1. The effect of hydrocortisone on the development of fetal rat skin in organ culture, and on its repair after exposure to a mixed beam from a mercury lamp, are described. 2. The addition of hydrocortisone (7.5 microg/ml) to the culture medium (HC medium) caused accelerated differentiation and keratinisation of the epidermis followed by atrophic changes as in vivo. 3. Explants were grown for 2 days in either normal or HC medium and then irradiated with light from an Hanovia lamp. 4. Irradiation of the control explants produced severe necrosis in both epidermis and dermis and much disorganisation of the dermal intercellular material; 2 days after exposure the s. corneum with adherent cellular debris had become either completely detached from the denuded dermis, or raised to form a fluid-filled blister. Epidermal regeneration had begun by the 4th day after irradiation and was usually complete by the 6th day. 5. Hydrocortisone modified the response to irradiation as follows: (1) reduced and retarded cellular breakdown, (2) prevented vesication, (3) preserved the organisation of the dermal intercellular material, (4) hastened epithelialisation, (5) accelerated the differentiation of the new epidermis. Effects (2), (3), and (4) were probably secondary to (1). 6. Experiments with various light filters showed that the effective wavelengths for producing lesions in the skin explants were those below 3000 A. 7. It is suggested that the beneficial effect of hydrocortisone on the repair of irradiated skin explants might be due, at least in part, to a reduced proteolytic activity in the damaged tissue through a stabilising action of the hormone on the lysosomes. 8. The relationship of these findings to clinical observations is discussed.

OBJECTIVE

There are only limited data on bone mineral density (BMD) in adult patients with 21-hydroxylase deficiency (21-OHD). We have defined the effects of different glucocorticoid substitution therapies on BMD and body composition in these patients.

METHODS

Cross-sectional.

METHODS

Thirty-two adult patients with 21-OHD.

METHODS

Patients were examined auxologically and biochemically. BMD was examined in the left femoral neck and lumbar vertebrae 2-4 (L2-4) with dual X-ray absorptiometry. The results were compared with national reference data.

RESULTS

Mean height was 170.1 cm (-1.36 standard deviation scores (SDS) for the men and 156.3 cm (-1.68 SDS) for the women. These were significantly less (P < 0.001) than the mean national final heights. Mean BMD Z-score ((raw score - population reference mean)/SD) was -0.52 in L2-4 and -0.83 in the left femoral neck. Both these values were significantly less than the reference mean values (P = 0.045 and < 0.001, respectively). Both current and long-term mean glucocorticoid doses showed significant negative correlations with BMD in the left femoral neck as well as in L2-4. Patients substituted with hydrocortisone were less often over-treated and had better BMD Z-score means than patients substituted with prednisone, prednisolone or dexamethasone.

CONCLUSIONS

In the follow-up of patients with 21-hydroxylase deficiency, care needs to be exercised to keep the glucocorticoid substitution dose to a minimum. In most cases decreased bone mineral density is a result of over-substitution.

Corticosteroids are potent antiinflammatory agents that modulate human T-lymphocyte responses. Controversy remains as to their possible differential effects on Th1 and Th2 subsets. This study explores the kinetics and efficacy of these agents in human, antigen-driven peripheral blood mononuclear cells (PBMCs) and in nontransformed, antigen-specific Th1 and Th2 clones. Ragweed- and tetanus toxoid-driven proliferative responses of PBMCs from dually sensitized individuals were downregulated equally by dexamethasone (inhibitory concentration of 50% [IC(50)] = 3 x 10(-9) and 2 x 10(-9) mol/L, respectively). The addition of dexamethasone as late as 36 hours after ragweed stimulation still resulted in more than 75% inhibition of the proliferative response, whereas the efficacy of dexamethasone was less than 50% when added 24 hours after tetanus toxoid stimulation. Antigen-induced gene expression for proinflammatory cytokines (IL-4, IL-5, IL-13, and interferon-gamma) from PBMCs was also downregulated by dexamethasone. Proliferation of antigen-specific Th1 and Th2 clones was inhibited by several corticosteroids (hydrocortisone < budesonide < dexamethasone; IC(50) = 10(-6) to 10(-8) mol/L), but no significant differences between Th1 and Th2 clones were evident. IC(50) values in the clones were 10-fold greater than in PBMCs. Gene expression and protein secretion for IL-4, IL-13, and interferon-gamma were downregulated in a concentration-dependent manner by each of the corticosteroids in Th1 and Th2 clones. These data suggest that Th1 and Th2 responses are equally affected by corticosteroids.

