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The major US treatment guidelines now recommend starting antiretroviral therapy (ART) later in the course of HIV infection because of an increasing awareness of the difficulties associated with these regimens. Most of the data to support this change come from observational cohort studies. When deciding to start ART, several patient-specific factors and other issues should be considered. Because of the many choices for initial ART, clinicians should individualize the choice, taking into account regimen antiretroviral potency, durability, side effects, toxicities, and convenience to ensure a sustained clinical benefit for the patient.

The insulin gene variable number of tandem repeats minisatellite (INS-VNTR) class III allele is associated with altered fetal growth, type 2 diabetes risk (especially when paternally inherited), and insulin and IGF2 gene expression. Further studies are needed to establish the role of the INS-VNTR in fetal growth and assess whether its effects depend on the parent of origin. We analyzed the INS-VNTR-linked -23 Hph1 polymorphism in 2283 subjects, comprising 1184 children and 1099 parents. There were no differences (P < 0.05) in birth weight between offspring of the three genotypes: III/III (n = 108) vs. I/I (n = 558), effect size, -8 g (P = 0.87); and I/III (n = 464) vs. I/I, effect size, -19 g (P = 0.54). We observed no differences in head circumference [III/III (n = 95) vs. I/I (n = 470), effect size, -0.14 cm; P = 0.31] or birth length. No differences were observed when stratifying by postnatal growth realignments [nonchangers III/III (n = 37) vs. I/I (n = 170), effect size, -43 g; P = 1.00] or by parent of origin of the class III allele (presence of paternal III allele effect size, -15 g; P = 0.74). INS-VNTR was nominally associated (P < 0.05) with body mass index and insulin resistance, but not with beta-cell function, in young adults. In the largest study to date, we found a lack of support for a role for INS-VNTR in fetal growth and nominal association with type 2 diabetes-related intermediate traits.

For a decade or more, poor nutrition during gestation, expressed as low weight at birth, was held to be the factor responsible for insulin resistance later in life. Birth weights, however, are rising and insulin resistant states, such as diabetes mellitus, faster still. Alternative explanations are needed to explain insulin resistance in contemporary industrialised populations. EarlyBird is a non-intervention prospective cohort study that asks the question 'Which children develop insulin resistance, and why?' It is unique in taking serial blood samples from a young age with which to monitor the behaviour of insulin resistance and its metabolic correlates. This, the baseline report of the EarlyBird Study, describes the rationale, design and methodology of the study, and the profile of the population at entry. It situates the anthropometric, physical activity and dietary status of the EarlyBird children and provides a detailed metabolic profile of the British 5 year-old in the year 2000.

Objective: Previous reports have predicted greater risk of type 1 diabetes among people who were heavier as young children. The Accelerator Hypothesis predicts earlier onset in heavier people, without necessarily a change in risk, and views type 1 and type 2 diabetes as the same disorder of insulin resistance, set against different genetic backgrounds. Insulin resistance is a function of fat mass, and increasing body weight in the industrialized world has been accompanied by earlier presentation (i.e., acceleration) of type 2 diabetes. We wanted to establish whether increasing body weight was also associated with the earlier presentation of type 1 diabetes, as the Accelerator Hypothesis would predict., Research Design and Methods: The relationships between fatness and age at diagnosis were examined in context of birth weight, weight change since birth, weight at diagnosis, BMI at diagnosis, and BMI 12 months later in 94 children aged 1-16 years (49 boys and 45 girls) presenting for management of acute-onset type 1 diabetes., Results: BMI standard deviation score (SDS) at diagnosis, weight SDS change since birth, and BMI SDS 12 months later were all inversely related to age at presentation (r = -0.39 to -0.40, P < 0.001). The boys were significantly fatter than the girls (BMI SDS 0.56 vs. -0.08, respectively; P = 0.006) and presented with diabetes at a significantly younger age (6.74 vs. 8.32 years, respectively; P < 0.05). The sex difference in age at diagnosis, however, disappeared when corrected for BMI (P = 0.31), suggesting that fatness or something related to it was the responsible factor., Conclusions: The data are consistent with the hypothesis that the age at presentation of type 1 diabetes is associated with fatness. The implications for prevention of type 1 diabetes may be important.

