The bioavailability of circulating and/or endogenous hydrocortisone (cortisol) in epidermal cells is a key determinant in inflammatory disease and chronic wounds. It is not known, however, whether epidermal cells can regulate tissue cortisol and whether they are capable of producing endogenous glucocorticoids. In the present study, we show by microarray analysis that epidermal cells express mRNAs to all the major enzymes involved in the metabolic chain from cholesterol to cortisol, including cytocrome P450 chain, 11β-hydroxysteroid dehydrogenases (HSD11Bs), adrenocorticotropic hormone (ACTH) receptor (MC2R), and glucocorticoid receptor. The two enzymes mediating activation/deactivation of cortisone to cortisol, namely HSD11B1 and HSD11B2, were expressed at the protein level in cultured keratinocytes as well as human skin samples, as shown by Western blotting and immunohistochemistry, respectively. In functional assays, we show that keratinocytes are not only able to activate cortisone to cortisol in a HSD11B-dependent manner but also silencing of either HSD11B1 or HSD11B2 specifically modulates the bioavailability of the inactive glucocorticoid and the active steroid, respectively. A further key observation was that keratinocytes responded to stimulation with ACTH by a significant increase in the de novo synthesis of cortisol. Taken together, we provide evidence for a novel non-adrenal steroideal system in human keratinocytes.

OBJECTIVE

The anti-inflammatory effect and adrenal suppressive side effect of methylprednisolone sodium succinate (MP) on the postoperative sequelae of third molar surgery were evaluated using objective methods in a double-blind, crossover study.

METHODS

Twenty patients who were to undergo surgical removal of bilateral, symmetrically placed lower third molars were studied. Each patient was given 125 mg MP intravenously before surgery on one side, and a placebo before surgery on the opposite side on a random basis. Ultrasonographic and computed tomographic examinations were performed to determine the amount of facial edema. Trismus was evaluated by measuring maximal interincisal opening, and pain was evaluated by recording the number of standard analgesic tablets used on the day of surgery and the first postoperative day. Hypothalamic-pituitary-adrenal (HPA) axis function was tested by measuring basal plasma cortisol (hydrocortisone) levels preoperatively and postoperatively. The adrenocorticotropic hormone (ACTH) stimulation test also was performed before and after administration of MP, to evaluate adrenal function.

RESULTS

Statistical analysis of the data indicated a significant decrease in edema, trismus, and pain in the MP group. Plasma cortisol levels showed a nonsignificant decrease in both the MP- and placebo-treated groups. The ACTH stimulation test indicated normal HPA axis function before and after MP administration. No clinically apparent infection, disturbance of wound healing, or other corticosteroid-related complications were noted. Eighteen patients (90%) indicated a preference for the overall postoperative course when MP was used.

CONCLUSIONS

In the absence of contraindications for corticosteroid administration, preoperative use of MP appears to be a safe and effective method of reducing postoperative complications in third molar surgery.

OBJECTIVE

To delineate some of the characteristics of septic vascular hypotension, to assess the most commonly cited and reported underlying mechanisms of vascular hyporesponsiveness to vasoconstrictors in sepsis, and to briefly outline current therapeutic strategies and possible future approaches.

METHODS

Source data were obtained from a PubMed search of the medical literature with the following MeSH terms: Muscle, smooth, vascular/physiopathology; hypotension/etiology; shock/physiopathology; vasodilation/physiology; shock/therapy; vasoconstrictor agents.

RESULTS

Nitric oxide (NO) and peroxynitrite are crucial components implicated in vasoplegia and vascular hyporeactivity. Vascular ATP-sensitive and calcium-activated potassium channels are activated during shock and participate in hypotension. In addition, shock state is characterized by inappropriately low plasma glucocorticoid and vasopressin concentrations, a dysfunction and desensitization of alpha-receptors, and an inactivation of catecholamines by oxidation. Numerous other mechanisms have been individualized in animal models, the great majority of which involve NO: MEK1/2-ERK1/2 pathway, H(2)S, hyperglycemia, and cytoskeleton dysregulation associated with decreased actin expression.

CONCLUSIONS

Many therapeutic approaches have proven their efficiency in animal models, especially therapies directed against one particular compound, but have otherwise failed when used in human shock. Nevertheless, high doses of catecholamines, vasopressin and terlipressin, hydrocortisone, activated protein C, and non-specific shock treatment have demonstrated a partial efficiency in reversing sepsis-induced hypotension.

