[The new Parkinson's disease pain classification system (PD-PCS)]. / Die neue Parkinson-Schmerzklassifikation (PSK).

BACKGROUND: Chronic pain is a common non-motor symptom in patients with Parkinson's disease (PD). AIM: To facilitate the diagnosis of pain in PD, we developed a new classification system the Parkinson's disease pain classification system (PD-PCS) and translated the corresponding validated questionnaire into German. METHODS: A causal relationship of the respective pain syndrome with PD can be determined by four questions before assigning it hierarchically into one of three pain categories (neuropathic, nociceptive and nociplastic). RESULTS: In the initial validation study 77% of the patients (122/159) had PD-associated pain comprising 87 (55%) with nociceptive, 36 (22%) with nociplastic and 24 (16%) with neuropathic pain. The study revealed a high validity of the questionnaire and a moderate intrarater and interrater reliability. The questionnaire has been adapted into German and employed in 30 patients. DISCUSSION: The PD-PCS questionnaire is a valid and reliable tool to determine the relationship of a pain syndrome with PD before classifying it according to the underlying category, facilitating further diagnostics and treatment.

Identifying the assembly intermediate in which Gag first associates with unspliced HIV-1 RNA suggests a novel model for HIV-1 RNA packaging.

During immature capsid assembly, HIV-1 genome packaging is initiated when Gag first associates with unspliced HIV-1 RNA by a poorly understood process. Previously, we defined a pathway of sequential intracellular HIV-1 capsid assembly intermediates; here we sought to identify the intermediate in which HIV-1 Gag first associates with unspliced HIV-1 RNA. In provirus-expressing cells, unspliced HIV-1 RNA was not found in the soluble fraction of the cytosol, but instead was largely in complexes ≥30S. We did not detect unspliced HIV-1 RNA associated with Gag in the first assembly intermediate, which consists of soluble Gag. Instead, the earliest assembly intermediate in which we detected Gag associated with unspliced HIV-1 RNA was the second assembly intermediate (~80S intermediate), which is derived from a host RNA granule containing two cellular facilitators of assembly, ABCE1 and the RNA granule protein DDX6. At steady-state, this RNA-granule-derived ~80S complex was the smallest assembly intermediate that contained Gag associated with unspliced viral RNA, regardless of whether lysates contained intact or disrupted ribosomes, or expressed WT or assembly-defective Gag. A similar complex was identified in HIV-1-infected T cells. RNA-granule-derived assembly intermediates were detected in situ as sites of Gag colocalization with ABCE1 and DDX6; moreover these granules were far more numerous and smaller than well-studied RNA granules termed P bodies. Finally, we identified two steps that lead to association of assembling Gag with unspliced HIV-1 RNA. Independent of viral-RNA-binding, Gag associates with a broad class of RNA granules that largely lacks unspliced viral RNA (step 1). If a viral-RNA-binding domain is present, Gag further localizes to a subset of these granules that contains unspliced viral RNA (step 2). Thus, our data raise the possibility that HIV-1 packaging is initiated not by soluble Gag, but by Gag targeted to a subset of host RNA granules containing unspliced HIV-1 RNA.

Formation of RNA Granule-Derived Capsid Assembly Intermediates Appears To Be Conserved between Human Immunodeficiency Virus Type 1 and the Nonprimate Lentivirus Feline Immunodeficiency Virus.

