Search

Tubulointerstitial nephritis is a common cause of kidney failure and may have diverse etiologies. This form of nephritis is sometimes associated with autoimmune disease, but the role of autoimmunemechanisms in disease development is not well understood. Here, we present the cases of three patients with autoimmune polyendocrine syndrome type 1 who developed tubulointerstitial nephritis and ESRD in association with autoantibodies against kidney collecting duct cells. One of the patients developed autoantibodies targeting the collecting duct-specificwater channel aquaporin 2, whereas autoantibodies of the two other patients reacted against the HOXB7 or NFAT5 transcription factors, which regulate the aquaporin 2 promoter. Our findings suggest that tubulointerstitial nephritis developed in these patients as a result of an autoimmune insult on the kidney collecting duct cells.

Autoimmune polyendocrine syndrome type 1 (APS1) is a rare monogenic autoimmune disorder caused by mutations in the autoimmune regulator (AIRE) gene. High-titre autoantibodies are a characteristic feature of APS1 and are often associated with particular disease manifestations. Pituitary deficits are reported in approximately 7% of APS1 patients, with immunoreactivity to pituitary tissue frequently described. Using APS1 patient serum to immunoscreen a pituitary cDNA expression library, testis specific, 10 (TSGA10) was isolated. Immunoreactivity against TSGA10 was detected in 5/99 (5.05%) patients with APS1, but also in 5/135 (3.70%) systemic lupus erythematosus (SLE) patients and 1/188 (0.53%) healthy controls. TSGA10 autoantibodies were not detected in the serum from patients with any other autoimmune disease. Autoantibodies against TSGA10 were detectable from a young age in 4/5 positive APS1 patients with autoantibody titres remaining relatively constant over time. Furthermore, real-time PCR confirmed TSGA10 mRNA to be most abundantly expressed in the testis and also showed moderate and low expression levels throughout the entire body. TSGA10 should be considered as an autoantigen in a subset of APS1 patients and also in a minority of SLE patients. No recognizable clinical phenotype could be found to correlate with positive autoantibody reactivity.

Chronic mucocutaneous candidiasis (CMC) is frequently associated with T cell immunodeficiencies. Specifically, the proinflammatory IL-17A–producing Th17 subset is implicated in protection against fungi at epithelial surfaces. In autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED, or autoimmune polyendocrine syndrome 1), CMC is often the first sign, but the underlying immunodeficiency is a long-standing puzzle. In contrast, the subsequent endocrine features are clearly autoimmune, resulting from defects in thymic self-tolerance induction caused by mutations in the autoimmune regulator (AIRE). We report severely reduced IL-17F and IL-22 responses to both Candida albicans antigens and polyclonal stimulation in APECED patients with CMC. Surprisingly, these reductions are strongly associated with neutralizing autoantibodies to IL-17F and IL-22, whereas responses were normal and autoantibodies infrequent in APECED patients without CMC. Our multicenter survey revealed neutralizing autoantibodies against IL-17A (41%), IL-17F (75%), and/ or IL-22 (91%) in >150 APECED patients, especially those with CMC. We independently found autoantibodies against these Th17-produced cytokines in rare thymoma patients with CMC. The autoantibodies preceded the CMC in all informative cases. We conclude that IL-22 and IL-17F are key natural defenders against CMC and that the immunodeficiency underlying CMC in both patient groups has an autoimmune basis.

Autoimmune polyendocrine syndrome type I (APS-I) is a monogenic model disease of autoimmunity. Its hallmarks are chronic mucocutaneous candidosis, hypoparathyroidism and adrenal insufficiency, but many other autoimmune disease components occur less frequently. The first components usually appear in childhood, but may be delayed to adolescence or early adult life. There is enormous variation in presentation and phenotype, which makes the diagnosis difficult. Antibodies against interferon-omega and -alpha have recently been shown to be sensitive and relatively specific markers for APS-I, and mutational analysis of the autoimmune regulator gene gives the diagnosis in >95% of cases. The treatment and follow-up of patients is demanding and requires the collaboration of specialists of several fields. However, the literature is especially sparse regarding information on treatment and follow-up; hence, we present here a comprehensive overview on clinical characteristics, treatment and follow-up based on personal experience and published studies.

The clinical and metabolic aspects of hereditary fructose intolerance (HFI) are reviewed and some new observations on children with HFI are reported. The acute rise in plasma FFA level which was earlier shown to follow an acute exposure to fructose in these patients, was found to be associated with an increase in epinephrine excretion and a decrease in plasma TG level. Abolition of the fructose induced hypoglycemia by an infusion of glucose after injection of fructose prevented the rise in plasma FFA, but did not modify the increase in plasma lactate or urate concentration. Maintaining normal or high plasma inorganic phosphate levels after fructose injection by infusion of phosphate buffer did not alter the fructose-induced changes in blood glucose or lactate, or in plasma FFA or urate concentration. The hyperuricemia and hyperuricosuria after fructose were larger in HFI patients than in normal children. Administration of fructose in the small doses of 0.33-1.3 g/kg daily for 3–5 days brought about a gradual fall in plasma cholesterol level, and a rise in the excretion of urate and 17-ketogenic steroids, but no increase in proteinuria.

BACKGROUND: Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED, APS1) is an autosomal recessive disease exceptionally common in Finland. Most patients have chronic oral candidiasis from early childhood and this infection has been shown to be carcinogenic. Hence, patients receive repeated treatment and prophylactic courses of antifungals throughout life. In Finland, 92 patients have been diagnosed with APECED and 66 of them are currently alive. Our aim was to study the effect of long-term azole treatment on the candidal colonization of APECED patients and the influence on antifungal susceptibilities. METHODS: We evaluated the culture reports from 1994 to 2004 of 56 APECED patients followed in Helsinki University Central Hospital. Candida albicans strains of all 11 patients initially reported resistant (n = 27) and 12 patients reported susceptible (n = 16) to fluconazole were re-analysed for their susceptibility to fluconazole. Antifungal usage was analysed up to 30 years back. RESULTS: A total of 162 fungal cultures had been performed. Of these, 75% had been reported positive for Candida and 63% for C. albicans. Eleven patients (31.4%) had been reported to harbour at least once a C. albicans strain resistant to fluconazole. Re-analysis of the stored C. albicans strains originally reported to be resistant to fluconazole revealed a mean MIC of 19.5 mg/L. CONCLUSIONS: Multiple courses (>6) of fluconazole annually and low dose prophylaxis are major risk factors for persistent colonization with C. albicans with decreased susceptibility in APECED patients.