BACKGROUND

Because of the disability associated with surgery for anal fissure and the risk of incontinence, medical alternatives for surgery have been sought. Most recently, pharmacologic methods that relax the anal smooth muscle, to accomplish reversibly what occurs in surgery, have been used to obtain fissure healing.

OBJECTIVE

To assess the efficacy and morbidity of various medical therapies for anal fissure.

METHODS

Search terms include "anal fissure randomized". Timing from 1966 to August 2010. Further details of the search below.

METHODS

Studies in which participants were randomized to a non-surgical therapy for anal fissure. Comparison groups may include an operative procedure, an alternate medical therapy or placebo. Chronic fissure, acute fissure and fissure in children are included in the review. Atypical fissures associated with inflammatory bowel disease or cancer or anal infection are excluded.

METHODS

Data were abstracted from published reports and meeting abstracts, assessing method of randomization, blinding, "intention to treat" and drop-outs, therapies, supportive measures (applied to both groups), dosing and frequency and cross-overs. Dichotomous outcome measures included Non-healing of the fissure (a combination of persistence and recurrence), and Adverse events (including incontinence, headache, infection, anaphylaxis). Continuous outcome measures included measures of pain relief and anorectal manometry.

RESULTS

In this update 23 studies including 1236 participants is added to the 54 studies and 3904 participants in the 2008 publication, however 2 studies were from the last version reclassified as un included, so the final number of participants is 5031.49 different comparisons of the ability of medical therapies to heal anal fissure have been reported in 75 RCTs. Seventeen agents were used (nitroglycerin ointment (GTN), isosorbide mono & dinitrate, Botulinum toxin (Botox), diltiazem, nifedipine (Calcium channel blockers or CCBs), hydrocortisone, lignocaine, bran, minoxidil, indoramin, clove oil, L-arginine, sitz baths, sildenafil, "healer cream" and placebo) as well as Sitz baths, anal dilators and surgical sphincterotomy. GTN was found to be marginally but significantly better than placebo in healing anal fissure (48.9% vs. 35.5%, p < 0.0009), but late recurrence of fissure was common, in the range of 50% of those initially cured. Botox and CCBs were equivalent to GTN in efficacy with fewer adverse events. No medical therapy came close to the efficacy of surgical sphincterotomy, though none of the medical therapies in these RCTs were associated with the risk of incontinence.

CONCLUSIONS

Medical therapy for chronic anal fissure, currently consisting of topical glyceryl trinitrate, botulinum toxin injection or the topical calcium channel blockers nifedipine or diltiazem in acute and chronic fissure and fissure in children may be applied with a chance of cure that is marginally better than placebo. For chronic fissure in adults all medical therapies are far less effective than surgery. A few of the newer agents investigated show promise based only upon single studies (clove oil, sildenifil and a "healer cream") but lack comparison to more established medications.

OBJECTIVE

Glucocorticoids, such as prednisone, hydrocortisone, and dexamethasone, are known to produce some clinical benefit for patients with hormone-refractory prostate cancer (HRPC). However, the underlying mechanisms by which glucocorticoids affect HRPC growth are not well established as yet. Here, we hypothesize that the therapeutic effect of glucocorticoids on HRPC can be attributed to a direct inhibition of angiogenesis through the glucocorticoid receptor by down-regulating two major angiogenic factors, vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8).

METHODS

The effects of dexamethasone on VEGF and IL-8 expression and cell proliferation were examined using DU145, which expresses glucocorticoid receptor. The effects of dexamethasone on DU145 xenografts were determined by analyzing VEGF and IL-8 gene expression, microvessel density, and tumor volume.

RESULTS

Dexamethasone significantly down-regulated VEGF and IL-8 gene expression by 50% (P < 0.001) and 89% (P < 0.001), respectively, and decreased VEGF and IL-8 protein production by 55% (P < 0.001) and 74% (P < 0.001), respectively, under normoxic condition. Similarly, hydrocortisone down-regulated VEGF and IL-8 gene expression. The effects of dexamethasone were completely reversed by the glucocorticoid receptor antagonist RU486. Even under hypoxia-like conditions, dexamethasone inhibited VEGF and IL-8 expression. In DU145 xenografts, dexamethasone significantly decreased tumor volume and microvessel density and down-regulated VEGF and IL-8 gene expression, whereas dexamethasone did not affect the in vitro proliferation of the cells.