The major US treatment guidelines recently recommended starting antiretroviral therapy (ART) later in the course of HIV infection due to an increasing awareness of the difficulties associated with these regimens. Most of the data to support this change come from observational cohort studies. When deciding to start ART, a number of patient-specific factors and other issues should be considered. Given the many choices for initial ART, one should individualize the choice, taking into account antiretroviral regimen potency, durability, side effects, toxicities, and convenience to ensure a sustained clinical benefit for the patient.

Aim/hypothesis: Radiobinding assays (RBA) are unable to differentiate insulin autoantibodies (IAA) from insulin antibodies (IA). We sought to establish whether random peptide phage display might generate reagents with which to distinguish IAA idiotopes from IA idiotopes., Methods: Two insulin-binding sera were used to select phagotopes from a phage library. The first, designated IAS, came from an insulin-treated patient with the insulin autoimmune syndrome, and was known to contain both IA and a high titre of human insulin specific (B30 threonine dependent) IAA. The second, designated IDD, was taken from a newly-diagnosed IAA(+) Type 1 diabetic patient. Phage colonies selected by insulin-purified IgG extracts of IAS and IDD were selected at random for DNA sequencing, and tested for their reactivity with insulin antibodies and ability to distinguish disease-associated idiotopes., Results: Seven phagotopes bound IAS and the phagotope designated IAS-9, corresponding to sequence KRSRLDV, gave the highest binding standard deviation (SD) score. Seven phagotopes bound IDD and the phagotope designated IDD-10, corresponding to sequence LGRGGSK, bound most strongly. IAS-9 was able to displace insulin binding in IAS and all of ten insulin-treated Type 2 diabetic patients, but not the IAA present in any of the eight patients with newly-diagnosed Type 1 diabetes. IDD-10, on the other hand, could displace insulin binding detected in the sera of eight patients with untreated Type 1 diabetes (IAA), but not in IAS or sera of the insulin-treated Type 2 diabetics., Conclusion: Phagotopes provide reagents which between them can distinguish positively as well as negatively diabetes-associated IAA from non-diabetes associated IAA and from IA.

Accelerometers revealed a fivefold variation in physical activity among healthy 5 year old children. They singled out habitually inactive children, most of them girls, who did little, whether at school or over the weekend. Accelerometers are of potential value in identifying, from an early age, children at risk of becoming obese.

Variation within the calpain-10 gene (CAPN10) has been proposed to account for linkage to type 2 diabetes on chromosome 2q in Mexican-Americans, and associations with diabetes have been reported in several other populations. Given the epidemiological, physiological, and genetic overlap between type 2 diabetes and polycystic ovary syndrome (PCOS), CAPN10 represents a strong candidate gene for a role in PCOS susceptibility. Using both family based and case-control association resources (146 parent-offspring trios; 185 additional PCOS cases; 525 control subjects, all of European ancestry), we sought association between CAPN10 variation and PCOS, focusing on four single nucleotide polymorphism (SNP) variants (SNP-44, SNP-43; SNP-19; SNP-63). On single-locus transmission disequilibrium analysis in the 146 trios, there was nominal evidence (P = 0.03) of excess transmission of the more common allele at SNP-63. This association was not, however, replicated in the case-control analysis. No other significant associations were observed at the single-locus or haplotype level in either the transmission-disequilibrium or case-control analyses. The relative risk for the high-risk diabetes susceptibility 112/121 genotype (SNPs 43-19-63) was 0.84 (95% confidence intervals, 0.40-1.71). No associations were seen with intermediate traits of relevance to diabetes and PCOS pathogenesis. We have found no evidence from these analyses that CAPN10 gene variation influences susceptibility to PCOS.

Blood glucose concentrations are controlled by a loop incorporating two components, the beta cells which secrete insulin and the insulin-sensitive tissues (liver, muscle, adipose) which respond to it. Loss of blood glucose control might result from failure of the beta cells to secrete insulin, resistance of the tissues to its action, or a combination of both. The distinctions between Type I (insulin-dependent) and Type II (non-insulin-dependent) diabetes mellitus are becoming increasingly blurred both clinically and aetiologically, where beta-cell insufficiency is the shared characteristic. The 'Accelerator Hypothesis' identifies three processes which variably accelerate the loss of beta cells through apoptosis: constitution, insulin resistance and autoimmunity. None of the accelerators leads to diabetes without excess weight gain, a trend which the 'Accelerator Hypothesis' deems central to the rising incidence of both types of diabetes in the industrially developed world. Weight gain causes an increase in insulin resistance, which results in the weakening of glucose control. The rising blood glucose (glucotoxicity) accelerates beta-cell apoptosis directly in all and, by inducing beta-cell immunogens, further accelerates it in a subset genetically predisposed to autoimmunity. Rather than overlap between two types of diabetes, the 'Accelerator Hypothesis' envisages overlay. Body mass is central to the development and rising incidence of all diabetes. Only tempo distinguishes the 'types'. The control of weight gain, and with it insulin resistance, could be the means of minimising both.