Context: Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy is known as a rare hereditary disease with classic triad of mucocutaneous candidiasis, hypoparathyroidism, and adrenocortical failure, two of which, diagnostic dyad, are required for the diagnosis. Evidently many patients suffer unrecognized because the condition is more variable and complex. Objective: The objective of the study was to describe the variability of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy for promoting recognition and adequate follow-up of patients. Setting: The Finnish series of patients is the largest internationally. Patients: The study population was all 91 known Finnish patients. Results: Besides the classical triad, a dozen autoimmune endocrine and other components occurred variably, several of them dangerous. The initial manifestation appeared within the age range of 0.2–18 yr, mucocutaneous candidiasis being part of it in 60% of the patients, hypoparathyroidism in 32%, and adrenocortical failure in 5%. But 23% of the patients had one to six other components before the diagnostic dyad: hepatitis, keratoconjunctivitis, chronic diarrhea, periodic rash with fever. The dyad appeared 0.2–20 yr later. Prevalence of most components increased with age, diabetes mellitus, hypothyroidism, and testicular failure becoming common toward middle age. Tubulointerstitial nephritis occurred in 9% of the patients, apparent mineralocorticoid excess in 9%, asplenia in 19% of adults, and oral or esophageal squamous cell carcinoma in 10% of patients older than 25 yr. Conclusions: Any child or young adult with one of the many disease components should be examined for others and consideration of AIRE mutation assay.

Summary Objective Autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED) is characterized by chronic mucocutaneous candidiasis and autoimmune destruction of endocrine organs. The resulting endocrinopathies and their treatment may impact bone health. The purpose of our study was to assess bone health and its correlates in adult patients with APECED. Patients and methods Twenty-five adults (12 males) with APECED were prospectively assessed. Data on their previous medical history were collected from hospital records. Areal bone mineral density (aBMD) for the lumbar spine (L1–L4), femoral neck and whole body as well as volumetric BMD (vBMD) for the lumbar spine (L2–L4) were measured with dual-energy X-ray absorptiometry (DXA). Results Mean age was 34 years (range 21–59 years). All patients had 1–4 autoimmune endocrinopathies, the most common being adrenocortical failure (20 patients) and hypoparathyroidism (18 patients). Osteopaenia or osteoporosis was present in 28%. The median (range) aBMD Z-scores were for the lumbar spine −0·3 (−2·3 to +3·3) and for the femoral neck, −0·1 (−2·2 to +2·0). The BMD Z-scores tended to be higher in patients with hypoparathyroidism than in patients with normal parathyroid function (at the lumbar spine +0·4 vs.–1·2, P = 0·016, and at the femoral neck +0·3 vs.−0·4, P = 0·090). Adrenocortical failure had a negative impact on BMD. Six patients had had low-impact fractures and three were diagnosed with compression fractures. Conclusions Despite the complex endocrine problems, the overall prevalence of symptomatic osteoporosis is low in adults treated for APECED. Osteopaenia is frequently observed and warrants follow-up. Treated hypoparathyroidism may have a positive, and adrenocortical failure a negative, impact on bone health.

The prevalence of autoantibodies against nine intracellular enzyme autoantigens, namely 21-hydroxylase, side-chain cleavage enzyme (SCC), 17 alpha-hydroxylase, glutamic acid decarboxylase 65, aromatic L-amino acid decarboxylase, tyrosine phosphatase-like protein IA-2, tryptophan hydroxylase (TPH), tyrosine hydroxylase, cytochrome P450 1A2, and against the extracellular calcium-sensing receptor, was assessed in 90 patients with autoimmune polyendocrine syndrome type I. A multivariate logistic regression analysis was performed for the presence of autoantibodies as independent predictors for different disease manifestations. Reactivities against 21-hydroxylase and SCC were associated with Addison's disease with odds ratios (ORs) of 7.8 and 6.8, respectively. Hypogonadism was exclusively associated with autoantibodies against SCC with an OR of 12.5. Autoantibodies against tyrosine phosphatase-like protein IA-2 were associated with insulin-dependent diabetes mellitus with an OR of 14.9, but with low sensitivity. Reactivities against TPH and, surprisingly, glutamic acid decarboxylase 65, were associated with intestinal dysfunction, with ORs of 3.9 and 6.7, respectively. TPH reactivity was the best predictor for autoimmune hepatitis, with an OR of 27.0. Hypoparathyroidism was not associated with reactivity against any of the autoantigens tested. No reactivity against the calcium-sensing receptor was found. Analysis of autoantibodies in autoimmune polyendocrine syndrome type I patients is a useful tool for establishing autoimmune manifestations of the disease as well as providing diagnosis in patients with suspected disease.

The clinical picture and course of APS-I or APD-I/APECED is widely variable: the list of possible disease components includes some 30 disorders. The initial manifestation may not include any of the known characteristic components, namely, mucocutaneous candidiasis, hypoparathyroidism, or adrenocortical insufficiency. Although mutation detection is available, it does not help to exclude this disease. Diagnostic strategy needs to be based on knowledge of the clinical picture, including the features of ectodermal dystrophy.

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is caused by lack of functional products of the autoimmune regulator gene located on chromosome 21q22.3. The patients are at high risk of developing insulin-dependent (type 1) diabetes, but the positive predictive value of GAD65 or islet cell antibodies for type 1 diabetes is only 27%. Autoantibodies against the IA-2 tyrosine phosphatase-like protein (IA-2 ab) or insulin (IAA) have been suggested to be better markers for active ss-cell destruction. We studied these antibodies in sera from 60 Finnish patients with APECED, 12 of whom subsequently developed type 1 diabetes. Four (36%) of the 11 patients for whom we had prediabetic samples had IA-2 ab, and 4 (36%) had IAA. None of the 48 nondiabetics had IAA, and only 2 (4%) had IA-2 ab. Both had the antibodies for years without diabetes. Thus, IA-2 ab or IAA have a low sensitivity (36%), but high specificity (96% or 100%), with a positive predictive value of 67% for type 1 diabetes in patients with APECED. Data for human leukocyte antigen haplotypes were available for 59 of the patients, including 11 diabetics, and for 8 additional nondiabetic Finnish patients. No association between type 1 diabetes and high risk genotypes was seen. None of the 11 patients with type 1 diabetes, but 15 of the 56 (27%; P: < 0.05) nondiabetic patients and 24 of 93 (26%; P: < 0.05) of the control subjects had the DQB1*0602 allele, which is considered protective for type 1 diabetes. This is remarkable, as previously no positive or negative associations have been reported for any disease components of APECED with human leukocyte II antigens.

Autoimmune polyendocrine syndrome type I (APS I) is characterized by autoantibodies, often directed towards tissue-specific enzymes in the affected organs. We have earlier reported the identification of tryptophan hydroxylase (TPH) and tyrosine hydroxylase (TH) as autoantigens in APS I associated with intestinal dysfunction and alopecia, respectively. These two enzymes, together with phenylalanine hydroxylase (PAH), constitute the group of biopterin-dependent hydroxylases, which all are involved in the biosynthesis of neurotransmitters. A clone encoding PAH was used for in vitro transcription/translation, followed by immunoprecipitation with sera from 94 APS I patients and 70 healthy controls. Of the APS I patients, 25% had PAH antibodies, and no reactivity was detected in the controls. No association with the main clinical components of APS I was found with PAH antibodies. Altogether, 59 sera from the 94 APS I patients reacted with at least one of TPH, TH, or PAH, whereas 35 showed no reactivity. Nineteen of the sera contained antibodies towards all enzymes, 12 to TPH only and 12 to TH only. No sera showed antibodies that reacted to only PAH. An immunocompetition assay demonstrated that the reactivity against PAH represents a cross-reactivity with TPH, whereas antibodies against TPH and TH are directed towards epitopes unique for the two enzymes.