CONCLUSIONS

Glucocorticoids suppressed androgen-independent prostate cancer growth possibly due to the inhibition of tumor-associated angiogenesis by decreasing VEGF and IL-8 production directly through glucocorticoid receptor in vivo.

The effects of insulin, hydrocortisone, and prolactin on the morphology of explants from midpregnant mouse mammary glands were studied. Insulin promotes the formation of daughter cells within the alveolar epithelium which are ultrastructurally indistinguishable from the parent cells. The addition of hydrocortisone to the medium containing insulin brings the daughter cells to a new, intermediate level of ultrastructural development by effecting an extensive increase of the rough endoplasmic reticulum (RER) throughout the cytoplasm and an increase in the lateral paranuclear Golgi apparatus. When prolactin is added to the insulin-hydrocortisone medium, the daughter cells complete their ultrastructural differentiation. There is a translocation of the RER, Golgi apparatus, and nucleus and the appearance of secretory protein granules within the cytoplasm. There is excellent correlation between the ultrastructural appearance of the alveoli and their capacity to synthesize casein.

OBJECTIVE

Systemic corticosteroids remain controversial in the treatment of pediatric patients with severe sepsis. Recent studies in septic adults have shown decreased mortality with the use of hydrocortisone in patients with relative adrenal insufficiency. We conducted this large retrospective cohort study to further characterize severe sepsis in infants and children and correlates of outcome, including the use of steroids.

METHODS

Retrospective cohort study.

METHODS

The Pediatric Health Information System (PHIS), an administrative database of the Child Health Corporation of America (CHCA), was queried for inpatients 0-17 yrs of age with severe sepsis (defined here as an International Classification of Disease 9th edition code for infection with use of simultaneous mechanical ventilation and vasoactive infusions) from 2001 to 2002. In addition to demographic information, use of systemic corticosteroids (hydrocortisone, methylprednisolone, or dexamethasone) concurrent with the ventilatory and vasoactive support was collected.

METHODS

Data from PHIS.

METHODS

None.

RESULTS

Patients (n = 6693) were identified at 27 PHIS-participating CHCA member hospitals. Overall mortality was 24%; univariate predictors of death included use of steroids (odds ratio [OR], 1.9; 95% confidence interval (CI), 1.7, 2.2), older age (e.g., 13-17 yrs vs. neonates; OR, 1.6; 95% CI, 1.3, 2.0), a hematologic-oncologic diagnosis (OR, 5.87; 95% CI, 4.19, 8.23), and moderate vs. high case volume (OR, 1.25; 95% CI, 1.09, 1.44). Age, hematologic-oncologic diagnosis, case volume, and use of steroids remained independent predictors of mortality in multivariable analysis.

CONCLUSIONS

From this administrative database analysis, there is no evidence that steroids are associated with improved outcome in critically ill infants and children with sepsis. Although steroids may be given preferentially to more severely ill children, their use was associated with increased mortality. Clinicians should maintain equipoise on this topic pending prospective randomized clinical trials.

Idiopathic low back pain has confounded health care practitioners for decades. Although there has been much advance in the understanding of the biomechanics of the lumbar spine over the past 25 years, the cellular and neural mechanisms that lead to facet pain are not well understood. An extensive series of experiments was undertaken to help elucidate these mechanisms and gain a better understanding of lumbar facet pain. Biomechanic and neuroanatomic studies were performed in human cadaveric facet joints and neurophysiologic studies were performed in New Zealand White rabbits. These studies provide the following evidence to help explain the mechanisms of lumbar facet pain: (1) The facet joint can carry a significant amount of the total compressive load on the spine when the human spine is hyperextended. (2) Extensive stretch of the human facet joint capsule occurs when the spine is in the physiologic range of extreme extension. (3) An extensive distribution of small nerve fibers and free and encapsulated nerve endings exists in the lumbar facet joint capsule, including nerves containing substance P, a putative neuromodulator of pain. (4) Low and high threshold mechanoreceptors fire when the facet joint capsule is stretched or is subject to localized compressive forces. (5) Sensitization and excitation of nerves in facet joint and surrounding muscle occur when the joint is inflamed or exposed to certain chemicals that are released during injury and inflammation. (6) Marked reduction in nerve activity occurs in facet tissue injected with hydrocortisone and lidocaine. Thus, the facet joint is a heavily innervated area that is subject to high stress and strain. The resulting tissue damage or inflammation is likely to cause release of chemicals irritating to the nerve endings in these joints, resulting in low back pain.