Avascular necrosis of bone (osteonecrosis) that is atraumatic is most frequently associated with corticosteroid excess or alcoholism and usually involves the femoral head. We report a case of multifocal avascular necrosis in a 38-year-old woman with autoimmune Addison's disease taking corticosteroid replacement therapy. The onset of joint symptoms occurred 6 months after a pregnancy complicated by acute fatty liver and disseminated intravascular coagulation. Although both knees and ankles were involved, an unusual feature is that the hips were spared. As illustrated in this patient, avascular necrosis is frequently misdiagnosed in cases of joint pain of acute onset and may occur in the context of physiologic replacement doses of corticosteroids. Etiologic factors can precede the onset of symptoms and the diagnosis by several months.

Objective: This study was performed to test the hypothesis that an increased prevalence of activated protein C (APC) resistance in women with polycystic ovary syndrome (PCOS) puts them at increased risk of miscarriage and thrombosis., Design: Case control study., Setting: A district general hospital in the United Kingdom., Patient(s): Forty-one women with PCOS and 25 controls., Intervention(s): Clinical histories, ultrasound scans, and venepunctures., Main Outcome Measure(s): Diagnosis of PCOS or control, clinical histories, APC resistance according to an activated partial thromboplastin time-based assay., Result(s): There was no significant difference in the proportion of women with APC resistance in both groups (three women in the PCOS group [7%] vs. one woman in the control group [4%]). The prevalence of APC resistance in the entire study population was 6.5%. In the PCOS group, 29% (12/41) gave a positive family history of thrombosis compared with 8% (2/25) in the control group. None of the women with a positive family history of thrombosis had abnormal antithrombin 111, protein C, or protein S levels., Conclusion(s): This study suggests that women with PCOS may have the same prevalence of APC resistance as the background population and that APC resistance may not put them at a higher risk of thrombosis or miscarriage compared with the case of the general population.

Insulin autoantibodies (IAA) are one of several markers for Type I (autoimmune) diabetes, but alone deserve special attention. Unlike the other markers, their ligand is unique to the beta cell. IAA are the first markers to appear during the symptomless period which precedes diabetes and they are present in the vast majority of young children destined to develop diabetes. The primary and tertiary structures of insulin have been known for decades. Binding studies with insulin variants have shown epitope restriction that can distinguish Type 1 diabetes-predictive from non-predictive IAA-positive sera, thereby improving specificity for the test. With two major international Type 1 diabetes prevention trials underway, there is a pressing need to refine markers that reliably indicate the presence of, and remission from, autoimmune insulitis. The binding regions of antibodies are assembled from three multi-gene families, and some of their diversity derives from random mutation during their antigen-driven maturation. There is evidence that mature IAA derive from germline-encoded 'natural' antibodies, and that the gene segments utilised by IAA may be influenced by clinical context. Monoclonal anti-idiotypic (anti-Id) antibodies can serve as probes for antibody variable region determinants, and antibodies to the different epitopes of beef and porcine insulins have already been analysed with monoclonal reagents. Used as antibodies in a radioimmunoassay format, monoclonal anti-Ids will identify and measure autoantibody idiotopes as if they were ligands. The challenge now is to replace the conventional radiobinding assays for IAA, which only detect and titrate, with radioimmunoassays that can be standardised in absolute units. There is sufficient evidence for the existence of Type 1 diabetes-predictive IAA idiotopes to justify the development of idiotope-specific radioimmunoassays which ignore Type 1 diabetes-unrelated IAA., (Copyright 2000 John Wiley & Sons, Ltd.)

Anovulation in women with polycystic ovary syndrome (PCOS) is incompletely understood. The concentration of the glycoprotein plasminogen activator inhibitor-1 (PAI-1) is raised in insulin resistance. This has been described in the granulosa and theca cell layers of the animal but not the human ovary. This study was performed to investigate the location of PAI-1 in the human ovary and investigate whether it may contribute to anovulation in PCOS. PAI-1 was localized immunohistochemically and quantitated using computer image analysis in 17 ovarian follicles from five women with a diagnosis of PCOS and compared with 15 follicles from six normal ovaries. PAI-1 was predominantly found in the granulosa and theca cells in both polycystic and normal ovaries. Image analysis did not reveal a difference in the PAI-1 signal from polycystic compared with normal ovaries. This study shows that PAI-1 plays a role in human ovulation, but its role in PCOS requires further research.

