Despite the absence of a clear-cut rationale for their use, corticosteroids are widely employed in the treatment of dengue shock syndrome. Previous comparative therapeutic trials have yielded contradictory results. Resolution of this therapeutic controversy has been attempted with a double-blind evaluation of the clinical effect of steroid administration in dengue shock syndrome. Placebo or a single dose of hydrocortisone hemisuccinate, 50 mg/kg of body weight, was administered randomly to 97 physiologically treated patients with dengue shock syndrome. The severity of disease on admission to the hospital and the effectiveness of treatment were quantified by a World Health Organization scoring system. The response to therapy as measured by mortality, duration of shock, and amount of replacement fluids required was virtually identical in 47 children who were and 50 children who were not treated with steroids. The comparison groups were composed of children similar in age, sex, and severity of illness. It is concluded that hydrocortisone is of no value in the treatment of dengue shock syndrome. Reliance should be placed on appropriate supportive and physiologic therapy.

Encapsulation of prespore cells of Dictyostelium discoideum is controlled by several intercellular signals to ensure appropriate timing during fruiting body formation. Acyl-CoA-binding protein, AcbA, is secreted by prespore cells and processed by the prestalk protease TagC to form the 34 amino acid peptide SDF-2 that triggers rapid encapsulation. AcbA is secreted when gamma-aminobutyric acid (GABA) is released from prespore cells and binds to GrlE, a G protein-coupled receptor (GPCR). Analysis of SDF-2 production in mutant strains lacking Galpha subunits and GPCRs, either as pure populations or when mixed with other mutant strains, uncovered the non-cell-autonomous roles of GrlA, Galpha4 and Galpha7. We found that Galpha7 is essential for the response to GABA and is likely to be coupled to GrlE. GrlA-null and Galpha4-null cells respond normally to GABA but fail to secrete it. We found that they are necessary for the response to a small hydrophobic molecule, SDF-3, which is released late in culmination. Pharmacological inhibition of steroidogenesis during development blocked the production of SDF-3. Moreover, the response to SDF-3 could be blocked by the steroid antagonist mifepristone, whereas hydrocortisone and other steroids mimicked the effects of SDF-3 when added in the nanomolar range. It appears that SDF-3 is a steroid that elicits rapid release of GABA by acting through the GPCR GrlA, coupled to G protein containing the Galpha4 subunit. SDF-3 is at the head of the cascade that amplifies the signal for encapsulation to ensure the rapid, synchronous formation of spores.

The conjugated equine estrogens-only arm of the Women's Health Initiative trial, showing a trend toward protection from heart disease as opposed to women receiving also medroxyprogesterone acetate (MPA), strengthens the debate on the cardiovascular effects of progestins. We compared the effects of progesterone (P) or MPA on the synthesis of nitric oxide and on the expression of leukocyte adhesion molecules, characterizing the signaling events recruited by these compounds. Although P significantly increases nitric oxide synthesis via transcriptional and nontranscriptional mechanisms, MPA is devoid of such effects. Moreover, when used together with physiological estradiol (E2) concentrations, P potentiates E2 effects, whereas MPA impairs E2 signaling. These findings are observed both in isolated human endothelial cells as well as in vivo, in ovariectomized rat aortas. A marked difference in the recruitment of MAPK and phosphatidylinositol-3 kinase explains the divergent effects of the two gestagens. In addition, both P and MPA decrease the adhesiveness of endothelial cells for leukocytes when given alone or with estrogen. MPA is more potent than P in inhibiting the expression of vascular cell adhesion molecule-1 and intercellular adhesion molecule-1. However, when administered together with physiological amounts of glucocorticoids, MPA (which also binds glucocorticoid receptor) markedly interferes with the hydrocortisone-dependent stabilization of the transcription factor nuclear factor kappaB and with the expression of adhesion molecules, acting as a partial glucocorticoid receptor antagonist. Our findings show significant differences in the signal transduction pathways recruited by P and MPA in endothelial cells, which may have relevant clinical implications.