Tritium-labeled hydrocortisone acetate and pilcarpine hydrochloride solutions were topically applied to the eyes of rabbits. In one group of animals, the drugs were excluded from contact with the cornea by a cylindrical well glued to the eye surface. In another group, the drug solutions were allowed contact with the entire anterior surface of the eye. Total application time in all cases was five minutes, then the eyes were flushed with saline. Samples of aqueous humor, stroma, and iris-ciliary body were taken after five, 20, 35, 65, and 125 minutes and counted in a liquid scintillation counter. With hydrocortisone, up to 70 times more drug reached the stroma when the cornea was exposed; 40 times more reached the iris. Peak stromal levels occurred by 20 minutes, dropping to one third of peak value by two hours. With pilocarpine, about five times more drug reached the iris-ciliary body when corneal access was allowed; the level peaked in about five minutes. These results illustrate the important role of tear film distribution and blinking in delivering remotely applied drugs over the cornea with subsequent entry to interior sites.

The immunopathology of human T cell lymphotropic virus type 1 (HTLV-I) uveitis was addressed by using T cell clones (TCC) established from the intraocular fluid of patients with HTLV-I uveitis. Proviral DNA of HTLV-I was identified in 55 out of 94 (59%) or 13 out of 36 (36%) TCC from the ocular fluid or the peripheral blood of these patients, respectively. Most of HTLV-I-infected TCC had a CD3+ CD4+ CD8- phenotype. HTLV-I infection on TCC was confirmed by analysis of the viral mRNA, nucleotide sequence, virus-associated proteins, and virus particles. HTLV-I-infected TCC, but not HTLV-I negative TCC, constitutively produced high amounts of IL-6 (1,336 +/- 1,050 pg/ml) and TNF-alpha (289 +/- 237 pg/ml) in the absence of any stimuli. HTLV-I-infected TCC from the ocular lesion also constitutively produced high amounts of IL-1 alpha (12,699 pg/ml), IL-2 (61 pg/ml), IL-3 (428 pg/ml), IL-8 (1,268 pg/ml), IL-10 (28 pg/ml), IFN-gamma (5,095 pg/ml), and GM-CSF (2,886 pg/ml). Hydrocortisone, a drug effective in vivo for the treatment of HTLV-I uveitis, severely depressed cytokine production in vitro in most cases. In summary, the results demonstrated direct evidence of HTLV-I infection of the eye and suggest that cytokines produced by HTLV-I-infected T cells are responsible for the intraocular inflammation in patients with HTLV-I uveitis.