The extent to which an individual maintains his position relative to the rest of the population is called tracking. The objective of this study was to examine the effect of the apolipoprotein E (apoE) phenotype on the tracking of serum cholesterol and lipoproteins from birth to the age of 11 y. In a longitudinal follow-up study of healthy children, concentrations of total serum cholesterol and triglyceride were determined at birth (n = 193), and at the ages of 2 (n = 192), 4 (n = 192), 6 (n = 190), 9 (n = 188), and 12 mo (n = 196), and 5 (n = 162) and 11 y (n = 153). Concentrations of total HDL, HDL2, and HDL3, VLDL, and LDL cholesterol were determined at 2, 6, 9, and 12 mo (n = 36), and 5 (n = 162) and 11 y (n = 153). The apoE phenotype was determined in 151 children. The children had the following apoE phenotypes: 4 had type 4/4 and 40 type 3/4 (group apoE4), 94 had type 3/3 (group apoE3), and 11 had type 2/3 and 2 type 2/4 (group apoE2). The correlation coefficients for total cholesterol levels during childhood compared with the level at 11 y of age were: 0.03 at birth, 0.26 (p < 0.001) at 2 mo, 0.24 (p < 0.001) at 4 mo, 0.24 (p < 0.001) at 6 mo, 0.28 (p < 0.001) at 9 mo, 0.41 (p < 0.001) at 12 mo, and 0.60 (p < 0.001) at 5 y. When the children were divided into three groups according to their apoE phenotypes, these three groups had the following correlation coefficients at 4 mo, 12 mo, or 5 y of age compared with the level at the age of 11 y; group apoE2: r = 0.65 (p < 0.01), r = 0.59 (p < 0.01), and r = 0.72 (p < 0.01); group apoE3: r = 0.27 (p < 0.01), 0.43 (p < 0.001), and r = 0.64 (p < 0.001); and group apoE4: r = 0.14 (p = NS), r = 0.33 (p < 0.05), and 0.42 (p < 0.01). The apoE phenotype also strongly influenced the tracking of the LDL cholesterol levels; the correlation coefficients between 5 and 11 y of age were for group apoE2 r = 0.84 (p < 0.001), for group apoE3 r = 0.70 (p < 0.001), and for group apoE4 r = 0.37 (p < 0.05). Our results indicate that the apoE phenotype strongly influences the tracking of lipids. The children having apoE 2/3, 2/4, and 3/3 phenotypes maintained their relative cholesterol and lipoprotein levels better than the others throughout the first 11 y of age. Because the apoE phenotype strongly affects the tracking of serum cholesterol, the usefulness of cholesterol screening in predicting future cholesterol values should be analyzed, keeping the apoE phenotype in mind.

Interstitial lung disease (ILD) is a complex and heterogeneous disorder that is often associated with autoimmune syndromes. Despite the connection between ILD and autoimmunity, it remains unclear whether ILD can develop from an autoimmune response that specifically targets the lung parenchyma. We examined a severe form of autoimmune disease, autoimmune polyglandular syndrome type 1 (APS1), and established a strong link between an autoimmune response to the lung-specific protein BPIFB1 (bactericidal/permeability-increasing fold-containing B1) and clinical ILD. Screening of a large cohort of APS1 patients revealed autoantibodies to BPIFB1 in 9.6% of APS1 subjects overall and in 100% of APS1 subjects with ILD. Further investigation of ILD outside the APS1 disorder revealed BPIFB1 autoantibodies present in 14.6% of patients with connective tissue disease-associated ILD and in 12.0% of patients with idiopathic ILD. The animal model for APS1, Aire⁻/⁻ mice, harbors autoantibodies to a similar lung antigen (BPIFB9); these autoantibodies are a marker for ILD. We found that a defect in thymic tolerance was responsible for the production of BPIFB9 autoantibodies and the development of ILD. We also found that immunoreactivity targeting BPIFB1 independent of a defect in Aire also led to ILD, consistent with our discovery of BPIFB1 autoantibodies in non-APS1 patients. Overall, our results demonstrate that autoimmunity targeting the lung-specific antigen BPIFB1 may contribute to the pathogenesis of ILD in patients with APS1 and in subsets of patients with non-APS1 ILD, demonstrating the role of lung-specific autoimmunity in the genesis of ILD.

Almost all patients with autoimmune polyendocrine syndrome (APS)-I have high titer neutralizing autoantibodies to type I interferons (IFN), especially IFN-ω and IFN-α2, whatever their clinical features and onset-ages. About 90 % also have antibodies to interleukin (IL)-17A, IL-17F and/or IL-22; they correlate with the chronic mucocutaneous candidiasis (CMC) that affects ~90 % of patients. Our aim was to explore how early the manifestations and endocrine and cytokine autoantibodies appear in young APS-I patients. That may hold clues to very early events in the autoimmunization process in these patients.Clinical investigations and autoantibody measurements in 13 APS-I patients sampled before age 7 years, and 3 pre-symptomatic siblings with AIRE-mutations in both alleles.Antibody titers were already high against IFN-α2 and IFN-ω at age 6 months in one sibling-8 months before onset of APS-I-and also against IL-22 at 7 months in another (still unaffected at age 5 years). In 12 of the 13 APS-I patients, antibody levels were high against IFN-ω and/or IL-22 when first tested, but only modestly positive against IFN-ω in one patient who had only hypo-parathyroidism. Endocrine organ-specific antibodies were present at age 6 months in one sibling, and as early as 36 and 48 months in two of the six informative subjects.This is the first study to collate the onset of clinical features, cytokine and endocrine autoantibodies in APS-I infants and siblings. The highly restricted early autoantibody responses and clinical features they show are not easily explained by mere loss of broad-specific self-tolerance inducing mechanisms, but hint at some more sharply focused early event(s) in autoimmunization.

Our aim was to ascertain the adequacy of human milk as the sole source of vitamin B6 and the associations between maternal and infant status during extended exclusive breast-feeding. Vitamin B6 status was followed in lactating mothers and their exclusively breast-fed infants by determinations of erythrocyte pyridoxal 5'-phosphate concentration and the erythrocyte aspartate transaminase stimulation test at 2 months (n = 118), 4 months (n = 118), 6 months (n = 112), 7.5 months (n = 70), 9 months (n = 36), 10 months (n = 14), 11 months (n = 11), and 12 months (n = 7) postpartum. Of the mothers, 54% had used vitamin B6 supplement during pregnancy, and all received a pyridoxine hydrochloride supplement of 1 mg/day throughout lactation. The infants had a higher vitamin B6 status than their mothers. During the first 4 months, infant vitamin B6 status was generally adequate independently of the actual vitamin status of the nursing mother. Most of the infants with low status at 2 months were those born to mothers who were not supplemented during pregnancy. By 6 months of exclusive breast-feeding, 30% of cases of low vitamin B6 status in nursing mothers were reflected in their infants. Thereafter, the risk of low vitamin B6 status in exclusively breast-fed infants increased even if the mother's status was adequate. Our findings suggest that gestationally accumulated stores are important for the maintenance of adequate vitamin B6 status of infants during the early months and that for some infants, human milk alone, without supplementary foods, may be insufficient to meet vitamin B6 needs after 6 months of age.