Background: It has been postulated that an insulin-driven increase in plasminogen activator inhibitor-1 (PAI-1) levels may link insulin resistance to anovulatory infertility in women with PCOS and that it may place them at increased risk of thromboembolic disease. However, previous studies have been conflicting because many have failed to control for body mass index (BMI) which may affect PAI-1. The aim of this study was to investigate PAI-1 activity in women with PCOS and to compare it with unaffected controls of a similar BMI., Design and Patients: 41 women with PCOS and 25 weight-matched controls participated in this cross-sectional study. Patients were evaluated clinically and by pelvic ultrasound and fasting blood samples were taken for haematological and biochemical tests., Measurements: PAI-1 activity, insulin, glucose, triglycerides, total cholesterol, LDL cholesterol, HDL cholesterol, FSH, LH, PRL, testosterone, SHBG, 17-hydroxyprogesterone, plasminogen, fibrinogen (alpha2 antiplasmin, blood pressure and insulin sensitivity with a homeostasis model assessment (HOMA) computer programme., Results: There was no significant difference in BMI or in (log) PAI-1 activity in women with PCOS compared with controls (BMI 29.5 +/- 5.6 vs. 28.4 +/- 6.3 kg/m2, P = 0.25 and PAI-1 2.56 (SD 0.85) vs. 2.14 (SD 0.98) au/ml, P = 0.07). The median fasting insulin level was significantly higher (17 (4.6-134.5) vs. 9.6 (3.7-41.5) mU/l, P < 0.01), and insulin sensitivity significantly lower in the PCOS group, ( 43.17% (5. 48-160) vs. 82.8% (21.8-193), P < 0.01). Women with PCOS also had a significantly higher free androgen index, LH/FSH ratio and a lower HDL/total cholesterol ratio. However blood pressure and all other lipid and haematological measurements were not significantly different between both groups. There were significant positive correlations between (log) PAI-1 activity and BMI (rho = 0.61), triglycerides (rho = 0.49) and fasting insulin (rho = 0.60) and a negative correlation with HDL cholesterol (rho = - 0.46). Triglyceride concentrations showed the most significant relationship with (log) PAI-1 activity on multiple regression. 29% of PCO women (12/41) gave a positive family history of thrombosis compared to 8% (2/25) in the control group., Conclusion: Plasminogen activator inhibitor-1 activity is not raised in women with PCOS independent of obesity and these results do not support the hypothesis that it may contribute to their anovulatory infertility, or increase their risk of thrombosis. The only significant metabolic features of the PCOS independent of obesity are insulin resistance, hyperinsulinaemia and lower HDL/total cholesterol ratio. The higher frequency of a positive family history of thrombosis in these women nevertheless requires further explanation.

Insulin autoantibodies (IAA) are markers for autoimmune insulitis, and are reported in up to 100% of diabetic children before the age of five years, but in fewer than 1% of their controls. Their origins are unknown. In this report a cluster of high titre IAA in cord blood is reported, distinct from the low titre 'non-specific' binding previously described. The distributions of displaceable insulin binding measured in adults (Group A, n = 79), adolescents (Group B, n = 19), primary school children (Group C, n = 32) and third trimester pregnant women (Group D, n = 60) were all unimodal, normal and not different from each other (A = 0.57+/-0.64%, B = 0.87+/-0.45%, C = 0.81+/-0.87% and D = 0.35+/-0.48%). The distribution of insulin binding in the cord sera of consecutive newborns (n = 428) born between October and the following May, however, was bimodal. The first distribution, included 400 sera, was symmetrical and not different (0.79+/-0.45%) from groups A, B, C and D. The second distribution comprised the remaining 28 sera (7% of the total sample) with insulin-displaceable binding values in an IDW-validated radio assay ranging from 2.2% to 31.1%. The appearance of IAA was not HLA-restricted, but the frequency of IAA+ samples was seen to vary over five consecutive months. The timing is consistent with acute viral infection, but the implications for future insulin dependent diabetes will await long-term follow-up of the children and mothers involved.