During immature capsid assembly in cells, human immunodeficiency virus type 1 (HIV-1) Gag co-opts a host RNA granule, forming a pathway of intracellular assembly intermediates containing host components, including two cellular facilitators of assembly, ABCE1 and DDX6. A similar assembly pathway has been observed for other primate lentiviruses. Here we asked whether feline immunodeficiency virus (FIV), a nonprimate lentivirus, also forms RNA granule-derived capsid assembly intermediates. First, we showed that the released FIV immature capsid and a large FIV Gag-containing intracellular complex are unstable during analysis, unlike for HIV-1. We identified harvest conditions, including in situ cross-linking, that overcame this problem, revealing a series of FIV Gag-containing complexes corresponding in size to HIV-1 assembly intermediates. Previously, we showed that assembly-defective HIV-1 Gag mutants are arrested at specific assembly intermediates; here we identified four assembly-defective FIV Gag mutants, including three not previously studied, and demonstrated that they appear to be arrested at the same intermediate as the cognate HIV-1 mutants. Further evidence that these FIV Gag-containing complexes correspond to assembly intermediates came from coimmunoprecipitations demonstrating that endogenous ABCE1 and the RNA granule protein DDX6 are associated with FIV Gag, as shown previously for HIV-1 Gag, but are not associated with a ribosomal protein, at steady state. Additionally, we showed that FIV Gag associates with another RNA granule protein, DCP2. Finally, we validated the FIV Gag-ABCE1 and FIV Gag-DCP2 interactions with proximity ligation assays demonstrating colocalization in situ Together, these data support a model in which primate and nonprimate lentiviruses form intracellular capsid assembly intermediates derived from nontranslating host RNA granules.IMPORTANCE Like HIV-1 Gag, FIV Gag assembles into immature capsids; however, it is not known whether FIV Gag progresses through a pathway of immature capsid assembly intermediates derived from host RNA granules, as shown for HIV-1 Gag. Here we showed that FIV Gag forms complexes that resemble HIV-1 capsid assembly intermediates in size and in their association with ABCE1 and DDX6, two host facilitators of HIV-1 immature capsid assembly that are found in HIV-1 assembly intermediates. Our studies also showed that known and novel assembly-defective FIV Gag mutants fail to progress past putative intermediates in a pattern resembling that observed for HIV-1 Gag mutants. Finally, we used imaging to demonstrate colocalization of FIV Gag with ABCE1 and with the RNA granule protein DCP2. Thus, we conclude that formation of assembly intermediates derived from host RNA granules is likely conserved between primate and nonprimate lentiviruses and could provide targets for future antiviral strategies.

Lineage-specific dynamic and pre-established enhancer-promoter contacts cooperate in terminal differentiation.

Chromosome conformation is an important feature of metazoan gene regulation; however, enhancer-promoter contact remodeling during cellular differentiation remains poorly understood. To address this, genome-wide promoter capture Hi-C (CHi-C) was performed during epidermal differentiation. Two classes of enhancer-promoter contacts associated with differentiation-induced genes were identified. The first class ('gained') increased in contact strength during differentiation in concert with enhancer acquisition of the H3K27ac activation mark. The second class ('stable') were pre-established in undifferentiated cells, with enhancers constitutively marked by H3K27ac. The stable class was associated with the canonical conformation regulator cohesin, whereas the gained class was not, implying distinct mechanisms of contact formation and regulation. Analysis of stable enhancers identified a new, essential role for a constitutively expressed, lineage-restricted ETS-family transcription factor, EHF, in epidermal differentiation. Furthermore, neither class of contacts was observed in pluripotent cells, suggesting that lineage-specific chromatin structure is established in tissue progenitor cells and is further remodeled in terminal differentiation.

A LncRNA-MAF:MAFB transcription factor network regulates epidermal differentiation.

Progenitor differentiation requires remodeling of genomic expression; however, in many tissues, such as epidermis, the spectrum of remodeled genes and the transcription factors (TFs) that control them are not fully defined. We performed kinetic transcriptome analysis during regeneration of differentiated epidermis and identified gene sets enriched in progenitors (594 genes), in early (159 genes), and in late differentiation (387 genes). Module mapping of 1,046 TFs identified MAF and MAFB as necessary and sufficient for progenitor differentiation. MAF:MAFB regulated 393 genes altered in this setting. Integrative analysis identified ANCR and TINCR lncRNAs as essential upstream MAF:MAFB regulators. ChIP-seq analysis demonstrated MAF:MAFB binding to known epidermal differentiation TF genes whose expression they controlled, including GRHL3, ZNF750, KLF4, and PRDM1. Each of these TFs rescued expression of specific MAF:MAFB target gene subsets in the setting of MAF:MAFB loss, indicating they act downstream of MAF:MAFB. A lncRNA-TF network is thus essential for epidermal differentiation.

Bulgeless dwarf galaxies and dark matter cores from supernova-driven outflows.

