Objectives: To describe the growth of children treated with growth hormone and to evaluate the prognostic factors for height at the end of treatment. Design: Register based cohort study. Setting: French national register of all children treated with growth hormone.

Few data are available on the reliability of measurements of adrenocortical and corticotroph hormones for use in clinical pharmacology. Two placebo controlled crossover trials in 20 normal healthy male subjects offered the opportunity to perform three repeat samplings of adrenocortical and corticotroph hormones at 1 to 5 week intervals during the placebo periods. Measurements of baseline levels of plasma, salivary and urinary cortisol, plasma adrenocorticotroph hormone (ACTH), lipotrophic hormone (LPH), ,-endorphin, post tetracosactrin levels of plasma and salivary cortisol, post corticotrophin releasing hormone (CRH)-lysine vasopressine (LVP) levels of plasma cortisol, ACTH and LPH; and post metyrapone levels of plasma cortisol and 11-deoxycortisol (compound S), ACTH, LPH, ,B-endorphin were performed in the same laboratory. The reliability of the measurements was estimated by computing the intraclass correlation coefficient (R) and by using Altman-Bland graphical method. The Rs of baseline parameters varied from 0.18 (for 08.00 h salivary cortisol) to 0.55 (for 08.00 h plasma cortisol and nocturnal urinary cortisol). In contrast, parameters obtained after direct stimulation or inhibition of the producing targets were much more reliable: Rs were above 0.80 for post tetracosactrin levels of plasma and salivary cortisol, post CRH-LVP levels of plasma ACTH and LPH. The Rs were below 0.50 for post metyrapone levels of plasma 11-deoxycortisol, ACTH, LPH and ,B-endorphin. The interval between sampling did not affect R estimates. These data show that peak levels of plasma cortisol and ACTH after direct stimulation are highly reliable whereas baseline and main post-metyrapone levels are not. A single post stimulation level of these hormones may suffice to characterize normal subjects in trials while three or more baseline or post-metyrapone level measurements may be needed to obtain a satisfactory reliability of the mean.

Evaluation of GH secretion using pharmacological GH stimulation tests (GHST) remains a current practice, although the reliability of GHST has been questioned, and many pitfalls have been pointed out. We have analyzed all of the 6373 GH stimulation tests that led to the initiation of GH therapy in 3233 children treated in France from [1973][1974][1975][1976][1977][1978][1979][1980][1981][1982][1983][1984][1985][1986][1987][1988][1989]. Tests and GH measurements were performed by individual centers and collected by the Association France-Hypophyse. GH deficiency (GHD) was due to craniospinal irradiation (11%), was due to organic causes or associated with multiple deficiencies (22%), or was considered idiopathic (65%); 2% of the patients were considered non-GHD. Eleven different pharmacological tests were used, and 62 of the 66 theoretical pairs of tests were used at least once. The most frequent combination of tests (ornithine in one instance and insulin in another) was used in 12.7% of patients. The reliability of the GH peak measured by comparing the results of 2 tests in the same patient was poor, as measured by intraclass correlation coefficients below 0.8. Multivariate analysis identified several parameters positively or negatively associated with peak plasma GH: calendar year of initiation of treatment, etiology of GHD, height SD score, bone age SD score, puberty, weight SD score, genetic target height SD score, and the nature of the pharmacological agent used. We believe that several of these factors (weight SD score, genetic target height SD score, and nature of the agent) identify biases in the diagnosis of GHD. We conclude that GHST should be performed with a very limited number of agents, interpreted after the establishment of reference values in age-matched normal children, and associated with other clinical and biochemical parameters for establishing the diagnosis of GHD. (J Clin Endocrinol Metab 82: [2117][2118][2119][2120][2121] 1997) T HE RELIABILITY of pharmacological tests used for evaluating GH secretion have repeatedly been questioned (1-4) for the lack of normal age-related reference values, the use of variable cut-off values with time, the use of different pharmacological stimuli, the dependence on physiological parameters (age, puberty, and body weight), poorly reproducible results, and the use of different laboratory methods and standards for the measurement of plasma GH. Although the diagnosis of GH deficiency (GHD) involves the analyses of height, growth velocity, GH secretion, and GH-dependent plasma proteins and the search for an etiology (4 -7), GH stimulation tests (GHST) are still one of the essential elements of diagnosis. GHST are used to regulate the use of GH in most countries, with the exception of Australia (8). How several potentially confounding factors can influence the results of GHST, the diagnosis, the decision to initiate GH substitutive therapy, and ultimately the results of treatment have not, to our knowledge, been analyzed in a populationbased cohort of tr...