An enzymatic activity that synthesizes (2'-5')-oligo(A) from ATP is induced in animal cells treated with interferon. This activity, designated (2'-5')A polymerase, is also elevated in human lymphoblastoid Daudi and Raji cells treated with hydrocortisone. The polymerase activity increases significantly after 24 hr of treatment and declines when hydrocortisone is removed from the culture medium. The product of the enzyme prepared from hydrocortisone-treated cells is indistinguishable from (2'-5')oligo(A) synthesized with polymerase of interferon-treated cells either by an endonuclease activation assay or by chromatographic analysis. The increase in (2'-5')A polymerase is not mediated by secretion of interferon by hydrocortisone-treated cells; less than 1 unit of interferon per ml is present in the culture medium during treatment with this glucocorticoid hormone. Moreover, this increase is related to the concentration of hydrocortisone in the culture medium and is inhibited by the addition of cortexolone. This steroid interferes with the interaction between glucocorticoid hormones and their receptor. Cortexolone has no effect, however, on the induction of (2'-5')A polymerase by interferon. The synthetic glucocorticoid dexamethasone also increases the polymerase activity. Experiments with inhibitors show that such an increase requires RNA and protein synthesis.

Hydrocortisone inhibits the ameboid migration of human leucocytes when added in vitro. The dose-response curve for the reaction between this steroid and leucocytes can be best expressed by a logarithmic plot of the steroid concentrations. Tetrahydrocortisone and desoxycorticosterone had no effect on in vitro leucotyte migration.

Prostaglandin E (PGE) concentration the aqueous humor of an intact rabbit eye was less than 0.1 ng. per milliliter and increased to 19 +/- 3 ng. per milliliter 60 minutes following paracentesis. The rise in PGE level was associated with clinical signs of ocular inflammation. Pretreatment with triamcinolone reduced both the accumulation of PGE in the aqueous humor and the inflammatory response following paracentesis. intravitreal injection of E. coli endotoxin into rabbit eyes increases PGE level in the anterior chamber to 72 +/- 17 ng. per milliliter and induced acute uveitis. slices of iris and ciliary body (ICB) derived from either rabbit eyes with endotoxin-induced uveitis or normal eyes were incubated for 60 to 240 minutes and the rate of PGE release into the medium was measured by radioimmunoassay. after a 4 hour incubation, the PGE release from inflamed ICB was threefold higher than that of normal ICB. incubation of inflamed ICB with hydrocortisone, or Millicorten (100 mug per milliliter) for 4 hours reduced PGE accumulation in the medium by 50 and 81 per cent, respectively. Aldosterone had no effect on the rate of PGE release from inflamed ICB throughout the incubation period. Hydrocortisone or Millicorten also reduced PGE tissue content of inflamed ICB by about 74 per cent during the period of incubation. Indomethacin (100 mug per milliliter) abolished PGE accumulation. The suppressive action of hydrocortisone on PGE release into the incubation medium was prevented by the addition of arachidonic acid (2 mug per milliliter), a substrate for prostaglandin synthesis. By contrast , the inhibitory action of indomethacin was not affected by provision of arachidonic acid. We suggest that glucocorticosteroids reduce PGE accumulation by limiting the availability of the substrate for prostaglandin biosynthesis and thus suppress the inflammatory response.