In a follow up study of 34 patients with premature adrenarche we examined serum adrenal androgen levels and growth. The majority (28/34) showed an upward bend in the growth curve which, at the mean age of 2.3 years, preceded other signs of adrenarche on average by 3.8 years. Pubertal growth spurt was missing or reduced in 50% of the patients (8/16), however, final height did not differ from that expected from parental heights. Adrenal androgens did not remain elevated at adolescence. The mean age at menarche for all the girls was 0.5 years younger than in the general population. Our findings imply that premature adrenarche may start earlier than previously recognized. Compared to ordinary growth these children seen to use a greater part of their potential for adult height already at that early age.

usc Autoimmune polyendocrine syndrome type 1 (APS-1) is a multiorgan autoimmune disease caused by mutations in the autoimmune regulator (AIRE) gene. Chronic mucocutaneous candidiasis, hypoparathyroidism and adrenal failure are hallmarks of the disease. The critical mechanisms causing chronic mucocutaneous candidiasis in APS-1 patients have not been identified although autoantibodies to cytokines are implicated in the pathogenesis. To investigate whether the Th reactivity to Candida albicans (C. albicans) and other stimuli was altered, we isolated PBMC from APS-1 patients and matched healthy controls. The Th17 pathway was upregulated in response to C. albicans in APS-1 patients, whereas the IL-22 secretion was reduced. Autoantibodies against IL-22, IL-17A and IL-17F were detected in sera from APS-1 patients by immunoprecipitation. In addition, Aire-deficient (Aire 0/0 ) mice were much more susceptible than Aire +/+ mice to mucosal candidiasis and C. albicans-induced Th17- and Th1-cell responses were increased in Aire 0/0 mice. Thus an excessive IL-17A reactivity towards C. albicans was observed in APS-1 patients and Aire 0/0 mice. Refereed/Peer-reviewed

The effect of exclusive lactation on lipid levels was investigated by evaluating serum concentrations of total and lipoprotein cholesterol, triglyceride (TG), and apoprotein (apo) B in mothers during and after exclusive, prolonged lactation. Serum total cholesterol concentrations were measured at delivery (n = 195), at 2 (n = 165), 6 (n = 119), 9 (n = 74), and 12 months (n = 32) of lactation, and 2 months (n = 27) after ending this exclusive lactation. In a subgroup of 34 mothers, serum levels of very-low-density lipoprotein (VLDL), low-density lipoprotein (LDL), high-density lipoprotein 2 (HDL2), HDL3, and LDL apo B were determined at 2, 6, 9, and 12 months of lactation. The mean value of serum total cholesterol concentrations decreased from 6.2 +/- 0.12 (SEM; n = 195) at delivery to 4.8 +/- 0.1 mmol/L (n = 116) at 6 months of exclusive lactation (P < .001). The average decrement in total cholesterol level was 0.80 mmol/L (P < .001) from delivery to 2 months of lactation and 0.55 mmol/L (P < .001) from 2 to 6 months of lactation, and levels were stable thereafter. In the 27 mothers who were exclusively breast-feeding their infants at 9 months of lactation and whose serum cholesterol levels were measured 2 months after the end of lactation, cholesterol levels increased rapidly to 5.7 +/- 0.21 mmol/L (P = .001). In the subgroup of 34 mothers who were examined more closely, the course just described was also true for serum TG, LDL and VLDL cholesterol, and LDL apo B levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Fifty-nine tall girls were treated with oestrogen to reduce final height, starting at the ages of 9.1 to 16.2 years. We assessed the result of this treatment by comparison with matched controls. The epiphyseal bone age at the start of therapy, the final height, the Bayley-Pinneau (BP) and Roche-Wainer-Thissen (RWT) predictions of final height, and the errors in both predictions were evaluated. The matched pairs were divided into three groups according to bone age at the start of treatment; I less than 10.5 (n = 16), II 10.5-12.0 (n = 22) and III greater than 12.0 years (n = 21). The mean (SD) intrapair reduction of height for these groups was 9.7 (4.0) cm, 4.3 (4.3) cm and 3.5 (3.2) cm, respectively, according to BP predictions and 6.3 (4.3) cm, 3.4 (3.0) cm and 1.2 (3.3) cm according to RWT predictions. No method of predicting height is accurate for tall girls and simultaneous predictions may differ greatly. Close agreement between the BP and RWT predictions does not indicate greater accuracy. The earlier therapy is started, the greater is the effect. Young girls need psychosocial support with therapy.

The concentration of epidermal growth factor (EGF) in tear fluid (TF) was recently shown to decrease with increasing tear fluid flow (TFF). The purpose of the present study was to clarify the effects of ocular surface disease on the TF EGF concentrations. Tear fluid samples (n = 243) were collected from diseased eyes by means of blunted glass capillaries. The time of collection was measured for each sample, and the tear fluid flow in the capillaries (TFFc) was calculated. The concentration of human EGF (hEGF) was determined using a time-resolved immunofluorometric assay (TR-IFMA). For statistical analysis diagnosis-dependent multigrouping was performed and the data of the patient groups were compared to the data for a control group. The control material consisted of 271 TF samples collected from healthy eyes before (n = 59) and after stimulation of reflex tearing (n = 212). It was shown that TF specimens of patients (n = 243) contained significantly (p less than 0.001) less EGF (mean 952 pg/ml) than the TF of healthy control individuals before (n = 59 samples; mean 6589 pg/ml) or after stimulation of reflex tearing (n = 212 samples; mean 2762 pg/ml). The EGF concentration of every patient group was significantly lower than that found in the TF of control individuals both before and during reflex tearing (p less than 0.001). The rate of EGF released with TF during collection did not differ significantly between the various groups of patients or from that released with the TF of normal individuals before induction of reflex tearing.(ABSTRACT TRUNCATED AT 250 WORDS)

Patients with the autoimmune polyendocrine syndrome I (APS I) have high titers of neutralizing IgG autoantibodies against type I interferons (IFNs), in particular IFN-omega. Until now, the most specific assay has been the antiviral interferon neutralizing assay (AVINA), which has the drawbacks of requiring a cytolytic virus, being cumbersome and difficult to standardise. We have developed a fast and reliable immunoassay based on radiolabelled IFN-omega for quantifying anti-IFN-omega antibodies. Sera from 48 APS I patients were analysed together with those from 5 control groups. All sera from APS I patients were positive for anti-IFN-omega, while, except one serum, all sera from the controls were negative. This method has the advantage over bioassays that it is readily adapted to high throughput. It provides an alternative, sensitive and specific diagnostic test for APS I, and an ideal screening tool to precede mutational analyses of the AIRE gene in suspected APS I cases.

