for urinary albumin, and its comparison with radioimmunoassay

Interest in early albuminuria (microalbuminuria) has intensified recently, particularly in the area of diabetes. We describe a sandwich type enzyme-linked immunoassay for urinary albumin and compare it with a conventional radioimmunoassay (RIA) using the same commercial antiserum. The assay ranges for ELISA and RIA were 7.5-500 micrograms/l and 20-5000 micrograms/l respectively and the corresponding sensitivities were 1.5 ng and 2.0 ng. The correlation coefficient between ELISA and RIA in the measurement of albumin in overnight urine samples from 74 children was r = 0.89 (P less than 0.001). ELISA has several practical advantages over radioimmunoassay, and we believe it has the potential to replace RIA in the screening and study of albuminuria.

An enzyme-linked immunosorbent assay (ELISA) for urinary growth hormone suitable for use in the routine laboratory: The wessex growth study

An avidin-biotin enzyme-linked immunoassay was developed to measure human growth hormone (hGH) in urine. The assay was validated in terms of sensitivity, specificity and reproducibility. Parallelism was demonstrated between the standard curve (4-500 pg/ml) and serially concentrated urine. There was no interference from 125 ng/ml of adrenocorticotrophin, follicle stimulating hormone, luteinising hormone, prolactin or thyroid stimulating hormone. Recovery of exogenous human growth hormone in urine ranged from 91 to 103%. Intra- and interassay variations were less than 10% and sensitivity was 1.4 pg/ml. Application to timed overnight urine samples from both normal and short children or from acromegalic patients suggests the assay may be useful for simple, non-invasive assessment of growth hormone secretion. Moreover, use of standard laboratory equipment and commercially available components, together with the avoidance of radioisotopes, facilitate its use as a routine screening assay.

Antibody markers in predicting type 1 diabetes: a review.

Table 1. Antibody markers described in association with type 1 diabetes Thus, alternative explanations may be needed for at least some cases of diabetes. It is possible, for example, that a proportion of type 1 diabetes is not immune mediated, or that the immune response recognized as autoimmunity is a secondary, clearing up operation after cell death caused by some other primary event, and of genetically determined intensity as we and others have arguedv-P. Alternatively, the insulin deficiency in such cases may result from islet cell dysfunction rather than destruction. Functional antibodies capable of stimulating and blocking gland function have been described in the thyroidll•l 2, and adrenal systems, and recently in the islet system as welll4•15• Immunoglobulin preparations from diabetic sera can block, sometimes entirely, the insulin response to glucose.

Antibody Specificity in the Immune Response to Insulin

The immune response to insulin in Balb/c mice has been investigated with regard to the fine specificity of antibodies present during the primary stage of immune responsiveness. Hybridoma technology was used to raise monoclonal antibodies and a solid phase enzyme-linked immunoassay to test their specificity for human, bovine and porcine insulins. Heteroclitic antibodies were observed. These showed greater binding to the cross-reactive bovine and porcine insulins than to the inducing human insulin.

Improved ELISA for Thyroid Microsomal Auto-Antibodies

Thyroid microsomal antibodies (TMA) and thyroglobulin antibodies (TGA) are strongly associated with auto-immune thyroid disease. TMA and TGA have been mostly detected by means of either immunofluoresc

Autoantibodies to Endogenous Growth Hormone in Short Children (The Wessex Growth Study)

Small stature is associated with low growth hormone secretion, but in most cases the reason is unknown. The commonest cause of hormone insufficiency is autoimmunity, and autoantibodies to hormones are often found where there is autoimmune disease of the corresponding gland. Displaceable growth hormone binding by the sera of 125 short (< 3rd centile) but otherwise normal school entrants was significantly higher (P < 0.05) than by the sera of 100 age-matched children of normal height (10th-90th centile), and binding in 21 (17%) of the small children exceeded the upper limit of 95% of the normal population. Furthermore, urinary growth hormone excretion was significantly lower in the small children (total overnight output 0.6-1.7 ng) compared with controls (1.5-3.7 ng) (P < 0.05) even when corrected for body surface area. Thus, growth hormone binding and growth hormone excretion discriminated between two groups of children selected only on the basis of height. The assay used for growth hormone binding was specific for IgG, suggesting that the binding factor was antibody. Autoimmunity merits further investigation as a basis for poor growth.