An optimized basal nutrient medium, MCDB 131, has been developed that supports clonal growth of human microvascular endothelial cells (HMVEC) with as little as 0.7% dialyzed fetal bovine serum (dFBS) when also supplemented with 10 ng/ml epidermal growth factor (EGF) and 1 microgram/ml hydrocortisone. An extensive initial survey of available media showed that MCDB 402, a medium optimized for low-serum growth of Swiss 3T3 cells, supported the best clonal growth of HMVEC with 10% dFBS. Quantitative adjustment of the composition of MCDB 402 for improved clonal growth of HMVEC with reduced amounts of dFBS resulted in development of MCDB 131. Although many different adjustments contributed to the optimal properties of MCDB 131 for growth of HMVEC, the most unusual feature of this medium is its high magnesium concentration. A major benefit was achieved by increasing Mg2+ from 0.8 mM in MCDB 402 to 10.0 mM in MCDB 131. In the absence of defined supplements, MCDB 131 supports good clonal growth of HMVEC with 2% dFBS. This can be reduced to 0.7% by adding EGF and hydrocortisone, which act synergistically to improve growth with low levels of dFBS.

Psychological stress has been correlated with breast cancer development in numerous epidemiological studies. However, physiological and molecular models which may account for this association are not readily available. We have found that the stress hormone hydrocortisone (cortisol) down-regulates the expression of the breast cancer susceptibility gene BRCA1 in the nonmalignant mouse mammary cell line EPH4. This effect is concentration-dependent, is reliant on the continuous presence of hydrocortisone, and is not affected by the addition of lactogenic hormones, or growth conditions. Hydrocortisone was also found to negate a known positive effect of estrogen on BRCA1 expression and, therefore, may interfere with estrogen-related signaling in mammary epithelial cells. The repressive effect of hydrocortisone is diminished or lost in the mouse mammary lines HC-11 and SP1, respectively, suggesting regulation of the BRCA1 may differ between lines. We have uncovered two promoter regulatory sites, which are involved in BRCA1 regulation by hydrocortisone, namely the RIBS and UP regulatory elements. Binding of the transcription factor GABP to both sites is lost upon hydrocortisone addition, though the levels of these factors are not altered by hydrocortisone treatment. Because BRCA1 activity is important for a number of intracellular pathways involved in prevention of tumorigenesis, its observed down-regulation may represent a novel molecular mechanism for cortisol's involvement in breast cancer development.

The metabolism of 3H-noradrenaline released by nerve stimulation in the isolated nerve-muscle preparation of the cat nictitating membrane was determined under control conditions and in the presence of hydrocortisone, 28 muM, a concentration which inhibits the high affinity extraneuronal uptake of noradrenaline in this tissue. In the controls the main fraction in the overflow elicited by stimulation at 10 Hz during 2 min was the deaminated glycol, 3H-DOPEG (3,4-dihydroxyphenylglycol), which accounted for 45.2 +/- 2.96% of the total radioactivity. Under these conditions, 3H-noradrenaline represented 30.8 +/- 1.92%, while 3H-normetanephrine accounted for 14.5 +/- 0.94% of the total overflow of radioactivity. During exposure to hydrocortisone there was a selective inhibition in 3H-normetanephrine formation from 3H-noradrenaline released by stimulation while the other fractions were not affected significantly. In contrast to these results, there were no changes in the spontaneous outflow of 3H-normetanephrine during exposure to hydrocortisone. The results obtained support the view that 3H-normetanephrine in spontaneous release originates from the activity of prejunctional catechol-O-methyltransferase. On the other hand, 3H-normetanephrine formed during transmitter release elicited by nerve stimulation is due to the activity of extraneuronal catechol-O-methyltransferase. Access of 3H-noradrenaline released by nerve stimulation to extraneuronal catechol-O-methyltransferase is mediated through the high-affinity, hydrocortisone-sensitive extraneuronal uptake mechanism.