usc Background: Autoimmune polyendocrine syndrome type 1 (APS-1) is a multiorgan autoimmune disorder caused by mutations in AIRE, the autoimmune regulator gene. Though recent studies concerning AIRE deficiency have begun to elucidate the molecular pathogenesis of organ-specific autoimmunity in patients with APS-1, the autoantigen responsible for hypoparathyroidism, a hallmark of APS-1 and its most common autoimmune endocrinopathy, has not yet been identified. Methods: We performed immuno screening of a human parathyroid complementary DNA library, using serum samples from patients with APS-1 and hypoparathyroidism, to identify patients with reactivity to the NACHT leucine-rich-repeat protein 5 (NALP5). Subsequently, serum samples from 87 patients with APS-1 and 293 controls, including patients with other autoimmune disorders, were used to determine the frequency and specificity of auto antibodies against NALP5. In addition, the expression of NALP5 was investigated in various tissues. Results: NALP5-specific auto antibodies were detected in 49% of the patients with APS-1 and hypoparathyroidism but were absent in all patients with APS-1 but without hypoparathyroidism, in all patients with other autoimmune endocrine disorders, and in all healthy controls. NALP5 was predominantly expressed in the cytoplasm of parathyroid chief cells. Conclusions: NALP5 appears to be a tissue-specific auto antigen involved in hypoparathyroidismin patients with APS-1. Auto antibodies against NALP5 appear to be highly specific and may be diagnostic for this prominent component of APS-1. Refereed/Peer-reviewed

To define the clinical picture and course of the autosomal recessive disease called autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), we report data from our 10-month to 31-year follow-up of 68 patients from 54 families, now 10 months to 53 years of age. The clinical manifestations varied greatly and included from one to eight disease components, 63 percent of the patients having three to five of them. The initial manifestation was oral candidiasis in 41 patients (60 percent), intestinal malabsorption in 6 (9 percent), and keratopathy in 2 (3 percent). All the patients had candidiasis at some time. The earliest endocrine component appeared at 19 months to 35 years of age. Hypoparathyroidism was present in 54 patients (79 percent), adrenocortical failure in 49 (72 percent), and gonadal failure in 15 (60 percent) of the female patients greater than or equal to 13 years of age and 4 (14 percent) of the male patients greater than or equal to 16 years of age. There were multiple endocrine deficiencies in half the patients. From 4 to 29 percent of the patients had periodic malabsorption, gastric parietal-cell atrophy, hepatitis, alopecia, vitiligo, or a combination of these conditions. Dental-enamel hypoplasia and keratopathy were also frequent but were not attributable to hypoparathyroidism. In the patients whose initial manifestation (other than candidiasis) was adrenal failure, the other components developed less often than in the remaining patients. We conclude that the clinical spectrum in patients with APECED is broad. The majority of patients have three to five manifestations, some of which may not appear until the fifth decade. Therefore, all patients need lifelong follow-up for the detection of new components of the disease.

As part of our work aiming at facilitation of growth screening, we analyzed the growth of 741 healthy infants from birth to 2 years of age. We 1) show that weight depends on length rather than age, 2) present new growth standards in a format which allows direct reading of relative length and relative weight, and 3) define the normal variation of changes over different periods in terms of relative length (SD score, SDS) and relative weight (deviation of weight from the median weight for length and sex, % DW). The group mean values for changes in length SDS and % DW were zero, but there were wide individual variations, which decreased with age and length. We present curves defining these variations for use in growth screening.

To provide for early detection of abnormal changes in growth, we propose the monitoring of all children for changes in relative height and relative weight as indirect indicators of growth velocity. To this end we analyzed the growth of 2,156 children, as recorded by the child health surveillance services at ages 2 to 19 years. From their data we constructed growth standards on charts of a novel type, which allow direct reading of relative height (SD score, SDS) and relative weight (percentage deviation of weight from median weight for height and sex, %DW). Variation in height explained most (mean 60%) of the variation in weight, and age did not contribute significantly. Hence, our weight charts are height-based. Next, we defined the variations of changes in (delta) SDS and %DW during the different periods of growth. The group means of changes in each period were zero. Variation in delta SDS is widest at the earliest ages, then decreases until year 9-10 (girls) and 10-11 (boys), and again increases. For delta %DW the picture is similar. We present these variations as diagrams for use in growth screening.

Pulsatile secretion of LH and FSH was examined in 10 prepubertal (aged 4.5-12.9 y) and seven early pubertal (aged 12.8-14.5 y) boys with ultrasensitive (0.019 and 0.014 IU/L) time-resolved immunofluorometric assays. Plasma LH and FSH levels were measured every 15 or 20 min for 6 h during the day and night. The lowest mean LH level in a prepubertal boy was 0.02 IU/L and in eight other prepubertal boys mean LH levels were less than 0.4 IU/L. In early pubertal boys the mean LH levels ranged from 0.3 to 6.5 IU/L. The difference in mean FSH level between prepubertal (0.61 IU/L) and early pubertal boys (1.85 IU/L) was smaller than the difference in LH level. All boys had significant LH and FSH pulses. The LH interpulse interval was 135 +/- 86 min (mean +/- SD) and 76 +/- 65 min for the prepubertal and pubertal boys, respectively (p less than 0.01). For FSH, the respective values were 150 +/- 122 and 221 +/- 157 min (p = NS). The mean LH pulse amplitudes were 11-fold greater in the early pubertal boys than in the prepubertal boys, whereas the mean FSH pulse amplitudes were similar between the two groups. The present method shows that the mean LH levels in prepubertal boys are much lower, and the increase during puberty larger, than previously reported. The increase is apparently due to increased pulse frequency and amplitude. The increase in mean FSH level is smaller and evidently not caused by an increase in pulse frequency or pulse amplitude.

The concentrations of plasmin and epidermal growth factor were determined in tear fluid (TF) samples from wearers of different types of contact lenses (CLs) during and after cessation of CL wear (CLW). TF samples of 50 healthy eyes served as controls. The plasmin concentrations in the control group (0.4 +/- 0.1 microgram/ml; mean +/- SEM) were significantly lower (p less than 0.001) than in the group of soft CL (SCL) wearers during CLW (1.2 +/- 0.2 microgram/ml). Cessation of CLW led to a decrease in TF plasmin concentrations from 1.2 +/- 0.2 to 0.6 +/- 0.1 micrograms/ml in the group of SCL wearers (p less than 0.001), from 1.5 +/- 1.1 to 0.3 +/- 0.2 micrograms/ml in the group of extended-wear SCL wearers (p greater than 0.05) and from 0.4 +/- 0.3 to 0.0 +/- 0.0 microgram/ml in the group of gas-permeable CL wearers (p greater than 0.05). After CLW cessation, TF plasmin levels of CL wearers did not differ from those of controls. The occurrence of plasmin in TF was associated with a higher degree of corneal neovascularization and with the presence of limbal injection. The concentrations of epidermal growth factor in TF were not significantly altered by the discontinuation of CLW.