Short term studies have demonstrated the acceleration of growth velocity after the administration of GH in short children born with intrauterine growth retardation (IUGR). We report the final heights of 70 IUGR children whose short stature was attributed to idiopathic GH deficiency (peak plasma GH <10 ng/mL at 2 provocative tests) and treated with GH at a mean dosage of 0.4 +/- 0.1 U/kg x week during an average of 4.6 +/- 2.5 yr. They were compared to a control group of 40 untreated short children born with IUGR, without GH deficiency. At the time of evaluation, age, auxological data, and pubertal status were similar in the 2 groups (height, -2.9 +/- 0.8 and -2.8 +/- 0.7 SD score). Final heights were comparable in both groups of children (-2 +/- 0.7 and -2.2 +/- 1.1 SD score). A multivariate analysis identified 4 independent predictors of final height, namely target height, age and body mass index at evaluation, and GH treatment. Treatment was associated with a gain of 0.6 SD score, suggesting a final height gain of about 3.4 cm. Fifty-three of 70 treated children were reevaluated after completion of growth, and 43 of 53 had a peak plasma GH level of 10 ng/mL or more. Auxological characteristics of these 53 patients were not different from those of nonreevaluated patients. We believe that the transient character of the GH deficiency in most patients and the nonstringent initial criteria used for the diagnosis of GH deficiency render the spontaneous growth potentials identical in the 2 groups of patients. Our data, therefore, suggest that GH treatment at this dosage has a limited effect on the final height of short children born with IUGR.

The combined administration of CRH and vasopressin to man now offers a powerful means to directly assess the pituitary corticotroph reserve. A double blind, randomized, placebo-controlled, cross-over trial offered the opportunity to perform the combined CRH/lysine vasopressin (LVP) test (100 micrograms ovine CRH, followed by 1 IU LVP over 15 min) on 3 different occasions without treatment in 10 normal male subjects. We showed that peak ACTH plasma levels after stimulation had wide intersubject variation, whereas they were remarkably stable in a given individual, with a mean intraclass correlation coefficient of 0.90 (95% confidence limits, 0.74-0.96). Peak ACTH plasma levels after CRH/LVP administration were not significantly correlated with basal plasma cortisol levels (r = -0.14; P > 0.45), but were strongly and inversely correlated with peak cortisol plasma levels after Cortrosyn stimulation (0.25 mg, im; r = -0.78; P < 0.0001). These data provide the first evidence that the overall hypothalamic-pituitary-adrenocortical axis has an intrinsic activity that is constitutively fixed for a given individual. The power of the combined CRH/LVP test offers a unique means to measure a genuine corticotroph phenotype in each individual.

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This study shows that purified murine monoclonal anti-DNA antibodies and human polyclonal anti-DNA antibodies (from systemic lupus erythematosus--SLE--patients), preincubated with DNA, acquire anti-histone reactivity. Conversely, DNAse I treatment of SLE patients' antibodies with anti-histone activity abolishes such activity. It has previously been demonstrated that anti-DNA antibodies bind to the cell membrane and recognize cell-surface polypeptides that have been identified with histones by partial sequencing. In a series of 33 sera from patients with clinically active disease and 29 sera from patients in clinical remission, positivity of an immunoblot analysis detecting antibodies against these polypeptides was associated with clinical activity of SLE (sensitivity, 0.88; specificity, 0.90). Anti-histone reactivity detected by ELISA appeared to be also a good marker of SLE activity (sensitivity, 0.64; specificity, 0.54). As expected, anti-native DNA antibody positivity and lowered complement dosage were also associated with clinical activity (sensitivity, 0.79 and 0.63, respectively; specificity, 0.48 and 0.93, respectively). Since anti-histone reactivity reflects, at least partly, the presence of anti-DNA antibodies complexed to DNA, which could bind to cell-membrane determinants, and is associated with disease clinical activity, it is suggested that this mechanism can contribute to explain the pathogenicity of anti-DNA antibodies.

Asthma is a chronic disease, which affects patients' daily lives. The goal of this study was the development of a disease-specific scale to evaluate quality of life in asthmatic patients in France: The Asthma Impact Record Index (AIR Index).The study was conducted with the participation of 486 asthmatic patients using the following steps: 1) selection of dichotomous items; 2) reduction of the number of items; 3) study of reproducibility of the questionnaire; 4) weighting of items; 5) study of the reliability and validity of the final version of the AIR Index.The final version of the AIR Index contains 63 unweighted items. The items were classified into subscales representing the main dimensions of quality of life: 1) physical, which was itself split into two subscales: a) physical activities; and b) symptoms; 2) psychological; and 3) social or relational. The internal consistency, measured by Cronbach's alpha coefficients, was found to be high, for the global scale and all subscales (range 0.79-0.94). The concurrent validity, evaluated by studying the relationship between the score values on the global scale and the subscales, and the parameters reflecting disease severity, was also high.We conclude that the AIR Index might represent a useful evaluative and discriminant instrument in studying quality of life in asthma in French populations.