Glucocorticoids are known to play a role in the regulation of peripheral glucose mobilization and metabolism. Although several animal studies have shown that hippocampal glucose metabolism is reduced acutely and chronically by the action of corticosterone and that excess glucocorticoids are harmful to hippocampal neurons, little is known about the central effects of glucocorticoids in the human. In this study we examined the brain glucose utilization (CMRglu) response to hydrocortisone (cortisol) in seven normal elderly and eight Alzheimer's disease (AD) patients. On 2 separate days, immediately after the administration of a bolus of either 35 mg hydrocortisone or placebo, we administered 2-deoxy-2-[18F]fluoro-D-glucose. After a 35-min radiotracer uptake period, positron emission tomography (PET) images were collected. PET CMRglu images were analyzed using two methods: an image transformation that allowed analyses across cases on a voxel by voxel basis, and an anatomically based region of interest method that used coregistered magnetic resonance imaging scans. Both image analysis methods yielded similar results, identifying relative to placebo, a specific hippocampal CMRglu reduction in response to the hydrocortisone challenge that was restricted to the normal group. The region of interest technique showed CMRglu reductions of 16% and 12% in the right and left hippocampi, respectively. Blood collected during the PET scans showed, for the normal group, a rise in plasma glucose levels, starting approximately 25 min after hydrocortisone administration. The AD group did not show this effect. Baseline cortisol was elevated in the AD group, but the clearance of hydrocortisone was not different between the groups. In conclusion, these data show that among normal individuals in the presence of a pharmacological dose of cortisol, the glucose utilization of the hippocampus is specifically reduced, and serum glucose levels increase. Based in part on other studies, we offer the interpretation that glucocorticoid-mediated regulation of glucose transport is altered in AD, and this may underlie both the hippocampal insensitivity to cortisol and the failure in these patients to mount a peripheral glucose response. As our findings could reflect an altered state of the AD patients, we interpret our results as preliminary with respect to evidence for metabolic abnormalities in AD. The results suggest the continued study of the hydrocortisone challenge as a test of hippocampal responsivity.

The increasing number of newly developed drugs demands for functional in vitro models of the blood-brain barrier to determine their brain uptake. Cultured cerebral capillary endothelial cells are considered to be such a model, however in serum containing media they exhibit low electrical resistances and high permeabilities compared to the in vivo situation. Here we report the establishment of a serum-free cell culture model. Withdrawal of serum already caused a twofold increase of transendothelial resistance (TER), which in presence of serum is about 100-150 Omega x cm2. We tested several supplements and found that hydrocortisone is a potent stimulator for the formation of barrier properties. TERs up to 1000 Omega x cm2 were measured in the presence of physiological relevant hydrocortisone concentrations. In correspondence to the TER increase hydrocortisone decreased cell monolayer permeability for sucrose down to 5x10(-7) cm/s, which is close to the in vivo value of 1.2x10(-7) cm/s and by a factor of five lower compared to cultures without hydrocortisone and in presence of serum.

The 3T3-L1 mouse fibroblast cell line develops morphological and biochemical characteristics of adipocytes when maintained at confluence. This conversion to adipocytes is accelerated by addition of insulin to the culture medium [Green, H. & Kehinde, O. (1975) Cell 5, 19-27]. During the course of the insulin-mediated adipocyte conversion, the specific activity (units/mg of protein) of glutamine synthetase [L-glutamate:ammonia ligase (ADP-forming), EC 6.3.1.2] increases more than 100-fold. The specific activities of hexokinase (ATP:D-hexose 6-phosphotransferase, EC 2.7.1.1) and glucose-6-P dehydrogenase (D-glucose-6-phosphate:NADP(+) 1-oxidoreductase, EC 1.1.1.49) also increase but less dramatically (1.5- to 3-fold). In contrast, confluent cells maintained in the absence of insulin for the same time (12-20 days after confluence) display only minimal increases in the activity of these enzymes. Maintenance of confluent cells in culture medium lacking added L-glutamine has little, if any, effect on glutamine synthetase activity in either control or insulin-treated cultures. Treatment of confluent 3T3-L1 cultures with hydrocortisone (1 mug/ml) for 3 days prior to harvesting results in an increase in glutamine synthetase specific activity of 12-fold for control cultures maintained for 13 days in the absence of insulin and 1.4-fold for adipocyte cultures maintained for 13 days in the presence of insulin (10 mug/ml). Treatment of 3T3-L1 control cells and adipocytes with dibutyryl cyclic AMP (1 mM) plus theophylline (1 mM) decreases the glutamine synthetase specific activity and almost completely reverses the insulin- and hydrocortisone-mediated increases in enzyme activity. In contrast, treatment with dibutyryl cyclic AMP plus theophylline has relatively little effect on the specific activities of hexokinase or glucose-6-P dehydrogenase or on the protein content of the cultures. These data indicate that glutamine synthetase activity is hormonally regulated in 3T3-L1 cells.