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is an autosomal recessive disease exceptionally common in Finland. It is associated with a limited T lymphocyte defect, an autoimmune response to various tissues, particularly endocrine glands. Most patients have chronic oral candidosis, which has been suggested to be carcinogenic. In Finland 92 patients have been diagnosed with APECED and 66 of them are alive. Our aim was to study the possible association of APECED with oral and oesophageal carcinoma. We evaluated the medical histories of all 92 patients for morbidity, causes of death, and known risk factors for oral cancer. We invited all current patients for a clinical examination of their oral mucosa. Six of the 92 had developed oral or oesophageal squamous cell carcinoma (SCC) by the mean age of 37 (29-44years) and four of them had died from it. The six represent 10% of the patients older than 25years. Five of the six patients had long-lasting oral candidosis. Four of the six had smoked regularly for 15years or more. One patient had been on immunosuppressive therapy for 6years following kidney transplantation when SCC in her mouth occurred. The partial T cell defect of APECED seems to favour the growth of Candida albicans and predispose to chronic mucositis and SCC. Aggressive control of oral candidosis and close follow-up of oral mucosa is a necessity in patients with APECED.

In autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy, hypoparathyroidism (HP) is the most common endocrine component. It occurs in most (but not all) patients. Determinants of its occurrence are unknown, and there is no proof for its autoimmune nature. Recently, the Ca2+-sensing receptor (CaSR) was reported to be an autoantigen in HP. With our group of 90 patients, we aimed at identifying the determinants and pathomechanism of HP. For the determinants, we evaluated gender and the HLA class II. For the pathomechanism, we searched for parathyroid autoantibodies, including antibodies against CaSR and PTH. Also, we studied whether AIRE is expressed in the human parathyroid, because its absence could be a pathogenetic factor. We found a clear gender linkage with lower and later incidence in males. Of the 14 patients who had escaped HP, 13 were males. This was associated with adrenal failure, which was the first or only endocrinopathy in 47% of males vs. 7% of females. In contrast, we found no linkage to the HLA class II. By immunofluorescence, 19% of the patients had antibodies to parathyroid epithelia. By immunoblotting, these recognized several parathyroid proteins. No antibodies were observed against the CaSR or PTH. By RT-PCR, AIRE mRNA was not found in the parathyroid.

In the autosomal recessively inherited autoimmune polyendocrine syndrome type I (APS I) patients have autoantibodies directed against several endocrine and nonendocrine organs. Alopecia areata is present in about one-third of the patients and usually in the more severe forms, alopecia universalis or totalis. Sera from 39 patients with APS I, diluted 1:150, were used in indirect immunofluorescence staining of cryo-sections from normal human scalp. Two hair follicle staining patterns were observed. A cytoplasmic staining of the differentiating matrix, cuticle, and cortex keratinocytes in the anagen hair follicle was seen in five (13%) APS I sera. All these five patients had alopecia totalis, representing 63% of the eight patients with alopecia totalis (p < 0.0001). Furthermore, four (10%) of the APS I sera stained the nuclei of the melanocytes in the hair follicle. Two of these patients had vitiligo. None of 20 healthy control sera stained the keratinocyte cells or the melanocyte nuclei. These data show that many patients with APS I have high-titer autoantibodies directed against the anagen matrix, cuticle, and cortex keratinocytes and a melanocyte nuclear antigen, and also that the hair follicle keratinocyte staining is associated with alopecia, especially alopecia totalis. This study emphasizes the role of the differentiating anagen keratinocytes as an important structure in the autoimmune etiology of alopecia, both in APS I and at least in a subgroup of patients with alopecia areata unrelated to APS I.

Individualized ACTH treatment of the West syndrome (WS) was assessed in a prospective multicenter study, in which each patient's dosage was increased stepwise according to response. Our series included six patients with cryptogenic and 24 with symptomatic infantile spasms. During the treatment period the total ACTH dose ranged from 58 to 373 IU / kg. In the cryptogenic group one patient responded to pre-ACTH pyridoxine and four to the lowest dosage of ACTH (3 IU / kg daily) with cessation of spasms and good outcome; one patient needed the highest dosage (12 IU / kg daily) for cessation of seizures and became developmentally retarded. In the symptomatic group, 21 of the 24 patients needed 6–12 IU / kg daily; 12 became seizure-free or having infrequent non-IS fits. Complications such as arterial hypertension, cerebral ventricle dilatation, cardiac hypertrophy, and prolonged adrenocortical hyporesponsiveness were related to the dose. The individualization provides all the benefits of ACTH treatment with minimal side effects and cost.

To evaluate the association of autoimmunity to glutamic acid decarboxylase (GAD) with insulin-dependent diabetes mellitus (IDDM) and IDDM-associated human leukocyte antigen (HLA) types, we studied a unique group of 47 patients with autoimmune polyendocrine syndrome type 1, a recessive disease not associated with HLA. GAD65 antibodies (GAD65-Ab), GAD67-Ab, islet cell antibodies, and HLA-DQA1, -DQB1, and -DRB1 were analyzed in relation to IDDM or a decreased insulin secretory capacity. GAD65-Ab were found in six of the eight diabetic patients 0.9-8.0 yr before the onset of IDDM and in 16 (41%) nondiabetic patients during a follow-up of 2.4-19.5 yr. Eleven (28%) nondiabetic patients had GAD67-Ab and islet cell antibodies. Fasting C peptide (mean +/- SD, 0.5 +/- 0.24 vs. 1.03 +/- 0.49 nmol/L; P = 0.003) and first phase insulin response (75.6 +/- 37.9 vs. 166.4 +/- 112.7 mU/L; P = 0.019) were lower in patients with than in those without GAD65-Ab. No HLA genotype predominated in the IDDM patients or GAD65-Ab-positive nondiabetic patients, but the IDDM high risk genotypes were decreased in frequency among the patients with GAD65-Ab. In conclusion, nondiabetic autoimmune polyendocrine syndrome type 1 patients frequently have GAD65-Ab together with a decreased insulin secretory capacity, suggesting subclinical islet cell inflammation not invariably progressing to diabetes. This is not associated with HLA haplotypes conferring susceptibility to or protection from IDDM.

To evaluate the effect of vitamin B6 status on infant growth, we studied longitudinally anthropometry and the erythrocyte parameters that reflect long-term vitamin B6 status [erythrocyte pyridoxal 5'-phosphate concentration (EPLP), erythrocyte aspartate transaminase basal activity (EAST0), and its activation co-efficient (alpha EAST)] in 44 infants. The infants were exclusively breast-fed for 6 mo, given additional solids according a uniform schedule from 6-9 mo, and formula after 9 mo, if needed. In seven of these infants, a low vitamin B6 status (EPLP10th, and EAST010th or alpha EAST90th percentile for these values in reference infants) was observed between 4 and 6 mo of age. These seven infants showed slower length velocity (0.30 +/- 0.05 versus 0.40 +/- 0.02 mm/d, por = 0.02) and deeper fall in length-for-age (-0.69 +/- 0.20 versus -0.25 +/- 0.07 SD score, por = 0.03) from 6 to 9 mo of age than the similarly fed infants with higher vitamin B6 status. Preceding vitamin B6 status remained a significant explanatory factor for length velocity and change in length-for-age in addition to preceding and concomitant weight velocity, when sex, birth size, preceding length gain, and mid-parent height were taken into account. Change in weight-for-age alone explained 16% and 18% and, together with vitamin B6 status, 23 and 27% of the variation in length velocity and in change in length-for-age, respectively. Thus, in healthy breast-fed infants, according to our results, low vitamin B6 status is associated with reversibly reduced gain in length.