For almost two decades the properties of 'dwarf' galaxies have challenged the cold dark matter (CDM) model of galaxy formation. Most observed dwarf galaxies consist of a rotating stellar disk embedded in a massive dark-matter halo with a near-constant-density core. Models based on the dominance of CDM, however, invariably form galaxies with dense spheroidal stellar bulges and steep central dark-matter profiles, because low-angular-momentum baryons and dark matter sink to the centres of galaxies through accretion and repeated mergers. Processes that decrease the central density of CDM halos have been identified, but have not yet reconciled theory with observations of present-day dwarfs. This failure is potentially catastrophic for the CDM model, possibly requiring a different dark-matter particle candidate. Here we report hydrodynamical simulations (in a framework assuming the presence of CDM and a cosmological constant) in which the inhomogeneous interstellar medium is resolved. Strong outflows from supernovae remove low-angular-momentum gas, which inhibits the formation of bulges and decreases the dark-matter density to less than half of what it would otherwise be within the central kiloparsec. The analogues of dwarf galaxies-bulgeless and with shallow central dark-matter profiles-arise naturally in these simulations.

A randomised study of two doses of biosynthetic human growth hormone on final height of pubertal children with growth hormone deficiency.

AIMS: To determine the effectiveness of different doses of r-hGH therapy during puberty in children with growth hormone deficiency (GHD). METHODS: Randomized controlled trial of different doses of r-hGH therapy administered during puberty in 49 children with GHD. The patients were allocated randomly using a random number table to one of two groups: group 1 (15 IU/m(2)/week) or group 2 (30 IU/m(2)/week). Patients were included if they had received r-hGH daily at a dose of 15 IU/m(2)/week (0.7 mg/m(2)/day) for at least 1 year before randomization. RESULTS: Height increase standard deviation scores (SDS) were similar between the two groups (group 1: 1.1; group 2: 1.2; p = 0.81). CONCLUSION: A higher dose of r-hGH administered during puberty does not appear to have a significant effect on final height of children with GH deficiency. Altering pubertal tempo or intensifying prepubertal r-hGH therapy may be a more promising approach to improving final height in children with GH deficiency.

A randomised study of the effect of two doses of biosynthetic human growth hormone on final height of children with familial short stature.

BACKGROUND/AIMS: The effects of biosynthetic human growth hormone (r-hGH) in children with familial short stature (FSS) are varied. We determined whether responsivity to r-hGH in FSS is dose-dependent. METHOD: Randomised trial of two doses (20 or 40 IU/m(2) body surface area/week by daily subcutaneous injection) of r-hGH in 29 (24 male, 5 female) FSS children with assessment at adult height. RESULTS: Age range at presentation was 5.1-10.5 years, height less than 1.5 standard deviation scores (SDS) below the mean, height velocity SDS greater than -1.5 and peak growth hormone response to provocative testing over 13.5 mU/l. Adult height data (SDS) at 16.5 +/- 2.1 years for the low-dose group and 16.1 +/- 1.1 years for the high-dose group (p = 0.62) were similar [low dose -1.06 (SD 0.75), high dose -1.02 (SD 0.83); p = 0.88]. The incremental effect of both doses on stature was minimal [low-dose difference in height actual-predicted 0.79 (SD 0.94), high dose 1.27 (SD 0.88); p = 0.12]. CONCLUSION: Using this r-hGH dosing schedule there were little short- or long-term effects on height in children with FSS.

Sexual dimorphism in the synchrony of joint growth hormone and cortisol dynamics in children with classic 21-hydroxylase deficiency.