The present study was undertaken to determine whether urinary excretion of aquaporin-2 (AQP-2) participates in the involvement of arginine vasopressin (AVP) in hyponatremia less than 130 mmol/L in 33 elderly subjects >> or =65 yr old) during the last 5-yr period. Subjects were separated into euvolemic hyponatremia groups: 13 with hypopituitarism, 8 with syndrome of inappropriate secretion of antidiuretic hormone (SIADH), 8 with mineralocorticoid-responsive hyponatremia of the elderly, and 4 with miscellaneous diseases. Approximately 40% of those with hyponatremia was derived from hypopituitarism, but severe hyponatremia was found in the patients with SIADH and mineralocorticoid-responsive hyponatremia of the elderly. Plasma AVP levels remained relatively high despite hypoosmolality and were tightly linked with exaggerated urinary excretion of AQP-2 and antidiuresis in the 3 groups of patients, except for one miscellaneous one. An acute water load test verified the impairment in water excretion, because the percent excretion of the water load was less than 42% and the minimal urinary osmolality was not sufficiently diluted. Also, plasma AVP and urinary excretion of AQP-2 were not reduced after the water load. The inappropriate secretion of AVP was evident in the patients with SIADH and hypopituitarism, and hydrocortisone replacement normalized urinary excretion of AQP-2 and renal water excretion in those with hypopituitarism. In contrast, the appropriate antidiuresis seemed to compensate loss of body fluid in the patients with mineralocorticoid-responsive hyponatremia of the elderly, who lost circulatory blood volume by 7.3% (mean). Fludrocortisone acetate increased renal sodium handling and body fluid, resulting in the reduction in AVP release and urinary excretion of AQP-2 in mineralocorticoid-responsive hyponatremia of the elderly. These findings indicate that urinary excretion of AQP-2 may be a more sensitive measure of AVP effect on renal collecting duct cells than are plasma AVP levels, and that increased urinary excretion of AQP-2 shows exaggerated AVP-induced antidiuresis in hyponatremic subjects in the elderly. In addition, mineralocorticoid-responsive hyponatremia of the elderly has to be carefully differentiated from SIADH in elderly subjects.

The mouse ear vesicant model (MEVM) provides a quantitative edema response as well as histopathological and biochemical endpoints as measurements of inflammation and tissue damage following exposure to the chemical warfare agent sulfur mustard (HD). In the MEVM, several topically applied anti-inflammatory agents provided a significant degree of protection against HD-induced edema and dermal-epidermal separation. This study evaluated the protective effects of three of these pharmacological compounds when administered systemically in the MEVM. Alzet osmotic pumps were used to deliver a subcutaneous dose of the appropriate anti-inflammatory agent, starting 24 h before exposure to sulfur mustard and continuing until 24 h post-exposure to HD. Twenty-four hours after pump implantation, 5 microl of a 195 mM (0.16 mg) solution of sulfur mustard (density = 1.27 g ml(-1); MW = 159; purity = 97.5%) in methylene chloride was applied to the inner surface of the right ear of each mouse. Sulfur mustard injury in the mouse ear was measured by both edema response (fluid accumulation) and histopathological damage (necrosis, epidermal-dermal separation). The systemic administration of hydrocortisone, indomethacin and olvanil provided a significant reduction in edema (24%, 26% and 22%, respectively) from the positive control. Compared to HD-positive controls, hydrocortisone, indomethacin and olvanil caused a significant reduction in subepidermal blisters (71%, 52% and 57%, respectively) whereas only hydrocortisone produced a significant reduction in contralateral epidermal necrosis (41%). We show here that these anti-inflammatory drugs are effective when administered systemically in the MEVM.

Growth of 92 Finnish patients with 21-hydroxylase deficiency (21-OHD) was analyzed retrospectively to study growth both before the diagnosis and during glucocorticoid substitution therapy. The patients were divided into two groups: those diagnosed at infancy (56 patients) and those diagnosed after the age of 1 y (36 patients). Birth lengths of those boys and girls diagnosed at infancy were greater than the national mean birth lengths (p < 0.001). Mean relative length diminished from +0.8 SD score (SDS) at birth to -1.0 SDS by the age of 1 y. Adult height was -1.0 SDS (159.9 cm) for women and -0.8 SDS (173.6 cm) for men. The difference from national mean height was significant only for women (p = 0.026). Mean relative weight during childhood correlated negatively with adult stature (r = -0.620; p = 0.006). In the group of children diagnosed later in their childhood, growth was already accelerated at infancy from +0.2 SDS at birth to +0.7 SDS by the age of 1 y (p = 0.023). The final height of girls diagnosed later in childhood was within normal limits (-0.5 SDS; 162.1 cm), whereas it was low in the corresponding group of boys (-2.1 SDS; 165.3 cm). Our data show increased mean birth length in babies with early diagnosis of 21-OHD and growth acceleration at infancy in children diagnosed later in their childhood, reflecting the growth accelerating effect of adrenal hyperandrogenism early during fetal life and infancy. To improve final height in patients with 21-OHD, lower doses of hydrocortisone should be used at infancy, and special attention should be paid to boys diagnosed later in childhood.