An inverse relationship between cAMP content and effector function is ascribed generally to immune and inflammatory cells. Previous reports imply, however, that human polymorphonuclear leukocytes (PMN) are less responsive than other inflammatory cells to adenylate cyclase (AC) agonists. We therefore examined the effects of isoproterenol, prostaglandin E1 (PGE1), adenosine, and histamine on the adenosine 3',5'-monophosphate (cAMP) content of PMN and on particle-stimulated lysosomal enzyme release. For comparison, the effect of AC agonists on the cAMP content of human peripheral lymphocytes was evaluated in parallel. Although potent stimuli for cAMP accumulation in lymphocytes, the AC agonists produced only marginal increases in the cAMP content of PMN; this difference in responsiveness was independent of agonist concentration or length of incubation. Inhibition of lysosomal enzyme release by the AC agonists was likewise marginal (< 20%). The addition of theophylline with isoproterenol produced additive inhibition without significant cAMP increases. Hydrocortisone, which caused a small increase in the cAMP content, markedly potentiated the effects of AC agonists on the cAMP level in PMN; the synergistic increases in cAMP were accompanied by additive effects on lysosomal enzyme release. It is concluded that human lymphocytes and PMN exhibit differential sensitivity to AC agonists and that this difference may provide a basis for the selective modulation of individual PMN- or lymphocyte-mediated events.

This study was undertaken to characterize the nature of carbohydrate loss due to endotoxin poisoning in mice and to elucidate mechanisms responsible for the changes. Female ICR mice, fasted overnight, were injected intraperitoneally with a mean lethal dose of endotoxin extracted from Salmonella typhimurium strain SR-11. Liver glycogen levels, alanine-U-(14)C and pyruvate-2-(14)C incorporation into blood glucose and liver glycogen, glucose-U-(14)C incorporation into liver glycogen, and liver glycogen synthase activities were measured at intervals after treatment. Liver glycogen in fasted mice given endotoxin was diminished significantly as early as 1 h after treatment. Liver glycogen synthase was significantly decreased in poisoned mice at 17 h. The use of actinomycin D showed that the induction of this enzyme due to fasting or hydrocortisone, or both, was inhibited by endotoxin. The incorporation of the (14)C-label from alanine-U-(14)C, pyruvate-2-(14)C, or glucose-U-(14)C into blood glucose and liver glycogen was substantially impaired in endotoxemic animals at 12 h. Decreases in incorporation occurred as early as 4 h after treatment. The progressive increase in glycogen synthase activity observed in fasted controls was not seen in endotoxin-poisoned mice. The administration of a glucose or pyruvate load to endotoxin-treated mice did not restore gluconeogenesis, glycogen synthesis, or liver glycogen synthase activity to normal levels. The in vivo activation of glycogen synthase by glucose was significantly reduced in endotoxemic animals. These changes indicate reduced carbohydrate synthesis as a probable cause for rapid sugar loss during endotoxemia in mice.

OBJECTIVE

This is a meta-analysis of randomized, controlled trials to assess the efficacy and morbidity of medical therapies for anal fissure.

METHODS

Medline and the Cochrane Controlled Trials Register and the Cochrane Colorectal Cancer Review Groups Controlled Trials Register were searched using the terms "anal fissure randomized" from 1966 to 2002. Studies in which participants were randomized to a nonsurgical therapy for anal fissure were the focus of this review. Comparison groups included an operative procedure, an alternate medical therapy, or placebo. Chronic fissure, acute fissure, and fissure in children were included in the review, however, atypical fissure associated with inflammatory bowel disease, cancer, or anal infection were excluded. Data were abstracted from published reports and meeting abstracts, assessing method of randomization, blinding, "intention to treat" and dropouts, therapies, supportive measures, dosing and frequency, and crossovers. Outcome measures included nonhealing of the fissure and adverse events.

RESULTS

Twenty one different comparisons of medical therapies to heal anal fissure have been reported in 31 trials, including 9 agents-glyceryl trinitrate, isosorbide dinitrate, botulinum toxin, diltiazem, nifedipine, hydrocortisone, lidocaine, bran, placebo-as well as anal dilators and surgical sphincterotomy. Glyceryl trinitrate was favored in the analysis over placebo (odds ratio = 0.55, 95 percent confidence interval, 0.41-0.74). After excluding two studies from analysis because of placebo response rates >2 standard deviations below the mean for all studies, the advantage of glyceryl trinitrate over placebo was no longer statistically significant (odds ratio = 0.78; 95 percent confidence interval, 0.56-1.08). Nifedipine and diltiazem did not differ from glyceryl trinitrate in their ability to cure fissure (0.66; 0.22-2.01). Botulinum toxin compared with placebo showed no significant efficacy (0.75; 0.32-1.77), and was also no better than glyceryl trinitrate (0.48; 0.21-1.10). Surgery was more effective than medical therapy in curing fissure (0.12; 0.07-0.22).