The construction of reference ranges that accurately represent the population at large is essential for the correct identification of osteoporosis from bone mineral density (BMD) measurements. In this study, reference data supplied by the manufacturer of the Lunar DPX+ bone densitometer were compared with data obtained locally. Lumbar spine, proximal femur and total body BMD measurements were made in an age-stratified random sample of 702 Southampton women aged 20 to 89 years. Relevant demographic and medical data were recorded for each subject using a questionnaire. Reference curves of BMD (mean +/- SD) were plotted against age for each measurement site and were found to be higher than the manufacturer's reference values at all ages and sites. Exclusion of women with factors known to affect bone mass only served to increase this discrepancy. According to World Health Organisation definitions, osteoporosis may be identified from BMD values alone. Based upon neck of femur BMD values, 100 (14.8%) of the women in this study group were categorized as osteoporotic using local young normal reference data, compared with only 39 (5.8%) using the manufacturer's data. By normalizing for age distribution, these findings were extrapolated to the local population where it was predicted that 26.0% and 10.1% of females over 50 years of age would be classified as osteoporotic using the respective reference ranges. This study clearly illustrates how the numbers of women diagnosed as osteoporotic vary with the use of different reference populations.

Nicotinamide, a derivative of the B vitamin niacin, is currently under trial for the prevention of insulin-dependent diabetes mellitus after success in the NOD mouse. However, the dose, route of administration, and formulation of nicotinamide given to humans is quite different from those used successfully in animals, and the aim of this study was to investigate the plasma pharmacokinetics of oral nicotinamide in humans in two doses and in two different formulations (standard and the long-acting Enduramide). There were no significant differences in the kinetics of the low dose of standard nicotinamide (2.5 mg/kg) and low-dose Enduramide (6.7 mg/kg) in young adult men. Nonlinear kinetics were found with both formulations at higher doses, e.g., a 10-fold increase in the dose of the standard nicotinamide produced a 62-fold increase in the area under the plasma concentration-time curve (AUC). The high dose of standard nicotinamide (25 mg/kg body wt) produced a mean peak plasma concentration 75% higher than that achieved with the sustained release nicotinamide preparation given in a dose similar to that currently used in prevention trials (2 g identical to 26.6 mg/kg body wt for a 75-kg subject). The AUC was also significantly greater with the standard formulation, indicating a higher bioavailability. Long-term plasma levels for high doses of both formulations were modeled from the single-dose kinetics by computer program. The AUC for standard nicotinamide was 1.7 times higher than that for Enduramide.(ABSTRACT TRUNCATED AT 250 WORDS)

Tetrahydrobiopterin (BH4) is a pteridine product which is released by rodent macrophages on activation by cytokines. We have used serial pancreatic biopsy, and measurement of serum biopterin at 30, 60, 90 and 120 days in the BB/S rat to relate histological change to macrophage activation during the course of pre-diabetes. Using immunohistochemistry, and an arbitrary scoring system read blind and standardised against day 30, we found that pancreatic MHC class I, MHC class II and infiltrating macrophage staining were up-regulated in the BB/S diabetes-prone rats (n = 17) at day 60, markedly so at day 90, and less so at day 120. Staining for resident pancreatic macrophages remained unchanged throughout in diabetes prone, diabetes resistant and Wistar (n = 28) control animals. Serum biopterin fell progressively and identically with age in BB diabetes resistant rats (n = 11) and Wistar controls. No change in weight gain or biopterin levels was observed in the biopsied animals. Mean serum biopterin levels in diabetes prone rats (of which 13 of 17 became diabetic at median 85 days) were the same as in diabetes resistant and Wistar rats at days 30, 60 and 120, but showed a striking and highly significant elevation (p < 0.001) at day 90. Although macrophages infiltrate the islet early in pre-diabetes, the timing of their activation is unknown. The rise in biopterin we observed is a potentially important immunological event which occurred late in the progression of pre-diabetes. This acute terminal event has not been reported previously, and may modify current concepts concerning the tempo of cell destruction during pre-diabetes.