BACKGROUND

Hippocampal volumes previously determined in monkeys by magnetic resonance imaging are used to test the hypothesis that small hippocampi predict increased stress levels of adrenocorticotropic hormone (ACTH).

METHODS

Plasma ACTH levels were measured after restraint stress in 19 male monkeys pretreated with saline or hydrocortisone. Monkeys were then randomized to an undisturbed control condition or intermittent social separations followed by new pair formations. After 17 months of exposure to the intermittent social manipulations, restraint stress tests were repeated to determine test/retest correlations.

RESULTS

Individual differences in postrestraint stress ACTH levels over the 17-month test/retest interval were remarkably consistent for the saline (r(s) = .82, p = .0004) and hydrocortisone (r(s) = .78, p = .001) pretreatments. Social manipulations did not affect postrestraint stress ACTH levels, but monkeys with smaller hippocampal volumes responded to restraint after saline pretreatment with greater increases in ACTH levels with total brain volume variation controlled as a statistical covariate (beta = -.58, p = .031). Monkeys with smaller hippocampal volumes also responded with diminished sensitivity to glucocorticoid feedback determined by greater postrestraint ACTH levels after pretreatment with hydrocortisone (beta = -.68, p = .010).

CONCLUSIONS

These findings support clinical reports that small hippocampi may be a risk factor for impaired regulation of the hypothalamic-pituitary-adrenal axis in humans with stress-related psychiatric disorders.

Neonatal dexamethasone (DEX) for chronic lung disease is associated with adverse outcome. We compared behavioral and motor development at school age of children who neonatally received DEX to children neonatally treated with hydrocortisone (HC) in a retrospective matched cohort study. DEX- and HC-treated groups matched for gestational age, birth weight and year, gender, and severity of respiratory distress syndrome were compared with a reference group (REF) and a group treated only antenatally with betamethasone (BMETH). REF and BMETH groups had a higher gestational age and less severe respiratory distress syndrome. From 192 children (DEX, n = 46; HC, n = 52; REF, n = 43; BMETH, n = 51), the Child Behavioral Checklists from parents and teachers (Teacher's Report Form) and the Movement Assessment Battery for Children to assess neuromotor function were analyzed. DEX girls had a poorer performance on nearly all behavioral scales of the Teacher's Report Form compared with HC girls. DEX boys did not differ from HC boys. The HC boys or girls did not differ from the REF or BMETH groups. Neuromotor development was poorer in DEX than the BMETH and REF groups. The HC group did not differ from REF and BMETH groups. We suggest that neonatal HC may be a "safer" alternative for DEX for the treatment of CLD.

The idiopathic hypereosinophilic syndrome (HES) comprises a heterogeneous group of disorders with unknown pathogenesis characterized by persistent peripheral blood and bone marrow eosinophilia and eosinophilic infiltrates of multiple organs leading to severe organ dysfunction. In the present study, T lymphocyte clones were randomly established from the blood of a patient with HES and propagated in culture with mitogen and interleukin 2. Whereas 28 of 29 clones were able to stimulate myeloid colony formation when co-cultured with normal bone marrow cells in a double-layer micro-agar culture system, one third of these clones preferentially stimulated pure eosinophil colonies (up to 98% of all colonies). This pattern differed markedly (p less than 0.001) from the pattern of release of hemopoietic factors by 126 T cell clones established from four other individuals. Eosinophil colony stimulation was due to the release of a lineage-specific eosinophilic colony-stimulating factor (Eo-CSF) by these clones after appropriate stimulation. Production of Eo-CSF in vitro was inhibited by hydrocortisone or cyclosporin A. All Eo-CSF-producing clones had the T4+8-phenotype and were capable of producing in addition interleukin 2 and interferon-gamma. Southern blot analysis of the T cell receptor beta-chain rearrangement of the Eo-CSF-producing clones showed a different rearrangement pattern for each clone. These studies suggest a reactive T cell-mediated eosinophilia as the pathogenetic mechanism in this case of HES and, for the first time, point to a biologic relevance of a lymphokine-induced stimulation of hemopoiesis.