Two neutral proteinases from human polymorphonuclear leukocytes (PMN), an elastase and the chymotrypsin-like cathepsin G, were purified, and their actions on lymphocytes in culture were studied. Both PMN proteinases stimulate lymphocytes from human peripheral blood and from mouse spleen in vitro, but do not affect thymic cells from either normal or hydrocortisone-treated mice. In stimulated mouse spleen cell cultures, most of the developing blast cells bear surface immunoglobulins, and subsequently appear to engage in antibody synthesis. In their stimulatory action, the two PMN proteinases thus resemble the classic B-cell mitogen LPS and neutral pancreatic proteinases such as trypsin, chymotrypsin, and elastase. The effects of proteinase inhibitors indicate that lymphocyte stimulation is dependent on the proteolytic activity of the enzymes. This work suggests that PMN proteinases, which are released at sites of inflammation, may modulate the function of lymphocytes.

An increasing number of studies are utilizing saliva sampling as a method of assessing adrenal steroid secretion. Saliva samples have certain advantages over plasma, being non-invasive and easily collected. However, some methods of collection may compromise the accuracy of the assay, particularly those which employ aids to stimulate saliva production. We sought to compare the accuracy of cortisol and dehydroepiandrosterone (DHEA) measurement by examining the association between plasma levels, saliva and saliva collected using a citric acid-treated salivette device. Twenty six healthy male volunteers were recruited for the study. To increase the range of steroid levels in the samples collected, half the subjects were pre-treated with hydrocortisone (20mg, twice a day for 7 days) and half with placebo. Saliva samples were then collected from each subject using both a 'passive drool' method and a citric acid-treated salivette. A plasma sample was also collected. Cortisol and DHEA levels were measured by radioimmunoassay. For cortisol levels, both methods of saliva collection correlated highly with plasma levels and with each other (r 0.85; R(2) 0.72 for all). For DHEA levels, only saliva samples collected using the unstimulated collection method correlated with plasma levels. DHEA collected using the salivette device did not correlate significantly with either plasma or the unstimulated saliva (r 0.2;R(2) 0.04). It is crucial that future studies are aware of these issues and are cognizant of the effects of the method of collection when examining steroid levels in saliva.

U937 is a human-derived lymphoma cell line that has monoblastic properties and high-affinity receptors for 1 alpha,-dihydroxyvitamin D3. Incubation of these cells with the vitamin D metabolite at 10 nM for 5 days produced marked stimulation in adherence and ingestion of Staphylococcus aureus (645% of control) and of C3b receptor (CR1) expression (292% of control) and a slight increase in hexose monophosphate shunt activity without changing cell growth rates or Fc fragment receptor expression. The changes in cellular association of S. aureus and the CR1 were detected as early as 48 hr of incubation and peaked between 3 and 5 days. Similar changes in the CR1 were induced by 25-hydroxy- and 24,25-dihydroxyvitamin D3 at micromolar concentrations. Dexamethasone, hydrocortisone, and progesterone had no effect on CR1 expression. U937 cells incubated in the presence of vitamin D metabolites exhibited a change in their phenotype. These results suggest that vitamin D metabolites may contribute to monocyte/macrophage differentiation.