CONCLUSIONS

Medical therapy for chronic anal fissure, acute fissure, and fissure in children may be applied with a chance of cure that is only marginally better than placebo, and for chronic fissure, far less effective than surgery.

Glucocorticoid-induced anti-phospholipase proteins were partially purified by using ion-exchange and molecular sieve chromatography. These proteins, as well as dexamethasone itself, inhibited the hind-paw rat oedema induced by carrageenin. This inhibition was reversed by arachidonic acid, Anti-phospholipase proteins as well as hydrocortisone, also reduced the formation of prostaglandin E2 and leukotriene B4 by phagocytosing leucocytes. A specific monoclonal antibody was able to reverse the inhibition of eicosanoid formation. The mechanism of the anti-inflammatory effect of glucocorticoids and anti-phospholipase proteins is discussed in the light of these results.

Messenger RNA was isolated from rat liver polysomes by phenol/chloroform extraction and subsequent oligo(dT)-cellulose chromatography. The mRNA was translated in a protein-synthesizing system in vitro derived from wheat germ. The system was optimized in respect to Mg2+ and K+. The presence of spermidine or spermine is necessary for the synthesis of polypeptides having molecular weights of over 20 000. In the absence of the bases only small molecular weight products are formed. The amount of protein synthesized is linearly dependent on the amount of mRNA added up to concentrations of 80 mug mRNA/ml. The synthesis of tyrosine aminotransferase and tryptophan oxygenase in the system in vitro has been demonstrated by specific immunoprecipitation and sodium-dodecylsulfate polyacrylamide gel electrophoresis of the precipitate with enzyme proteins as marker. The amount of specific product formed is linearly dependent on the amount of mRNA present. The amount of translatable tyrosine aminotransferase mRNA and tryptophan oxygenase mRNA increases after administration of hydrocortisone to adrenalectomized rats. At low doses of hormone (2 mg/100 g body weight) maximal values are observed at 4 h, control levels being reached at 6-8 h after hormone application. With higher doses of hydrocortisone (20 mg/100 g body weight) maximal values are attained at 6 h, tending to control levels 14 h after treatment. The enzyme activity curves are parallel to the mRNA curves, the peak of enzyme activity occurring 2 h after the peak of mRNA activity.

BACKGROUND

It is widely believed that glucocorticoids cause insulin resistance in all tissues. We have previously demonstrated that glucocorticoids cause insulin sensitization in human adipose tissue in vitro and induce insulin resistance in skeletal muscle.

OBJECTIVE

Our aim was to determine whether glucocorticoids have tissue-specific effects on insulin sensitivity in vivo.

METHODS

Fifteen healthy volunteers were recruited into a double-blind, randomized, placebo-controlled, crossover study, receiving both an overnight hydrocortisone and saline infusion. The tissue-specific actions of insulin were determined using paired 2-step hyperinsulinemic euglycemic clamps incorporating stable isotopes with concomitant adipose tissue microdialysis.

METHODS

The study was performed in the Wellcome Trust Clinical Research Facility, Queen Elizabeth Hospital, Birmingham, United Kingdom.

METHODS

The sensitivity of sc adipose tissue to insulin action was measured.