It is shown that a factor arising during the course of maturation in amphibian oocytes is by itself capable of inducing maturation when injected into recipient oocytes even after a series of 10 transfers. The mechanism of action of this phenomenon is shown to be under translational control. Experiments using cycloheximide suggest that MPF does not need protein synthesis for germinal vesicle breakdown (GVBD), but does require a translational step when serially transferred in order to sustain its renewal ("autocatalytic") capacity. It is further shown that oocytes of Xenopus laevis lend themselves to an in vitro system, since when matured under the action of some steroids (progesterone or hydrocortisone), they are capable of supporting functional maturation with cleavage and development after having received a transplanted blastula nucleus.

Conditions have been described for the selective growth, serial cultivation, and postconfluent morphological differentiation in vitro of normal adult human uroepithelial cells (HUC) on collagen gel substrates in a serum-free medium without the deliberate addition of undefined components and without a requirement for a polypeptide growth factor. The culture medium used (F12) was the standard Ham's F12 medium (0.3 mM calcium) supplemented with 1 microgram/ml hydrocortisone, 5 micrograms/ml transferrin, 10 micrograms/ml insulin, 0.1 mM nonessential amino acids, 2.0 mM L-glutamine, 2.7 mg/ml D-glucose, 10(-4) M ethanolamine or 10(-4) M phosphoethanolamine, and 5 X 10(-8) M selenium. HUC grown in F12 on Type I collagen gel substrates had a generation time of 33 hours and could be serially passed 3-5 times during log phase of growth (20-25 population doublings) before spontaneously senescing. Transmission electron microscopy showed that cultures of HUC grown entirely in serum-free F12 on collagen gel substrates morphologically differentiate postconfluence to resemble in some respects the stratified uroepithelium in vivo, although neither a basal lamina nor an asymmetric unit membrane develop. The addition of epidermal growth factor (EGF) to the F12 did not improve either the growth rate or the lifespan in vitro of HUC. In contrast, the addition of fetal bovine serum (FBS) to F12 was mitogenic to HUC in a dose-dependent manner in the concentration range 0.01-1.00% (4-400 micrograms/ml protein), but higher concentrations of FBS did not improve growth further. The generation time of HUC in 1% FBS-F12 decreased to 21 hours, and the potential population doublings in vitro increased to 31-36. Small amounts (140 micrograms/ml) of bovine pituitary extract (BPE) were similarly mitogenic to HUC in F12. Altering the calcium concentration in the standard Ham's F12 medium (0.3 mM), however, did not improve the growth of HUC in serum-containing or serum-free medium. Higher calcium concentrations (0.30-0.90 mM) were neither mitogenic nor inhibitory to HUC growth, but resulted in decreasing viability of HUC in growing cultures, suggesting an accelerating rate of cellular differentiation. In contrast HUC in low calcium, serum-free F12 (0.1 mM) failed to stratify and morphologically differentiate even in postconfluent cultures. This failure of HUC to differentiate in low calcium F12 medium did not confer a long-term growth advantage.(ABSTRACT TRUNCATED AT 400 WORDS)