Individually different growth responses of 10 cell lines newly derived from metastasizing mammary carcinomas were determined by cell counts in experimental incubations with the steroid hormones 17 beta-estradiol, progesterone, testosterone, hydrocortisone (cortisol), the antiestrogenic compound tamoxifen, or prolactin. Of 7 cell lines derived from ductal carcinomas, 5 were stimulated by prolactin. The growth of 4 of 7 cell lines established from the tumors of postmenopausal or ovariectomized patients was enhanced by doses of testosterone, which are in the range of the physiologic serum level. The proliferation of 5 cell lines was promoted by hydrocortisone in the physiologic concentration of 100 nM, supporting the notion that concentrations of testosterone or hydrocortisone normally present in body fluids may facilitate the in vivo growth of breast cancer. The in vitro growth of cells derived from tumors after relapse under treatment with medroxyprogesterone acetate or tamoxifen was markedly enhanced by progesterone or tamoxifen (CAS: 10540-29-1) in concentrations corresponding to therapeutical serum levels and in accordance with in vivo resistance to the endocrine therapy applied before cell sampling. The results of this suggest the occurrence of positive endocrine selection mechanisms operating in vivo on human mammary tumor cell populations.

BACKGROUND

Envenoming from snakebites is most effectively treated by antivenom. However, the antivenom available in South Asian countries commonly causes acute allergic reactions, anaphylactic reactions being particularly serious. We investigated whether adrenaline, promethazine, and hydrocortisone prevent such reactions in secondary referral hospitals in Sri Lanka by conducting a randomised, double-blind placebo-controlled trial.

RESULTS

In total, 1,007 patients were randomized, using a 2 × 2 × 2 factorial design, in a double-blind, placebo-controlled trial of adrenaline (0.25 ml of a 1∶1,000 solution subcutaneously), promethazine (25 mg intravenously), and hydrocortisone (200 mg intravenously), each alone and in all possible combinations. The interventions, or matching placebo, were given immediately before infusion of antivenom. Patients were monitored for mild, moderate, or severe adverse reactions for at least 96 h. The prespecified primary end point was the effect of the interventions on the incidence of severe reactions up to and including 48 h after antivenom administration. In total, 752 (75%) patients had acute reactions to antivenom: 9% mild, 48% moderate, and 43% severe; 89% of the reactions occurred within 1 h; and 40% of all patients were given rescue medication (adrenaline, promethazine, and hydrocortisone) during the first hour. Compared with placebo, adrenaline significantly reduced severe reactions to antivenom by 43% (95% CI 25-67) at 1 h and by 38% (95% CI 26-49) up to and including 48 h after antivenom administration; hydrocortisone and promethazine did not. Adding hydrocortisone negated the benefit of adrenaline.

CONCLUSIONS

Pretreatment with low-dose adrenaline was safe and reduced the risk of acute severe reactions to snake antivenom. This may be of particular importance in countries where adverse reactions to antivenom are common, although the need to improve the quality of available antivenom cannot be overemphasized.

Human peripheral neutrophils generated superoxide radicals as assessed by ferricytochrome C reduction in response to activation by the synthetic chemotactic factor, N-formyl-methionyl-leucyl-phenylalanine. Superoxide generation was inhibited by 2-deoxy-D-glucose (ID50 4 X 10(-5)M), 2-iodoacetate (ID50 5 X 10(-5)M), and N-ethyl-maleimide (ID50 5 X 10(-6)M), suggesting a dependence on anaerobic glycolysis and sulfhydryl groups. Ouabain, microtubule-disrupting agents, inhibitors of respiration, oxidative phosphorylation, and protein and nucleic acid synthesis were without appreciable effects. Indomethacin (ID50 1 X 10(-4)M), ibuprofen (ID50 9 X 10(-4)M, and phenylbutazone (ID50 1 X 10(-5)M) all caused dose-dependent inhibition of superoxide generation at concentrations approximating those plasma and tissue levels obtained in human beings at therapeutic doses. Acetylsalicylic acid (125-500) microgram/ml) and aurothioglucose (10(-3)-10(-6)M) were without appreciable effects. Superoxide generation was inhibited only by relatively high concentrations of hydrocortisone (ID50 greater than 10(-3)M). Because superoxide radicals have been implicated in the pathogenesis of tissue injury in several forms of inflammation and arthritis in vivo, these studies suggest that the production of a potential cytotoxic factor may be subject to pharmacologic manipulation and that at least some of the antiphlogistic effects of the nonsteroidal antiinflammatory agents may be mediated through effects on superoxide production.

BACKGROUND

There are few studies that describe the medical treatment and colitis response rates among patients with a severe relapse of inflammatory bowel disease (IBD) during pregnancy, and few studies of the effect of such a relapse on birth outcomes in these patients.

