Newborn screening for congenital adrenal hyperplasia in the Netherlands.

OBJECTIVE: To evaluate whether congenital adrenal hyperplasia (CAH) patients can be detected by newborn screening before the occurrence of life-threatening salt wasting and whether the prevalence, specificity, and sensitivity are adequate enough for a routine screening procedure. DESIGN: From 1998, a 2-year regional pilot screening for CAH was performed. In 1998, cutoff levels for 17OHP were primarily based on birth weight, and in 1999 on gestational age. In addition, nationwide, all newly diagnosed patients with CAH were reported to the Dutch Pediatric Surveillance Unit to compare screened CAH patients with CAH patients in the area without screening. RESULTS: In 2 years, 176 684 newborns were screened and 15 CAH patients (7 males/8 females) were detected. Therapy was started at the median age of 7 days. In the area without screening, 223 307 infants were born and 19 CAH patients (10 males/9 females) were reported to the Dutch Pediatric Surveillance Unit. Therapy was started at the median age of 14 days. The mean (standard deviation) serum sodium concentration was 134.5 (3.4) mmol/L in the area of screening versus 124.5 (10.8) mmol/L in the area without screening. The overall prevalence was 1:11 764. In 1998 and 1999, the specificity was 99.76% and 99.97%, respectively. The positive predictive value was 4.5% and 16%, respectively. To date, no false-negative cases have been detected. CONCLUSION: Severe salt wasting can be prevented by neonatal screening. The prevalence, specificity, and sensitivity allowed addition of screening for CAH to the routinely performed national neonatal screening program.

Hormonal status and the neuroendocrine response to a novel heterotypic stressor involving subchronic noise exposure.

Despite a number of studies on noise-induced health effects, it is still unclear to what extent different neuroendocrine pathways are affected by noise exposure. Male Wistar rats were housed in sound-attenuated rooms isolated for noise from outside. Three groups of chronically cannulated rats were exposed to either background noise (+/-64 dB) only or irregular experimental white noise (90 dB, 2-22 kHz). Two protocols, with approximately the same total amount of noise but with different densities, were used: protocol N1 (180 min random noise per day for 18 days) or protocol N2 (540 min random noise per day for 8 days). Basal levels of circulating hormones (ACTH, corticosterone, prolactin and catecholamines) and plasma glucose were measured. In control animals, no significant changes in any of these parameters were observed over 18 days. Except for plasma prolactin, N1 did not induce a significant elevation in basal hormonal levels. N2 however induced significant elevation in basal prolactin, corticosterone and noradrenaline levels. At the end of the exposure period, all animals were subjected to a novel heterotypic stressor (restraint stress) to monitor differences in neuroendocrine activation (ACTH, corticosterone and prolactin). Compared to nonexposed control animals, N1 animals showed a normal ACTH and an enhanced corticosterone response, whereas N2 animals showed an increased ACTH but a normal corticosterone response. The prolactin response of both N1 and N2 animals was significantly decreased. Adrenal cell suspension experiments revealed that in noise-exposed rats both basal- and ACTH-stimulated corticosterone production were significantly increased as compared to control animals. These results indicate that chronic noise exposure at mild intensities induces subtle but significant changes in hormonal regulation.

Effect of hormone depletion on cell survival in the EMR-86 rat mammary carcinoma.

Growth of the transplantable EMR-86 rat mammary carcinoma depends on elevated prolactin levels which are induced by oestrogenic stimulation of the pituitary. We investigated histological and cell kinetic changes during tumour regression after removal of implanted oestrogen pellets (EP), and we especially focused on the role of apoptosis. After EP removal, serum prolactin decreased to basal levels in 5 days, reaching its largest depletion during the first day. Similarly, S-phase cell fractions, assessed by bromodeoxyuridine (BrdUrd) incorporation, decreased to half the initial value during the first day and developed into a gradual decrease to basal levels thereafter. Within 10 days, tumour volumes were reduced to 20% without striking changes in tissue architecture. To quantify apoptosis, we applied a method that stains DNA breaks in tissue sections and subsequently measured the stained area by automated image cytometry. This procedure was necessary, as the subtle changes could not be detected by histological examination alone. One day after the rapid decline of the S-phase fraction, a 3-fold increase in apoptotic area was observed that remained for about 3 days and then gradually decreased. This correlated with the histologically observed reduction of tumour cells. In spite of the major cell loss, regression came to a halt after about 10 days. The surviving cell fraction is discussed within the context of a stem cell hypothesis, in which tumour cells with stem cell characteristics are less susceptible to hormone-induced apoptosis than their (non-stem) daughter cells. This notion has implications for the eradication of residual tumour cells, because a diminished susceptibility might also apply to apoptosis induced by radio- or chemotherapy.

Effects of subcutaneous versus intravenous administration of cyclosporin A on rat thymic histology and pharmacokinetics.

Cyclosporin A (CsA) was administered to rats by repeated subcutaneous (s.c.) or intravenous (i.v.) injections for 14 days. Changes in thymic histology were independent of the route of administration. Blood concentration--time profiles of CsA were similar at dose levels of i.v. 7.5 and s.c. 15 mg/kg/day, respectively. So, provided that the dose is reduced, i.v. injection can serve as an adequate alternative to s.c. injection, thereby preventing unwanted painful side-effects associated with the latter route of administration.