All endocrinologists would like to make glucocorticoid replacement therapy for their hypoadrenal patients as physiological as possible. Many would like the reassurance of a method of monitoring such treatment to confirm that they are achieving this aim. Advances in our knowledge of the normal physiology are relevant to our attempts to do this. The cortisol production rate in normal subjects is lower than was previously believed. The normal pattern of glucocorticoid secretion includes both a diurnal rhythm and a pulsatile ultradian rhythm. Glucocorticoid access to nuclear receptors is 'gated' by the 11-beta-hydroxysteroid dehydrogenase enzymes, which interconvert active cortisol and inactive cortisone. Such complexities make the target of physiological glucocorticoid replacement therapy hard to achieve. The available evidence suggests that conventional treatment of hypoadrenal patients may result in adverse effects on some surrogate markers of disease risk, such as a lower bone mineral density than age-sex matched controls, and increases in postprandial glucose and insulin concentrations. Although the quality of life of hypoadrenal patients may be impaired, there is no evidence of an improvement on higher doses of steroids, although quality of life is better if the hydrocortisone dose is split up, with the highest dose taken in the morning. Thus the evidence suggests that most patients may safely be treated with a low dose of glucocorticoid (e.g. 15 mg hydrocortisone daily) in two or three divided doses, with education about the appropriate action to take in the event of intercurrent illnesses.

To investigate the effect of glucocorticoids on beta-agonist-induced desensitization, we studied the effect of a single intravenous dose of methylprednisolone (2 mg/kg) on beta-receptor density and affinity in lymphocytes from four normal and four mildly asthmatic subjects at the end of 3 to 5 wk of terbutaline therapy and from four normal subjects taking no other drug. Terbutaline decreased (-)[3H]-dihydroalprenolol binding sites by 53% in normal and by 42% in asthmatic subjects. Methylprednisolone restored the number of binding sites to levels statistically indistinguishable from the preterbutaline values in both groups of subjects. In subjects not exposed to terbutaline beforehand there was no significant alteration in receptor density after methylprednisolone, nor in normal lymphocytes incubated in vitro for 90 min with hydrocortisone (10(-5)M). No significant change in the dissociation constant was observed in any situation. A single intravenous dose of methylprednisolone reverses terbutaline-induced down-regulation of beta-adrenoceptors. This may provide a mechanism for the beneficial effect of steroids in restoring catecholamine responsiveness in asthmatic subjects.

The activity of prolylcarboxypeptidase (PCP), or angiotensinase C, was measured in lung tissues, leukocytes, and cultured human cells using Cbz-Pro-[14C]Ala as a substrate. A lysosomal fraction of homogenized rat or human lung contained most of the PCP activity in that tissue. Polymorphonuclear neutrophils, macrophages, and lymphocytes isolated from human blood had PCP activity. Fibroblasts cultured from human tissues had the highest activity (0.56-1.15 mumol/h per 10(6) cells), more than endothelial cells cultured from human pulmonary arteries. PCP of cultured human fibroblasts was similar to the human renal enzyme because it was resistant to moderate heating and was not inhibited by p-chloromercuriphenyl sulfonic acid. These properties and the substrate specificity distinguish PCP from cathepsin A, which is also in fibroblasts. Antibody to human renal PCP reacted with fibroblast PCP in immunofluorescence, indicating common antigenic determinants. Hydrocortisone changed PCP activity in fibroblasts in parallel with changes in beta-glucuronidase activity and cell-protein concentration; the activity was depressed at low concentration of the hormone. PCP activity was also found in synovial fluid from arthritic joints and in fibroblasts from the synovium. That PCP is found in both inflammatory exudates and in cells that appear at sites of inflammation indicates that, in addition to inactivating angiotensins, this enzyme may have a role in inflammation.

The enzyme 11 beta-hydroxysteroid dehydrogenase (11 beta-OHSD), which catalyses the conversion of cortisol to the inactive steroid cortisone in man (and corticosterone to 11-dehydrocorticosterone in rodents), was demonstrated by immunohistochemistry in skin biopsy samples from healthy volunteers and from patients with psoriasis and eczema. In-vitro studies confirmed the presence of the enzyme in skin from nude mice and showed that it is inhibited by glycyrrhetinic acid, the major active component of liquorice. By means of the skin vasoconstrictor assay, glycyrrhetinic acid was shown to potentiate the action of hydrocortisone. This work suggests a novel means of targeting glucocorticoid therapy.