Background— Mulibrey nanism is a rare inherited disease characterized by growth failure and multiorgan manifestations, including constrictive pericarditis. Its long-term course, the results of pericardiectomy, and the details of myocardial involvement have not been reported previously. Methods and Results— We studied 49 patients (26 men) born before 1985 and followed for up to 25 years. By 1999, 25 patients (51%) had developed congestive heart failure (CHF), 19 (39%) had undergone pericardiectomy for constrictive pericarditis, 10 (22%) had died of cardiac causes, and 5 (10%) had died of noncardiac causes. Of the 19 pericardiectomized patients, 12 derived lasting clinical benefit, whereas 1 patient suffered an early noncardiac death and 6 died later of unrelieved or recurrent CHF. At echocardiography in 34 living patients, left ventricular mass adjusted for body height and weight averaged (±SEM) 149±5 g in 21 unoperated patients, 144±8 g in 13 pericardiectomized patients, and 104±7 g in 16 healthy persons matched for age and sex ( P =0.000). Autopsies of 11 patients showed fibrotic thickening of the pericardial leaves with myocardial hypertrophy and variable but mostly mild myocardial fibrosis. Endocardial thickening was seen in 3 patients. Conclusions— Constrictive pericarditis, myocardial hypertrophy, and variable myocardial fibrosis constitute the main elements of Mulibrey heart disease. At least one half of patients ultimately develop CHF. Pericardiectomy generally provides clinical benefit, but in approximately one third of patients, CHF may recur because of coexisting myocardial involvement.

To study the effect of type of feeding on infant vitamin B-6 status, we determined erythrocyte pyridoxal 5'-phos- phate concentration (EPLP) and erythrocyte aspartate amino- transferase basal activity (EASTO) and its activation coefficient (aEAST) in 109 infants at 2, 4, 6, 9, and 12 mo of age. Thirty- six infants were exclusively breast-fed for 9 mo. Forty-six infants were exclusively breast-fed for 6 mo, and then given solid foods in addition. Twenty-seven infants were weaned by 2-3 mo to an adapted cow milk-based formula (15 g proteinlL and 0.6 mg pyridoxinelL) and given solid foods from 3 to 4 mo. Infant vita- rain B-6 status was age-dependent; it was highest at 4 mo and thereafter gradually approached adult values. The larger the in- take of formula, the higher the vitamin B-6 status. In formula- fed infants at ages 2-6 mo, 71-96% of the EPLP values and 57-70% of the EASTO values were above the 95th percentile, and 35-53% of the aEAST values were below the 5th percentile for these values in breast-fed infants. These findings raise the question of whether the vitamin B-6 content of formulas, espe- cially in relation to protein content, should be reduced. Am J Clin Nutr l994;60:907-lO.

The effect of zinc supplementation of infant formula on zinc nutrition and growth of healthy infants was studied longitudinally from birth to age 12 mo. The zinc-supplemented group (n = 16) received the same formula as the unsupplemented group (n = 16) except for the addition of 61 mumol (4 mg) Zn/L as sulfate. After age 2 mo in the breast-fed and unsupplemented groups the mean serum zinc concentration remained stable at approximately 9.9 mumol/L. The zinc supplement increased the mean serum zinc concentration to 13.0 mumol/L by age 6 mo. With increasing intake of solid foods, the concentration fell by age 9 mo to the same concentration as in the other groups. The supplement did not increase the velocity of weight or length growth. In their growth the unsupplemented infants were not inferior to the breast-fed or zinc-supplemented infants.

We studied zinc nutrition in exclusively breast-fed infants whose growth deviated from the norm. Their number fell from 200 at birth to 116 at the age of 6 months and 36 at the age of 9 months. The mothers received 0, 20, or 40 mg Zn+ + as sulfate daily. Breast milk intake and concentrations of zinc in milk as well as in maternal and infant serum were measured. Individual zinc concentrations in milk showed channeling. The 20-mg supplement had no effect on the parameters measured. In contrast, 40 mg increased the maternal serum zinc concentration by 2 months and slowed the normal decline of milk zinc concentration by 6 months. Maternal supplementation had no effect on infant serum concen-trations; they remained lower than adult levels throughout the 1st year of life. Zinc intake was low (about one-tenth of RDA), but it seemed to be adequate; the serum concentrations of the infants were stable after the age of 2 months. Low zinc concentrations in serum were not associated with impaired growth. On the contrary, the infants with the highest rates of growth had the lowest zinc concentrations. The infant serum zinc concentrations were channeled, but they were also influenced by the zinc intake. Reference values for breast-fed infants are given.

Cartilage-hair hypoplasia is an osteochondrodysplasia with short-limbed short stature. The cartilage-hair hypoplasia gene is exceptionally prevalent in Finland; more than 100 patients have been identified. We have analyzed the growth of 100 Finnish patients and present cartilage-hair hypoplasia-specific growth charts of height and weight for height. The disproportions were analyzed by sitting height, subischial leg height, sitting height:height ratio, and span-height difference. The stature was short at birth with a mean relative length of −3.0 SD. The median adult height was 131.1 cm (-7.9 SD, range 110.7 to 149.0 cm) for 15 males and 122.5 cm (-7.9 SD, range 103.7 to 137.4 cm) for 20 females. The progression of the growth failure was partly explained by weakness or absence of pubertal growth spurt. Weight for height was above normal median in childhood and increased further at puberty. Most of the adults were overweight. The adults' mean relative head circumference was −0.9 SD. Growth was disturbed both in the limbs and in the spine, more severely in the limbs. Adult height showed no correlation with the midparent height. The charts are useful for assessment of growth, prediction of adult height, detection of superimposed disorders, and evaluation of growth-accelerating therapy.

As part of a prospective study of children with bacterial meningitis we analyzed in 36 patients of our hospital the fluid balance on admission and during the first three days of treatment. On admission 10 of them (28%) had inappropriate antidiuretic hormone secretion SIADH, 10 (28%) hypo-osmolal and 10 (28%) iso-osmolal contraction. Six patients (17%) had no clear fluid disorder. The patients with SIADH had significantly lower mean serum NA+ (127 vs. 132 mEq/l, p less than 0.01) and higher mean urine Na+ (111 vs. 26 mEq/l, p less than 0.01) concentration as well as higher mean urinary Na+/K+ ratio (2.23 vs. 0.365, p less than 0.005) than the patients with hypo-osmolal contraction. They also tended to be younger and have a shorter history of fever. The patients with SIADH had a less strict fluid restriction than the patients with hypo-osmolal contraction, and their fluid balance normalized more slowly. Our findings support initial water restriction for all children with bacterial meningitis.