In humans, growth hormone (GH) and cortisol are secreted in a pulsatile fashion and a mutual bidirectional interaction between the GH/insulin-like growth factor (IGF)-I axis and hypothalamic-pituitary-adrenal (HPA) axis has been established. Classic congenital adrenal hyperplasia (CAH) is characterized by a defect in the synthesis of glucocorticoids and often mineralocorticoids, and adrenal hyperandrogenism. In view of the sexually dimorphic pattern in GH secretion, we investigated the GH-cortisol bihormonal secretory dynamics in male and female children with classic CAH. Thirty-eight children with classic 21-hydroxylase deficiency (M: 13, F: 25; age range: 6.1-18.8 yr) were studied prospectively. Serum GH and cortisol concentrations were determined at 20 min intervals for 24 hours. The irregularity of GH and cortisol pattern was assessed using approximate entropy (ApEn), a scale- and model-independent statistic. The synchrony of joint GH-cortisol dynamics was quantified using the cross-ApEn statistic. Cross-correlation analysis of GH and cortisol concentrations was computed at various time lags covering the 24-h period. There was no gender difference in mean 24-hour serum GH (males vs females: 5.25 +/- 4.72 vs 4.44 +/- 2.64 mIU/l) or cortisol (156.2 +/- 44.6 vs 172.0 +/- 58.5 nmol/l) concentrations. For GH, ApEn values were significantly higher in females (0.66 +/- 0.14) than in males (0.53 +/- 0.16) (p = 0.009). No difference in cortisol ApEn values was noted between sexes (0.53 +/- 0.21 vs 0.54 +/- 0.12). Cross-ApEn values of paired GH-cortisol, with cortisol leading GH, were significantly higher in females (0.94 +/- 0.14) than in males (0.83 +/- 0.20) (p = 0.03). These findings suggest that females with classic 21-hydroxylase deficiency have a more irregular pattern of GH secretion and a more asynchronous joint GH and cortisol dynamics than their male counterparts.

Insights into the relationships of Palearctic and Nearctic lymnaeids (Mollusca: Gastropoda) by rDNA ITS-2 sequencing and phylogeny of stagnicoline intermediate host species of Fasciola hepatica.

Fascioliasis by Fasciola hepatica is the vector-borne disease presenting the widest latitudinal, longitudinal and altitudinal distribution known. F. hepatica shows a great adaptation power to new environmental conditions which is the consequence of its own capacities together with the adaptation and colonization abilities of its specific vector hosts, freshwater snails of the family Lymnaeidae. Several lymnaeid species only considered as secondary contributors to the liver fluke transmission have, however, played a very important role in the geographic expansion of this disease. Many of them belong to the so-called "stagnicoline" type group. Stagnicolines have, therefore, a very important applied interest in the Holarctic region, to which they are geographically restricted. The present knowledge on the genetics of stagnicolines and on their parasite-host interrelationships is, however, far from being sufficient. The present paper analyses the relationships between Palaearctic and Nearctic stagnicoline species on the base of the new light furnished by the results obtained in nuclear rDNA ITS-2 sequencing and corresponding phylogenetic studies of the lymnaeid taxa Lymnaea (Stagnicola) occulta, L. (S.) palustris palustris (topotype specimens) and L. (S.) p. turricula from Europe. Natural infections with F. hepatica have been reported in all of them. Surprisingly, ITS-2 length and GC content of L. occulta were similar and perfectly fitted within the respective ranges known in North American stagnicolines. Nucleotide differences and genetic distances were higher between L. occulta and the other European stagnicolines than between L. occulta and the North American ones. The ITS-2 sequence of L. p. turricula from Poland differed from the other genotypes known from turricula in Europe. The phylogenetic trees using the maximum-parsimony, distance and maximum-likelihood methods confirmed (i) the inclusion of L. occulta in the branch of North American stagnicolines, (ii) the link between the North American stagnicolines-L. occulta group with Galba truncatula, and (iii) the location of the L. p. turricula genotype from Poland closer to L. p. palustris than to other European L. p. turricula genotypes. The Palaearctic species occulta is included in the genus Catascopia, together with the Nearctic species catascopium, emarginata and elodes. The results suggest a potential of transmission capacity for C. occulta higher than that of other European stagnicolines or Omphiscola glabra. The relatively low genetic distances between C. occulta and G. truncatula and the clustering of both species in the same clade suggest that C. occulta may be potentially considered as the second lymnaeid intermediate host species of F. hepatica in importance in eastern and northern Europe, and probably also western and central Asia, after G. truncatula. L. p. turricula may be considered as a potential secondary vector of F. hepatica, at a level similar to that of L. p. palustris.

Spatial abilities following prenatal androgen abnormality: targeting and mental rotations performance in individuals with congenital adrenal hyperplasia.