RESULTS

Hydrocortisone induced systemic insulin resistance but failed to cause sc adipose tissue insulin resistance as measured by suppression of adipose tissue lipolysis and enhanced insulin-stimulated pyruvate generation. In primary cultures of human hepatocytes, glucocorticoids increased insulin-stimulated p-ser473akt/protein kinase B. Similarly, glucocorticoids enhanced insulin-stimulated p-ser473akt/protein kinase B and increased Insulin receptor substrate 2 mRNA expression in sc, but not omental, intact human adipocytes, suggesting a depot-specificity of action.

CONCLUSIONS

This study represents the first description of sc adipose insulin sensitization by glucocorticoids in vivo and demonstrates tissue-specific actions of glucocorticoids to modify insulin action. It defines an important advance in our understanding of the actions of both endogenous and exogenous glucocorticoids and may have implications for the development and targeting of future glucocorticoid therapies.

The effect of treatment with indomethacin on methylazoxymethanol-induced rat large bowel carcinomas was investigated. Eight-week-old male Donryu rats received an intraperitoneal injection of 20 mg/kg body weight of methylazoxymethanol acetate once a week for 6 weeks. Fifteen rats were sacrificed at the 25th week. It was confirmed that the incidence of large bowel tumors (adenocarcinomas) was 60% and the mean number of tumors per tumor-bearing rat was 2.0. The other rats (23 approximately 30 rats in each group) were given the treatment with an intrarectal instillation of 7.5 mg/kg body weight of indomethacin, 7.5 mg/kg of hydrocortisone, 75 mg/kg of PS-K, vehicle alone, or non-treatment daily from the 27th to 29th week. All of these rats were sacrificed at the 30th week. The tumor incidence was 50% or 55% in indomethacin- or hydrocortisone-treated rats. It was significantly lower than 83% or 87% of the rats treated wih PS-K or vehicle, or untreated. The mean number of tumors was also smaller in those 2 groups of rats (2.0 or 2.1 tumors) than in 3 groups (3.5 or 3.3 tumors). The results demonstrated that the intrarectal dose of indomethacin and hydrocortisone inhibited the development of tumors from microscopic carcinoma lesions in the large bowel and growing further. It seems that indomethacin might be effective to treat the early stage disease with relatively small number of growing tumor cells.

Rapid in vitro effects of aldosterone (ALDO) on intracellular sodium, potassium and calcium, cell volume and the sodium-proton-antiport have been described in human mononuclear leukocytes and rat vascular smooth muscle cells (VSMC). These nongenomic effects are signaled through membrane receptors with a high affinity for aldosterone, but not for hydrocortisone. Effects of ALDO on the production of diacylglycerol (DAG) and protein kinase C alpha (PKC) were measured in VSCM by enzymatic assay and immunoblotting. DAG production was stimulated twofold by ALDO >> or = 1 nM) within 30 sec while hydrocortisone was inactive at concentrations of up to 1 microM. The inhibitors of phospholipase C, neomycin and U-73122 completely blocked this effect. PKC translocation from cytosol to membranes by ALDO occurred within 5 min, the extent of this effect was comparable to that of angiotensin II. These data demonstrate rapid intracellular signaling for ALDO in VSMC through phospholipase C, DAG and PKC in addition to calcium and inositol-1,4,5-trisphosphate as determined earlier.

Several studies have shown that stress and glucocorticoids can impair prefrontal-dependent working memory (WM) performance. WM is the ability to attend to the task at hand, and to maintain relevant information in mind during a delay while ignoring irrelevant stimuli. Here, it is investigated whether stress hormones impair WM by reducing the ability to suppress distracting, irrelevant neutral and emotional stimuli. Hydrocortisone (35 mg) (n=23) or placebo (n=21) was administered to young, healthy men, who performed a Sternberg WM task with neutral and emotional irrelevant distracters shown in the delay-phase of the task, between encoding and recognition of the relevant stimuli for WM. Contrary to expectations, enhanced WM performance with higher processing speed and a reduction of errors was found in the hydrocortisone group compared to placebo. Moreover, hydrocortisone significantly reduced the distraction by emotional stimuli. These findings show that cortisol effects on WM are not unambiguous and contrast with previous findings on the impairing effects of cortisol on WM. Dose-response studies could give more insight into the specific modulating effects of glucocorticoids on suppression of irrelevant emotional distraction.