OBJECTIVE

To describe the treatment and response rates of severe colitis in pregnancy, and to assess the effects of a severe relapse of colitis during pregnancy on birth outcomes.

METHODS

We performed a case control study of pregnant patients with IBD hospitalized for a disease relapse at two large treatment centers between 1989 and 2001. Details of management of disease relapse and maternal and fetal outcomes were recorded.

RESULTS

Eighteen patients (11 ulcerative colitis, 6 Crohn's disease, 1 indeterminate colitis), mean age 28.6 yr (range 19-38) formed the study group; 41 age-matched pregnant IBD patients without disease relapse formed the control group. Study patients were hospitalized at a mean of 15.9-wk gestation (range 8-35) for a mean of 10.4 days (range 3-31). All 18 patients received IV hydrocortisone (mean dose 199 mg/day) and 7 patients (39%) either continued taking or were commenced on immunomodulators: IV cyclosporine (5 patients) and azathioprine/6-MP (3 patients). Fifteen patients (83%) had a clinical response to these medical treatments, 3 patients required colectomy. There were significant differences between study and control groups in gestation period (35.0 wk vs 38.7 wk, respectively, P= 0.0001) and birth weight (2,001 g vs 3,018 g, respectively, P < 0.0001).

CONCLUSIONS

Treatment with IV hydrocortisone and IV cyclosporine appears effective at inducing remission of colitis but their use must continue to be confined to severely ill patients being treated at specialized centers. Severe relapses of colitis during pregnancy increase the risk of preterm birth and low birth weight.

The effect of epidermal growth factor (EGF) on the in vitro growth of 186 malignant human tumor specimens (45 melanomas, 32 sarcomas, and 56 lung, 16 gynecological, 14 breast, 12 genitourinary, and 11 gastrointestinal carcinomas) was evaluated in the cellular adhesive matrix human tumor culture system supplemented with transferrin, insulin, hydrocortisone, and estradiol. EGF increased tumor growth by at least 50% in 81% of the 186 tumors and by over 100% in 54%. The enhanced growth induced by EGF was related to an accelerated cellular division independent of tumor type and not to an increase in the actual number of clonogenic units. The drug concentrations of cell cycle-independent Adriamycin and cisplatin needed to achieve a 90% tumor cell kill were not altered by the responsiveness of the tumor to EGF.

OBJECTIVE

In the vulnerability-stress concept of schizophrenia, schizophrenic patients are thought to display increased sensitivity to stress. Little is known about the biological mechanisms that are involved in stress processing in schizophrenic patients. In this study, hypothalarnic-pituitary-adrenal (HPA) function in schizophrenic patients was studied for its essential role in stress processing and adaptation to the environment.

METHODS

Eighteen schizophrenic patients were compared to 21 healthy controls in their salivary cortisol response to a physical (bicycle ergometry) and a psychosocial (public speaking) stressor. Coping questionnaires were included as a measure of stress processing at the psychological level. Basal HPA function was assessed by measuring cortisol day profiles and feedback activity by using dexamethasone and hydrocortisone.

RESULTS

Schizophrenic patients showed blunted cortisol responses to the psychosocial stressor, but not to the physical stressor, in spite of similar increases in heart rate. The cortisol response to the psychosocial stressor tended to be negatively correlated to the use of passive and avoidant coping strategies. Basal HPA function appeared intact in the schizophrenic patients.

CONCLUSIONS

The findings show a selective impairment in the response to psychosocial stress in schizophrenic patients. This suggests the involvement of brain systems that play a role in the activation of the HPA system to psycho-social stress, like arginin-vasopressin (AVP), and cognitive processes, like coping.

Stress modulates instrumental action in favor of habitual stimulus-response processes that are insensitive to changes in outcome value and at the expense of goal-directed action-outcome processes. The neuroendocrine mechanism underlying this phenomenon is unknown. Here, we tested the hypothesis that concurrent glucocorticoid and noradrenergic activity bias instrumental behavior toward habitual performance. To this end, healthy men and women received hydrocortisone, the alpha2-adrenoceptor antagonist yohimbine or both orally before they were trained in two instrumental actions leading to two distinct food outcomes. After training, one of the outcomes was devalued by inviting participants to eat that food to satiety. A subsequent extinction test revealed whether instrumental performance was goal-directed or habitual. Participants that received hydrocortisone or yohimbine alone decreased responding to the devalued action in the extinction test, i.e., they behaved goal-directed. The combined administration of hydrocortisone and yohimbine, however, rendered participants' behavior insensitive to changes in the value of the goal (i.e., habitual). These findings demonstrate that the concerted action of glucocorticoids and noradrenergic activity shifts instrumental behavior from goal-directed to habitual control.