In most mammals, behaviors that show sex differences are influenced by androgen during early life. In the current study, the hypothesis that androgen influences the development of human spatial abilities was investigated. Participants included 40 females and 29 males with congenital adrenal hyperplasia (CAH), a genetic disorder that causes overproduction of adrenal androgens beginning prenatally, and 29 unaffected female and 30 unaffected male relatives of individuals with CAH. Participants ranged in age from 12-45 years. Measures of spatial abilities included two mental rotations tasks and two targeting tasks, all of which showed large sex differences favoring males in the unaffected relative controls. Females with CAH (exposed to higher than normal levels of androgen prenatally) performed better than unaffected females on the targeting tasks, and resembled unaffected males and males with CAH in this respect. However, females with CAH did not perform better than unaffected females on the measures of mental rotations abilities. Males with CAH showed unaltered performance on the targeting tasks, and impaired performance on the mental rotations tasks. Results are discussed in terms of differences in experiential and hormonal contributions to different spatial abilities, as well as in terms of possible differences in critical periods for hormonal influences on targeting versus mental rotations abilities. Specifically, we speculate that, although androgen may influence targeting abilities prenatally, if hormones influence the development of mental rotations ability, they do so at some other time, perhaps during the first six months of postnatal life.

Increased incidence of renal parenchymal carcinoma in the Northern and Yorkshire region of England, 1978-1997.

Kidney cancer remains relatively rare, but incidence and mortality rates are reported to be rising steadily across the world. To determine if such increases were occurring in the UK, we examined the rates of incidence and mortality in different histological subtypes of kidney cancer in the Northern and Yorkshire region of England. Details of all 8741 cases diagnosed between 1978 and 1997 were extracted from the population-based Northern and Yorkshire Cancer Registry. For all types of tumour, both incidence and mortality rates increased over the study period. Overall age-standardised incidence rates increased by 86% for renal parenchymal carcinoma (RPC) (80% for males, 90% for females) from 2.8 to 5.2 cases per 100000 (3.8-6.8 male, 2.0-3.8 female). There were incidence increases in all age groups, all Carstairs index groups and in both urban and rural populations. Although increased incidental detection of kidney tumours by improved investigational techniques may account for some of this rise, we believe it unlikely that it accounts for all of the increase observed. Potential aetiological causes for the increased rates include hypertension, smoking, a diet lacking fruit and vegetables, analgesic use and, particularly, obesity.

Hypothalamo-pituitary-adrenal axis integrity after cranial irradiation for childhood posterior fossa tumours.

BACKGROUND: The evolution of anterior pituitary deficits after treatment for pituitary tumours has been largely attributed to local irradiation, but may be influenced as much by tumour mass or surgery. Other than growth hormone (GH) insufficiency, the late endocrinopathies after survival from non-central brain tumours have been little documented. The aim of this study was to investigate the hypothalamic-pituitary-adrenal (HPA) axis in long-term survivors of cranial irradiation for childhood posterior fossa tumours. PROCEDURE: We studied long-term data in patients treated prepubertally for posterior fossa brain tumours and systematically referred by radiation oncologists for growth and pubertal monitoring to the London Centre for Paediatric Endocrinology over the last 25 years. They must have undergone HPA axis assessment twice, first prepubertally at documentation of growth failure, and second at completion of growth and puberty. Data on sixteen patients (12 males, 4 females; median age: 5.7 years, range: 2.5-8.8 years), who had undergone excision surgery with high dose cranial irradiation and/or chemotherapy for childhood posterior fossa tumours, were examined. Patients were followed for a median of 11.0 (range: 6.8-21.4) years after radiotherapy. HPA axis assessment was undertaken with the insulin-induced hypoglycaemia test (ITT). Basal thyroid, cortisol and gonadal function tests were undertaken annually throughout the follow-up period and any deficits replaced. RESULTS: At each ITT, all patients mounted an inadequate GH response. By the end of the follow-up period all patients remained severely GH deficient, two (12.5%) had partial ACTH insufficiency, one (6.3%) had secondary hypothyroidism but none were gonadotropin deficient or hyperprolactinaemic. CONCLUSIONS: Unlike the severe, evolving multiple pituitary deficits after treatment of pituitary or central tumours in adults, these findings in children with posterior fossa tumours suggest that, with the exception of GH, neurotoxicity due to irradiation per se is associated with a low prevalence of anterior pituitary hormone deficiencies, even at a long follow-up. Since the children in this study were selected for assessment on the basis of growth failure, the high prevalence of GH insufficiency at first testing is to be expected; however, the early onset (within 1-3 years of irradiation) and permanence we have identified supports the view that GH is the most sensitive hormone to radiation injury.