Thyroid hormone autoantibodies (THAA) disrupt the equilibrium between thyroid hormones and their binding proteins. This may lead to spurious estimations of free thyroxine (FT4) and triiodothyronine (FT3) by radioimmunoassay (RIA). In the present study we highlight the importance of THAA by examining the frequency of THAA in consecutive sera sent to a routine district hospital laboratory. Over a period of six months, sera were collected from 200 consecutive hypothyroid, 200 hyperthyroid and seven patients whose clinical and biochemical thyroid status were contradictory. A further 200 patients with non-thyroid autoimmune conditions, 20 patients with insulin autoantibodies and 100 healthy blood transfusion donors were studied. In all sera, both effects of antigen removal on THAA detection and where THAA were found, the effect of their removal on FT4, were examined. The frequencies of THAA amongst hypothyroid, hyperthyroid and non-thyroid autoimmune conditions were 7%, 1.5% and 7.5% respectively, whilst no THAA were found in insulin autoantibody positive patients and 100 blood transfusion donors. However, THAA frequency was highest in those patients whose biochemical thyroid status was widely inappropriate to clinical state (5/7 = 64%). Sera stripped of thyroid hormones prior to THAA detection had significantly higher antibody activity than unstripped sera (p = 0.0027 and p = 0.0123 for T3 and T4 binding respectively). Free thyroxine levels measured by the Amerlex-M RIA kit after antibody removal fell in all 21 THAA positive sera tested. The correlation coefficient between antibody activity in serum with percentage fall in FT4 was 0.79 (Spearman's Rank Correlation Test).(ABSTRACT TRUNCATED AT 250 WORDS)

Despite nearly 40 years of organ specific autoimmunity research, a question of whether the immune response in autoimmunity is due to dysregulation of the immune system or to a primary lesion in the target organ remains unresolved. Strength in the immune dysregulation argument, for which there has never been direct evidence in man, has largely derived from failure to identify a primary lesion to account for it. That is, until recently. Just as inflammation was considered a primary cause of disease until microbes were discovered, so autoimmunity was looked upon as a state of immune dysregulation until the equivalent of microbes were discovered. The microbe equivalents are viral particles, expressed on the surface of target organ cells under certain circumstances, and often encoded in the host's genome. These neo-antigens induce a protective, rather than aggressive immune response and account for the very singular target specificity observed, for example in the beta cell destruction of type 1 diabetes.

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.

The expression of a novel regenerating (reg) gene has been reported previously in the regenerating islets of a surgical model of diabetes in rats. We exposed collagenase-isolated rat islets for three days to nutrient and non-nutrient growth factors in minimally supplemented RPMI medium (2.7 mmol/l glucose, 2% fetal calf serum), and investigated the relationship between reg gene expression and islet cell replication. RNA was prepared from half of the islets by homogenisation in guanidinium isothiocyanate followed by phenol/chloroform extraction. Northern/dot blot analyses were used to semi-quantify reg mRNA. Islet cell replication was estimated by culturing the remaining islets in radiolabelled thymidine to determine de novo DNA synthesis. Thymidine uptake was stimulated by the following factors: 11 mmol/l glucose (50% increase); 10% amino acids (126% increase); 10% fetal calf serum (39% increase); 100 ng/ml insulin (45% increase); 250 ng/ml growth hormone (65% increase); 1.5 nmol/l aldosterone (29% increase); 2 U/ml platelet derived growth factor (116% increase). The results are expressed as a percentage of the thymidine incorporated into control islets cultured in minimal RPMI (1118 +/- 100 (SD) cpm/microgram protein, n = 15). Increased islet cell replication was paralleled in each case by a clear rise in reg mRNA expression compared to controls. Furthermore, the rank order for reg gene expression was the same as that for thymidine uptake (r = 0.90). The present findings suggest a clear association between reg gene expression and islet cell replication in vitro, and are the first to demonstrate reg gene expression in response to individual growth factors.

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.

Both biochemical and auxological measurements can be used to assess growth. Quality control in routinely reported in laboratory studies, but the reproducibility of height measurements, and the height velocity data derived from them, is seldom considered. We have previously established our error and in this report we examine its implications for the screening of short children and subsequent monitoring of their growth. The 95% confidence interval for height for a 5 year old observed to be on the 3rd centile for height, spanned the 2nd-4th centile. However, the confidence interval for a 12 month height velocity appropriate to such a child spanned the 8th-52nd centiles, the lower limit pathological and the upper more than satisfactory. A single height velocity even over 12 months therefore lacks the precision to provide a reliable index of current growth in short children. Furthermore, serial height velocity calculations on a cohort of 78 short normal children showed no significant correlation from year to year, suggesting that velocity is also unable to predict future growth. Although the proportion of this cohort of short children lying beneath the 25th centile for velocity remained constant from year to year, the identity of the individuals comprising that proportion changed, a phenomenon which could be largely accounted for by the random error associated with height velocity. Our data suggest that, by the time a trend in abnormal velocity is reliably established, a deviation from the height centiles is clearly evident. Although velocity charts are attractive in concept, they seem to be no more discriminating than height charts in practice, and may be clinically deceptive unless interpreted with great care.