Little attention has been paid to the possibility that the immunoprotection conferred by breast milk may vary from mother to mother and that in some cases the milk may even be deficient in protective factors, which might result, for instance, in the development of food allergy. An earlier study showed that milk samples from mothers whose infants showed symptoms suggestive of cow milk (CM) allergy had low total IgA contents and low levels of IgA antibodies to cow milk1.

We have studied the nutritional adequacy of exclusive breast-feeding by following prospectively the growth and protein nutrition of healthy infants during the 1st yr of life. The number of exclusively breast-fed infants was 116 at the age of 6 months and 36 at 9 months. These infants had slower length velocity after age 3 months than a comparison group of 32 infants who were weaned early and given formula plus solids. As a group, the exclusively breast-fed infants lagged slightly, but progressively, behind in relative length. By 9 months, 45% of them versus 18% of the comparison group showed a greater than 1 SD decrease in relative length. No such decrease was found in relative weight. Skinfolds and weight for length index showed that they were heavier for their length than the comparison infants. At 6 and 9 months the calculated protein intake (0.9 g/kg/day) was much less than the recommended amount (2.0 g/kg/day). Serum prealbumin concentration was lower than in the comparison group but this was noted as early as 4 months. No relation was found between the parameters of growth and protein nutrition either individually or in general. Whether the slower growth of the exclusively breast-fed infants represents appropriate physiological growth or whether it indicates nutritional deficiency is not known but we did not find any evidence of protein deficiency. Six infants did, however, show subsequent catch-up growth which could indicate previous malnutrition.

There is accumulating evidence that in adult men excessive amounts of gonadotropins induce testicular desensitization to further gonadotropin stimulus. We evaluated the effects of endogenous gonadotropins and of repeated doses of exogenous human chorionic gonadotropin (hCG) on steroidogenesis by studying prepubertal and pubertal boys. The boys received either two intramuscular injections of hCG 4 days apart (protocol I) or four injections at 3- to 4-day-intervals (protocol II). In protocol I, serum testosterone, 17 alpha-hydroxyprogesterone, and estradiol were measured basally and for 6 days after the second injection, and in protocol II, before each injection and 4 days after the last injection. In the prepubertal-boys, serum testosterone increased from very low basal levels to 10.3 (protocol I) and 8.3 nmol/liter (protocol II). In protocol I the increase after the first injection was 64-fold and in protocol II there was an increase after each injection to a final level 144-fold of the basal. No significant changes were seen in the estradiol levels. In the pubertal boys at genital stage G2, the serum testosterone levels increased after the first two injections, but at genital stage G3, the levels increased only after the first injection. Maximal testosterone increases were 27- and 8-fold, respectively. In pubertal boys estradiol levels increased progressively throughout the stimulation. The major testosterone response ws seen after the first dose of hCG and repeated doses, at least in the pubertal boys, increased estradiol but not testosterone levels, thus causing an estrogen-mediated 17,20-lyase block. We therefore suggest that a single-dose hCG test deserves further evaluation for diagnostic use.

Insulin test was given twice to each of 41 reference subjects and 31 hypopituitary patients to establish the most precise parameters of glucose and hormone responses, and the intra-individual dependence of these responses on each other. The precision was highest for the glucose response, intermediate for the cortisol and epinephrine responses and lowest for the GH response. The most precise parameters were: for blood glucose, recovery index, maximum per cent decrement, maximum absolute decrement and minimum level; for plasma cortisol, maximum level, post-insulin area and increment area; for plasma GH, maximum level and post-insulin area; and for epinephrine excretion, absolute post-insulin rate and absolute post-insulin increment. Unacceptably poor precision was established for some parameters in common use: the maximum and 60 min increments in cortisol and GH, and the per cent increment in epinephrine. The intra-individual correlations suggest differences in the mode of stimulation of the different hormone secretions in response to acute hypoglycaemia. While the cortisol response correlated best with the absolute glucose decrement, the epinephrine response correlated best with the absolute minimum glucose level. Per cent glucose decrement showed no correlation with the hormone responses. GH response showed no correlation with any parameter of acute hypoglycaemia. Prolonged hypoglyaemia leads to responses in cortisol, GH and epinephrine secretion. No intra-individual correlations were present between the responses of these hormones, but the basal cortisol level was correlated both with the basal rate and with the response in epinephrine excretion. For maximum clinical information strict standardization of the test procedure is necessary, with use of the most precise parameters of the responses. For plasma cortisol and GH responses the preferable parameters are the maximum levels. The cortisol maximum should be corrected for its dependence on the basal level, so increasing its precision. For the epinephrine response the absolute post-insulin rate of excretion is convenient and precise.

A girl with the oral-facial-digital syndrome type I (OFD I) developed precocious puberty at early infancy. This is presumed to be due to a hamartoma in the tuber cinereum region. Hypothalamic hamartomas have not been described in OFD I earlier, wheras lingual hamartomas are a common feature in this condition.

A longitudinal dietary Se supplementation study on lactating mothers was performed to determine the possibilities of improving the Se status of exclusively breast-fed infants. A total of 200 mothers randomized into three groups received either no Se supplements, 100 micrograms of selenite, or 100 micrograms of yeast-Se daily. Maternal and infant serum Se concentrations showed a linear correlation during exclusive breast-feeding. Yeast-Se in the dose administered was safe and more effective than selenite in increasing the Se concentrations of maternal serum and milk, and infant serum. The mean estimated daily Se intakes of the infants were 7.7 +/- 2.2, 8.9 +/- 2.2, and 11.5 +/- 4 micrograms, in the control, selenite, and yeast-Se groups respectively. Though the infant Se intakes of the unsupplemented and selenite-supplemented mothers were below the lower limit of the safe and adequate range as set by the US National Research Council, their serum Se concentrations increased steadily over the 6-mo study period. As maternal serum Se also increased by over 50% during the same period the results suggest that a maternal daily intake of 50-75 micrograms is adequate during lactation.

The heights of 59 patients with acromegaly and their first-degree relatives were studied. The mean height SD score (SDS) for the patients was 0.93±1.19 (equivalent to 5.6 cm above the population mean), and for their siblings (N=166) 0.39 ±1.05 (2.3 cm above the population mean) (P 2.0) patients had increased by 2.5-10 (mean 5) cm after normal cessation of growth. This explains the extra height of the patients over their siblings. Only 2 of the 13 patients became oversized for their families during the normal growth period. We suggest that in a part of the population with acromegaly the disease is associated with primary genetic tallness.

Different parameters of the response to the 5-day metyrapone test were evaluated for their diagnostic accuracy in tests given to 58 children and adolescents as part of an investigation for short stature. Insulin test, vasopressin test and ACTH test were used for diagnostic reference. A log transformation of the data was clearly appropriate. The maximal daily excretion of 17-ketogenic steroids was distinctly positively correlated with the basal excretion. Consequently, the most correct parameter of the response is the SD score of the deviation of the maximal excretion from the regression of the maximal excretion on the basal excretion in the reference population. This parameter, 'relative maximal excretion' was shown to be the diagnostically most accurate index of the response of 11 parameters studied.