Treatment with flutamide decreases cortisol clearance: implications for therapy in congenital adrenal hyperplasia.

BACKGROUND: Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is characterized by a defect in cortisol and often aldosterone secretion, and adrenal hyperandrogenism. Current treatment is to provide adequate glucocorticoid and mineralocorticoid substitution to prevent adrenal crises and to suppress excess adrenocortical androgen secretion. Anti-androgen therapy with flutamide is an option that allows control of hyperandrogenism without recourse to supraphysiological doses of glucocorticoid. METHODS: We examined the pharmacokinetic parameters of hydrocortisone administered i.v. as a bolus at a dose of 15 mg/m2 in a 17.3 year-old female patient with classic CAH before and four weeks after institution of flutamide treatment by determining serum cortisol concentrations at 10 min intervals for 6 h following the i.v. bolus of hydrocortisone. RESULTS: Treatment with flutamide resulted in a decrease in cortisol clearance from 420 ml/l to 305 ml/l (27% reduction), and a decrease in volume of distribution from 51.61 to 451 (12.9% reduction). The half-life of cortisol increased from 85.3 min to 102.1 min. CONCLUSIONS: Flutamide treatment decreases cortisol clearance, thereby prolonging its half-life. These findings indicate that a reduction in the daily dose of glucocorticoid replacement may need to be considered when flutamide is added to the treatment regimen of patients receiving hydrocortisone.

Why is management of patients with classical congenital adrenal hyperplasia more difficult at puberty?

Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is an autosomal recessive condition in which deletions or mutations of the cytochrome P450 21-hydroxylase gene cause glucocorticoid and often mineralocorticoid deficiency. Despite optimal substitution therapy, control of classical CAH is often inadequate at puberty, and the problems encountered relate to hypocortisolism and/or hyperandrogenism. A number of physiological alterations in the endocrine milieu at puberty, which include alterations in the growth hormone/insulin-like growth factor axis, insulin sensitivity, as well as the activity of enzymes participating in cortisol metabolism and adrenal steroidogenesis, may account for the documented hypocortisolism and elevated androgen production, and may explain the difficulty in maintaining adequate adrenocortical suppression in pubertal patients with classical 21-hydroxylase deficiency.

Carriage of intestinal spirochaetes by humans: epidemiological data from Western Australia.

The purpose of this study was to investigate carriage of intestinal spirochaetes by selected population groups in Western Australia. Stool specimens from 293 rural patients with gastrointestinal disorders, and from 227 healthy migrants from developing countries were cultured. Spirochaete isolates were identified using PCR, and typed by pulsed field gel electrophoresis (PFGE). Brachyspira aalborgi was not isolated. Brachyspira pilosicoli was recovered from 15 rural patients, all Aboriginal. Prevalence was 9.9% in 151 Aboriginals and 0% in 142 non-Aboriginals. Carriage of B. pilosicoli amongst migrants was 10.6% (24/227). Carriage was significantly increased in Aboriginal children aged 2-5 years (P = 0.0027) and in migrant individuals from the Middle East and Africa (P = 0.0034). Carriage was significantly associated with detection of faecal protozoa in both Aboriginals (P = 0.0021) and migrants (P = 0.012). PFGE results indicated that the B. pilosicoli strains were genetically diverse.

Serum cortisol and 17-hydroxyprogesterone interrelation in classic 21-hydroxylase deficiency: is current replacement therapy satisfactory?