The use of adrenalectomy and hypophysectomy in the management of postmenopausal patients with metastatic breast carcinoma is reserved for highly selected patients. As an alternate approach, a pharmacologic method of inhibiting adrenal cortical secretion was developed which consisted of the daily administration of 1000 mg of aminoglutethimide to block steroidogensis and either dexamethasone (2.0-3.0 mg/day) or hydrocortisone (40-60 mg/day) as replacement glucocorticoid. This regimen markedly suppressed plasma levels of DHA-S, androstenedione, estrone, and estradiol, and urinary levels of aldosterone. Of 50 patients treated, 19 (38%) demonstrated either a complete (8/19) or a partial (11/19) objective disease remission which lasted for 18.05 +/- 3.1 months (mean +/- SEM). In 10 (20%) patients, there was stabilization of disease (7.8 +/- 1.2 months), accompanied by symptomatic relief of bone pain in six (12%). There was disease progression in 20 (40%) patients. The acute side effects of aminoglutethimide therapy were significant and consisted of transient lethargy (41.5%) and a cutaneous rash (35.8%). Chronic toxicity was negligible. The medical adrenalectomy regimen of aminoglutethimide plus glucocorticoid offers a suitable alternative to surgical adrenalectomy or hypophysectomy in the management of postmenopausal patients with metastatic breast carcinoma.

Teratogenic effects are observed following long-term administration of glucocorticoids, although short-term glucocorticoid therapy is still utilized to reduce fetal mortality, respiratory distress syndrome, and intraventricular hemorrhage in preterm infants. However, the mechanism of glucocorticoid-induced teratogenicity is unknown. We hypothesize that glucocorticoid-induced teratogenesis is mediated through the glucocorticoid receptor (GR) and results from altering the expression and activity of the matrix metalloproteinases (MMPs). During embryogenesis, degradation of the extracellular matrix to allow for proper cellular migration and tissue organization is a tightly regulated process requiring appropriate temporal and spatial expression and activity of the MMPs. Studies have demonstrated that MMP gene expression can be either inhibited or induced by glucocorticoids in a variety of model systems. Using the zebrafish (Danio rerio) as a model of development, the data presented here demonstrate that embryonic exposure to the glucocorticoids dexamethasone or hydrocortisone increased expression of two gelatinases, MMP-2 ( approximately 1.5-fold) and MMP-9 (7.6- to 9.0-fold), at 72 h postfertilization (hpf). Further, gelatinase activity was increased approximately threefold at 72 hpf following glucocorticoid treatment, and changes in craniofacial morphogenesis were also observed. Cotreatment of zebrafish embryos with each glucocorticoid and the GR antagonist RU486 resulted in attenuation of glucocorticoid-induced increases in MMP expression (52-84% decrease) and activity (41-94% decrease). Furthermore, the abnormal craniofacial phenotype observed following glucocorticoid exposure was less severe following RU486 cotreatment. These studies demonstrate that in the embryonic zebrafish, dexamethasone, and hydrocortisone alter expression and activity of MMP-2 and -9, and suggest that these increases may be mediated through the GR.

Infusion of hydrocortisone in man caused an immediate shortening of the plasma half-life of antipyrine. There was no change in the 'apparent' volume of distribution of antipyrine and the plasma concentrations of hydrocortisone during the infusion remained within physiological limits. Similar changes in plasma half-lives of antipyrine were observed in the dog, but in vitro studies of drug oxidation with dog liver failed to show any difference between biopsy samples taken before and during steroid infusion.Many drugs and chemicals are known to stimulate rates of drug oxidation in both man and animals. Administration of these inducing agents results in an increase in the activity of enzymes catalyzing drug oxidation, most of which are located with-in the endoplasmic reticulum of liver cells. In man there is usually a delay of 4-8 days before an appreciable change in rates of drug metabolism is seen when such an agent is administered (Breckenridge, Orme, Thorgeirsson, Davies & Brooks, 1971); in rats, the administration of enzyme-inducing agents causes increased rates of drug metabolism only 24-48 h after their administration.We wish to report in this paper an immediate and hitherto undescribed effect of hydrocortisone on rates of antipyrine elimination in man.