The relationship between short stature and school performance was examined by comparing an unselected cohort of 140 'normal' short children (below 3rd centile) aged between 7 and 9 years with 140 control children of normal height (10th-90th centiles). The short children had unimpaired self-esteem and normal patterns of behaviour, but a tendency towards hyperactivity and poor concentration. Their IQ scores were normal, but attainment, especially in reading, was low. The underachievement observed in the short children is largely due to the low socio-economic status of this group. All the children in the study were prepubertal and these data will serve as a baseline for further follow-up during and after puberty.

The relationship between insulin autoantibodies (IAA) and pancreatic islet cell histology was examined in 71 diabetes prone BB rats from the Toronto colony. Twenty-seven of the 71 became diabetic and of these, 18 (67%) were IAA positive by ELISA. IAA were also detected in 39/44 (89%) which did not develop diabetes, but in none of six control animals at 50-140 days of age. All 27 which became diabetic showed some evidence of lymphocytic infiltration scored + to ++++ histometrically and 26/27 evidence of beta cell degranulation. The frequency of diabetes increased with both intensity of insulitis and degree of beta cell degranulation, but there was no correlation between either and IAA. IAA are a marker for the BB strain of Wistar rat, but do not correlate with islet cell histology and do not predict clinical diabetes.

The two major components of reliability are accuracy and reproducibility. Three studies of the reliability of height measurement in children are reported. In the first, a standard metre rod was used to spot check the accuracy of installation of 230 measuring instruments in one health district in Wessex, UK. The readings obtained ranged from 90.0 to 108.5 cm and showed the urgent need for the positioning of instruments to be regularly checked. In a second study, to examine the reproducibility of height measurement, two experienced observers measured 10 young children (106.0 to 152.0 cm), three times on five instruments of different design. The observations were blind and in random order. The estimated standard deviation for a single height measurement was generally in the range 0.2-0.3 cm. Over 95% of the variance was attributable to the child, very little to the instrument or observer. Finally, the conditions of the second study were modified to examine the effect on reproducibility of non-blind and non-randomised measurements, as usually occurs in the clinic. A lower but inevitably false estimate of the error was obtained. It is recommended that the error of height measurement, appropriately established and expressed in simple terms, be stated in every published growth study.

The discovery in 1956 of the long-acting thyroid stimulator of Graves' disease, now known as thyroid-stimulating antibodies, was seminal. A new mechanism for disease was revealed that appears applicable to virtually all endocrine systems, involving the growth as well as the function of endocrine cells. An endocrine gland may fail through at least three autoimmune mechanisms: destruction, atrophy, and inhibition of function. Destruction is probably irreversible but is not usually distinguishable clinically from receptor blockade causing atrophy or from metabolic unresponsiveness. The contribution made by receptor autoimmunity to endocrine diseases other than thyroid disease is at present unclear, but with immunologic manipulation it is potentially reversible, improving the replicative capacity of the gland, its metabolic responsiveness, or both.

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.

We recently described autoantibodies that stimulate the release of insulin from pancreatic beta-cells both in vitro and in vivo. The aim of this study was to establish whether islet cell-stimulating antibodies (ICSTAs) also increase islet cell preproinsulin mRNA content. Wistar rat islets, isolated by collagenase digestion, were exposed to 2.7 and 11.1 mM glucose. Insulin release increased 10-fold in response to the higher glucose concentration, and dot-blot analysis of islet mRNA with a rat preproinsulin cDNA probe showed a concomitant increase in mRNA levels. The globulin fractions of four test serums, three from patients with type I (insulin-dependent) diabetes and one from a patient with the insulin autoimmune syndrome, showed clear (5- to 8-fold) stimulation of insulin release. The nonglobulin fractions of these serums and both fractions of three control serums failed to stimulate secretion of insulin. The insulin mRNA content of islets incubated with the ICSTA globulin fractions was greatly increased compared with levels observed in islets treated with control serum globulin fractions. We conclude that ICSTAs not only can stimulate the release of insulin but also increase the preproinsulin mRNA content of islet cells.