One of the main aims in the management of patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency is to achieve adequate suppression of the adrenal cortex with the smallest possible dose of glucocorticoid substitution. To evaluate the administration schedule of current replacement therapy regimens, we investigated the cortisol-17-hydroxyprogesterone interrelation in 36 patients (13 males and 23 females; median age, 12.3 yr; range, 6.1-18.8 yr) with salt-wasting congenital adrenal hyperplasia. As sufficient variation in 17-hydroxyprogesterone concentrations was required to allow analysis of the cortisol-17-hydroxyprogesterone interrelation, patients were divided into 2 groups depending on the adequacy of hypothalamic-pituitary-adrenal axis suppression. The first group consisted of 17 patients with suppressed 17-hydroxyprogesterone concentrations (group 1), and the second group consisted of 19 patients with nonsuppressed 17-hydroxyprogesterone concentrations (group 2). We determined serum cortisol and 17-hydroxyprogesterone concentrations at 20-min intervals for a total of 24 h while patients were receiving their usual replacement treatment with hydrocortisone and 9alpha-fludrocortisone. We also determined the lowest dose of dexamethasone required to suppress the 0800 h serum ACTH concentrations when administered as a single dose (0.3 or 0.5 mg/m(2)) the night before. Mean 24-h cortisol and 17-hydroxyprogesterone concentrations were 3.9 microg/dl (SD = 2.1) and 66.2 ng/dl (SD = 92.7), respectively, in group 1 and 4.1 microg/dl (SD = 2.5) and 4865.7 ng/dl (SD = 6951) in group 2. The 24-h 17-hydroxyprogesterone concentrations demonstrated circadian variation, with peak values observed between 0400-0900 h. In group 2, 17-hydroxyprogesterone concentrations decreased gradually in response to the rise in cortisol concentrations during the day, but remained low during the night despite the almost undetectable cortisol concentrations between 1600-2000 h. Mean 0800 h androstenedione concentrations correlated strongly with integrated 17-hydroxyprogesterone concentrations (r = 0.81; P < 0.0001), but not with integrated cortisol concentrations. There was a significant negative correlation between cortisol and 17-hydroxyprogesterone at lag time 0 min (r = -0.187; P < 0.0001), peaking at lag time 60 min (r = -0.302; P < 0.0001), with cortisol leading 17-hydroxyprogesterone by these time intervals. Finally, 0800 h serum ACTH concentrations were sufficiently suppressed after a dexamethasone dose of 0.3 mg/m(2) in all but three patients. These findings indicate that in classic 21-hydroxylase deficiency, hydrocortisone should be administered during the period of increased hypothalamic-pituitary-adrenal axis activity, between 0400-1600 h, with the biggest dose given in the morning. Blood investigations performed as part of monitoring of congenital adrenal hyperplasia patients should include androstenedione and 17-hydroxyprogesterone concentrations determined in the morning before the administration of hydrocortisone. It should also be emphasized that blood investigations are only complementary to the overall assessment of these patients, which is primarily based on the evaluation of growth and pubertal progress.

Molecular and structural analysis of two novel StAR mutations in patients with lipoid congenital adrenal hyperplasia.

Mutations in the gene encoding steroidogenic acute regulatory protein (StAR) cause lipoid congenital adrenal hyperplasia. We report a novel homozygous splice site mutation (IVS1 + 2T --> G) in STAR in two sisters (46XY, 46XX) who presented with primary adrenal insufficiency at birth and a novel homozygous R182H missense mutation in the putative lipid transfer domain of StAR in a phenotypic female (46XY) with adrenal failure and a parotid tumor. These cases highlight the importance of StAR-dependent steroidogenesis during fetal development and early infancy and of the critical functional role of R182 in cholesterol transport.

Congenital adrenal hyperplasia: management during critical illness.

BACKGROUND: Little is known of the optimal dose and administration schedule of hydrocortisone in critically ill patients with congenital adrenal hyperplasia (CAH) caused by 21-hydroxylase deficiency. AIM: To determine plasma cortisol concentrations after intravenous administration of hydrocortisone in children with CAH and to relate these to plasma cortisol concentrations achieved by endogenous secretion in the stress of critical illness in previously healthy children. METHODS: Plasma cortisol concentrations were measured in 20 patients with classical CAH (median age 11.2 years, range 6.1-16.4) following intravenous administration of hydrocortisone 15 mg/m(2); and in 60 critically ill mechanically ventilated children (median age 2.5 years, range 0.25-16.3) on admission to the paediatric intensive care unit and for 24 hours thereafter. RESULTS: In the CAH patients, plasma cortisol reached a mean peak of 1648.3 nmol/l (SD 511.9) within 10 minutes of the intravenous bolus, and fell rapidly thereafter; levels remained greater than 450 nmol/l for 2.5 hours only. In critically ill children, mean plasma cortisol on admission to the intensive care unit was 727 nmol/l (SD 426.1). Cortisol concentrations remained raised during the first 24 hours. CONCLUSIONS: Critically ill patients with classical CAH may be best managed with a single intravenous hydrocortisone bolus followed by a constant rate infusion of hydrocortisone.