Clones of epithelial-like cells were established from urethan-induced mouse lung adenoma. Electron microscopy of one clone showed that the cells contained lamellar inclusion bodies similar in appearance to those seen in the adenoma precursor, the type II alveolar pneumocyte. The clones exhibited characteristics associated with both "transformed" and "normal" cells in culture; i.e., although aneuploid, the cells grew at a slower rate than most transformed cells, did not form colonies in soft agar and, after prolonged subculture, were not tumorigenic when transplanted s.c. into appropriate hosts. Hydrocortisone treatment of the cloned cells led to growth stimulation and the eventual acquisition of neoplastic potential. Epithelial tumors were produced more readily in athymic, nude mice than in antilymphocyte serum-treated A/He mice. The cells are producing a C-type RNA virus into the culture medium.

OBJECTIVE

To determine the requirement for perioperative supplemental (stress) doses of corticosteroids in patients receiving long-term corticosteroid therapy and undergoing a surgical procedure. Corticosteroids are among the most commonly prescribed medications and will predictably result in suppression of the hypothalamic-pituitary-adrenal axis with long-term use. Patients receiving therapeutic dosages of corticosteroids frequently require surgery; these patients are almost universally treated with stress doses of corticosteroids during the perioperative period.

METHODS

MEDLINE, EMBASE, Cochrane Register of Controlled Trials, and citation review of relevant primary and review articles.

METHODS

Randomized controlled trials (RCTs) comparing stress doses of corticosteroids with placebo and cohort studies that followed up patients after surgery in which perioperative stress doses of corticosteroids were not administered.

METHODS

Data were abstracted on the study design, study size, study setting, patient population, dosage and duration of previous corticosteroid therapy, adrenal function testing results, surgical intervention, corticosteroid dosing regimen, intraoperative and postoperative hemodynamic profile, and incidence of adrenal crisis.

RESULTS

Nine studies met our inclusion criteria, including 2 RCTs and 7 cohort studies. These studies enrolled a total of 315 patients who underwent 389 surgical procedures. In the 2 RCTs, there was no difference in the hemodynamic profile between patients receiving stress doses of corticosteroids compared with patients receiving only their usual daily dose of corticosteroid. In the 5 cohort studies in which patients continued to receive their usual daily dose of corticosteroid without the addition of stress doses, no patient developed unexplained hypotension or adrenal crisis. One patient in each of the 2 cohort studies (5% and 1% of the cohort) in which the usual daily dose of corticosteroid was stopped 48 and 36 hours before surgery developed unexplained hypotension; both of these patients responded to hydrocortisone and fluid administration.

CONCLUSIONS

Patients receiving therapeutic doses of corticosteroids who undergo a surgical procedure do not routinely require stress doses of corticosteroids so long as they continue to receive their usual daily dose of corticosteroid. Adrenal function testing is not required in these patients because the test is overly sensitive and does not predict which patient will develop an adrenal crisis. Patients receiving physiologic replacement doses of corticosteroids owing to primary disease of the hypothalamic-pituitary-adrenal axis, however, require supplemental doses of corticosteroids in the perioperative period.