BACKGROUND

Corticosteroids, particularly dexamethasone, are commonly used for treatments in patients with subarachnoid haemorrhage (SAH) and primary intracerebral haemorrhage (PICH) despite the lack of evidence.

OBJECTIVE

This review aimed: (1) to determine whether corticosteroid therapy reduces the proportion of patients who die or have a poor outcome at one to six months after the onset of SAH or PICH; (2) to determine whether corticosteroid therapy reduces the frequency of delayed cerebral ischaemia (DCI) in patients with SAH; (3) to determine the frequency of adverse effects of corticosteroid therapy in patients with SAH or PICH within six months of the onset of the event.

METHODS

We searched the Cochrane Stroke Group Trials Register (last searched November 2003). In addition, we searched MEDLINE (1966 to March 2004) and EMBASE (1980 to March 2004), and searched reference lists of relevant studies identified. We also made an attempt to identify any relevant ongoing and published or unpublished studies by contacting trialists and pharmaceutical companies.

METHODS

We sought to identify all randomised or quasi-randomised clinical trials of corticosteroid therapy, in patients with SAH or PICH, that have a placebo or standard strategy arm as control. Patients of any age and either gender with clinically (bed-side) diagnosed PICH and cerebrospinal fluid documented SAH were included in the analysis. The data were analysed both separately and combined for computed tomography (CT)/magnetic resonance imaging (MRI)/autopsy/angiography verified patients.

METHODS

Data extracted from eligible clinical trials included: (1) death and poor outcome (death, severe disability, or vegetative state) within the first one to six months of the event onset (primary outcomes); (2) development of delayed cerebral ischaemia (as defined by the trialists) in patients with SAH; and (3) adverse effects of the treatment during the scheduled treatment or follow-up period (secondary outcomes). A pooled estimate of the effect size was computed, and the test for heterogeneity between trial results was carried out using The Cochrane Collaboration's Review Manager software, RevMan 4.2. Intention-to-treat analysis was carried out whenever possible.

RESULTS

Eight trials that fulfilled the eligibility criteria were identified, with a total of 256 randomised patients in three SAH trials, and 206 patients in five PICH trials. The studies differed substantially with regard to the study populations and drugs, and methodological quality. The number of patients allocated to either hydrocortisone or fludrocortisone acetate treatment in patients with SAH, or to dexamethasone treatment in patients with PICH, was too small to make any definitive conclusions (confidence intervals were wide for any of the outcome estimates).

CONCLUSIONS

Overall, there is no evidence of a beneficial or adverse effect of corticosteroids in patients with either SAH or PICH. Confidence intervals are wide and include clinically significant effects in both directions.

The effect of human recombinant interleukin-1 alpha (IL-1 alpha) on a systemic candidal infection in mice under various conditions of immunosuppression was investigated. In normal mice and in mice pretreated with cyclophosphamide, hydrocortisone acetate, or sublethal total body irradiation, the outgrowth of Candida albicans in the kidney was significantly reduced by the administration of a single intraperitoneal dose of 80 ng of IL-1 (P less than 0.05). In mice treated with either cyclophosphamide or irradiation, IL-1 also significantly reduced the outgrowth of C. albicans in the spleen. The protective effect of IL-1 was present when given 24 h before injection of C. albicans but also when IL-1 was given simultaneously with or 6 h after injection of C. albicans in cyclophosphamide-treated mice. The effect of IL-1 was independent of the presence or recruitment of granulocytes, since IL-1 inhibited the outgrowth of C. albicans in the kidneys and spleens of mice that were rendered severely granulocytopenic (less than 50 granulocytes per mm3) throughout the duration of the infection by either repeated injections of cyclophosphamide or sublethal total body irradiation. These results indicate that the enhancement of host resistance by IL-1 is not due solely to increased granulocytopoiesis or chemotaxis of granulocytes but strongly suggest that other mechanisms play a role in the protective effect of IL-1 against systemic infections.