Suramin, a polysulphonated napthylurea, has been extensively evaluated over the past 10 years as an anticancer agent, with the most interest in the treatment of prostate cancer. Early clinical results were promising with response rates of up to 70% being reported. However, a recent double-blind study showed only modest palliative effect in patients with androgen independent prostate cancer. In retrospect, it appears those initial reports failed to control for confounding variables such as antiandrogen withdrawal and hydrocortisone. Suramin causes numerous reversible toxicities (lethargy, rash, fatigue, anemia, hyperglycemia, hypocalcemia, coagulopathies, neutropenia, renal and hepatic complications). Neurotoxicity has been the most significant complication and appears to be related to the intensity of the dosing regimen. An optimal therapeutic dose has not been determined, but it is clear that adaptive controls add little benefit. Aside from moderate toxicities and the low therapeutic index in patients with prostate cancer, suramin's development has taught us some valuable lessons (i.e., anti-androgen withdrawal was noted during suramin's development, the use of PSA as an indicator of tumor burden was initiated during the evaluation of suramin). These lessons can be applied to all clinical trials in hormone refractory prostate cancer. Suramin has significantly enhanced the evolution of our knowledge in several areas of prostate cancer biology and treatment.

We have recently demonstrated that the combination of IL-2 and IL-4 blunts T cell responses to glucocorticoids in steroid resistant (SR) asthma by reducing glucocorticoid receptor (GCR)-binding affinity. Since immune activation appears to be involved in the acquisition of steroid resistance, we sought to identify whether other cytokines could also induce diminished GCR-binding affinity. In the current report, utilizing a [3H]dexamethasone radioligand-binding assay and Scatchard analysis, we found that IL-13, a cytokine with similar actions as IL-4, could induce diminished GCR binding-affinity (GCR Kd = 34.4 +/- 2.3 nM with IL-13 vs Kd = 8.8 +/- 0.7 nM for unstimulated control cells; p < 0.001) in PBMC from normal subjects. In contrast, PBMC incubated with IL-1, IL-3, IL-5, IL-7, IL-8, IL-12, or granulocyte-macrophage-CSF had no effect on GCR-binding affinity; and no additive effect to the decreased GCR-binding affinity was noted when IL-13 was cocultured with IL-2 or IL-4. The cell target of IL-13-induced GCR effects was studied and found to reside in the non-T cell population; specifically, the monocyte fraction. To determine the functional significance of the decreased GCR-binding affinity, monocytes were pretreated with and without IL-1 3 prior to stimulation with LPS and hydrocortisone. IL-13 pretreatment of monocytes significantly diminished (p = 0.005) the suppressive effects of hydrocortisone on LPS-induced IL-6 production. IL-13, by virtue of its ability to induce diminished GCR-binding affinity, may contribute to impaired GC responsiveness during inflammatory illnesses.

BACKGROUND

Recent studies suggest that current glucocorticoid replacement therapies fail to completely restore well-being in patients with adrenal insufficiency (AI).

OBJECTIVE

The objective of this study was to investigate health-related quality of life (QoL) in patients with AI depending on dose and frequency of daily intake of hydrocortisone (HC).

METHODS

In a cross-sectional study, primary and secondary AI patients were contacted and asked to complete three validated self-assessment questionnaires [Short Form-36 (SF-36), Giessen Complaint List (GBB-24), Hospital Anxiety and Depression Scale (HADS)]. HC doses were corrected for body surface area. Results were compared with sex- and age-matched controls drawn from the questionnaire-specific reference cohort.

RESULTS

Completed questionnaire sets were available from 334 patients on HC (primary AI n = 194; secondary AI n = 140). Patients on higher doses of HC (>30 mg/day) showed significantly impaired subjective health status in two of eight SF-36 dimensions, and three of five GBB-24 scales compared with those on lower HC doses. No significant differences in QoL were found between lower HC doses (15-30 mg/day) or between primary or secondary AI. Patients on HC with thrice daily intake showed significantly impaired QoL in one of eight SF-36 dimensions (15-20 mg/day, 20-25 mg/day), in one of five GBB-24 scales (15-20 mg/day), as well as higher anxiety scores.

CONCLUSIONS

Health-related QoL was impaired in patients with primary and secondary AI. HC doses above 30 mg/day were associated with a worse health status. Thrice daily intake of HC was not superior to twice daily intake. Our data support the perception that current replacement strategies are still insufficient to fully restore well-being and daily performance.