The in vitro mechanisms by which Entamoeba histolytica trophozoites lyse target Chinese hamster ovary (CHO) cells were examined. Calcium chelators ethylenediaminetetraacetate and ethyleneglycol bis (beta-aminoethyl ether)-N,N'-tetraacetate (10 mM) inhibited amebic cytolysis of target CHO cells (P less than .01). A putative antagonist of intracellular calcium flux, 8-(N,N-diethylamino)octyl-3,4,5-trimethoxybenzoate (TMB-8; greater than or equal to 250 microM), inhibited amebic adherence and cytolysis (P less than .001). Quinacrine, Rosenthal's inhibitor (dimethyl-dl-2,3-distearoyloxypropyl-2'-hydroxyethyl ammonium acetate), phosphatidylcholine, and hydrocortisone (greater than or equal to 10(-4) M), all pharmacological antagonists of eukaryotic phospholipase A enzymes, inhibited amebic killing of target CHO cells (P less than .001). At 37 C quinacrine and hydrocortisone reduced amebic adherence to CHO cells, whereas Rosenthal's inhibitor and phosphatidylcholine did not. Phosphatidylcholine and TMB-8 demonstrated a synergistic inhibitory effect on amebic killing of target CHO cells (P less than .001). These studies indicate that extracellular calcium ions, amebic intracellular calcium flux, and amebic phospholipase A activity are required for cytolysis of target cells by E. histolytica.

A method is described for growing high-density micromass cultures of chick and mouse limb mesenchyme cells in 96-well microtiter plates (microT microM cultures). Rapid quantitative estimates of chondrogenic expression were obtained by automated spectrophotometric analysis of Alcian-blue-stained cartilage matrix extracts performed in the wells in which the cells had been grown. Quantitative estimates of myogenic expression were obtained similarly using anti-sarcomere myosin monoclonal antibody and modified ELISA techniques. This microT microM-ELISA method may be adapted for use with other antigens for which specific antibodies are available. These methods were used to compare cartilage and muscle differentiation in 1 to 4 d microT microM cultures grown in serum-containing (SCM) and defined (DM) media. The DM contains minimal additives (insulin, hydrocortisone, and in some cases, ascorbate or transferrin) and supports both chondrogenesis and myogenesis. The colorimetric analyses agree well with the morphologic appraisal of chondrogenesis and myogenesis. Similar numbers of cartilage nodules formed in all cultures, but in DM the nodules failed to enlarge; explaining the reduced matrix synthesis in DM as compared with SCM, and suggesting that nodule enlargement is a discrete, serum-dependent step. Studies of selected additives to DM show that transferrin enhances myogenesis, ascorbic acid enhances chondrogenesis, and retinoic acid inhibits chondrogenesis. Together, the microT microM system, in situ colorimetric assays of chondrogenesis and myogenesis, and DM will allow rapid prescreening of teratogens and screening of various bioactive compounds (e.g., hormones, growth factors, vitamins, adhesion factors) for effects on limb mesenchymal cell differentiation.

An emerging theme in the neuroscience of emotion is the question of how acute stress shapes, and distorts, social-emotional behavior. The prevailing neurocircuitry models of social-emotional behavior emphasize the central role of the amygdala. Acute stress leads to increased central levels of norepinephrine (NE) and cortisol (CORT), and evidence suggests that these endogenous neuromodulators synergistically influence amygdala responses to social-emotional stimuli. We therefore hypothesized that amygdala responses to emotional facial expressions would be susceptible to pharmacologically induced increases in central NE and CORT levels. To specifically test this hypothesis, we measured amygdala activation to emotional faces using functional magnetic resonance imaging in 62 healthy subjects under four pharmacological conditions: (1) single oral dose of placebo, (2) 4 mg of the selective NE-reuptake inhibitor reboxetine (RBX), (3) 30 mg of hydrocortisone, or (4) both drugs in combination. We found that a decrease in amygdala activation to positive facial emotion was coupled with an increase in amygdala activation to negative facial emotion in the RBX-CORT combined challenge condition. In conclusion, a pharmacologically induced elevation of central NE and CORT levels in healthy subjects created a negative response bias in the amygdala that did not exist at baseline. Our results implicate a causative role of NE-CORT interactions in the emergence of a negative bias of cognitive and emotional functions which is germane in stress-related affective spectrum disorders.

It was previously reported from this laboratory that the secondary antibody response can regularly be elicited in vitro from fragments of rabbit lymph node node cultured in Eagle's medium supplemented with normal rabbit serum. Evidence is now presented that physiological levels of hydrocortisone (0.01 to 1.0 microM) can substitute for serum in the culture medium. However, with the omission of serum, serine (0.1 mM) must be included among Eagle's "essential" amino acids for consistent optimal antibody production. In some experiments the addition of insulin (0.5 unit/ml) and vitamin B(12) (0.5 microg/ml) has further enhanced the secondary response in this serum-free medium.

BACKGROUND

The role of antibiotics in the treatment of ulcerative colitis is controversial. This study aims at assessing the therapeutic role of ciprofloxacin as an adjunct to corticosteroids in acute severe ulcerative colitis.

METHODS

In this prospective, randomized, double-blind, placebo-controlled trial, 55 consecutive patients fulfilling the criteria of Truelove and Witts for severe ulcerative colitis were randomized on admission to the hospital to receive intravenously ciprofloxacin (400 mg b.i.d.) (n = 29) or placebo (n = 27). All patients received parenteral nutrition, intravenous hydrocortisone (100 mg q.i.d.) and hydrocortisone enemas (100 mg b.i.d.). Patients were assessed after 10 days of continuous treatment, or at any time a severe complication occurred.

RESULTS

At study entry, there were no significant differences between treatment groups in any patient or disease-related parameter. Twenty-three of 29 patients (79.3%) treated with ciprofloxacin and 20 of 26 patients (77%) treated with placebo showed substantial improvement and were given oral steroids (P>> 0.1). Six patients in each group did not improve (n = 10) or developed complications (n = 2). Nine of these 12 patients underwent emergency colectomy; three patients consented to receive intravenous cyclosporin but did not achieve remission of colitis and they underwent elective colectomy. There were no perioperative or late deaths.

CONCLUSIONS

A short course of intravenous ciprofloxacin does not seem to augment the effect of corticosteroids for patients with acute, severe ulcerative colitis.

Hypopituitarism refers to deficiency of one or more hormones produced by the anterior pituitary or released from the posterior pituitary. Hypopituitarism is associated with excess mortality, a key risk factor being cortisol deficiency due to adrenocorticotropic hormone (ACTH) deficiency. Onset can be acute or insidious, and the most common cause in adulthood is a pituitary adenoma, or treatment with pituitary surgery or radiotherapy. Hypopituitarism is diagnosed based on baseline blood sampling for thyroid stimulating hormone, gonadotropin, and prolactin deficiencies, whereas for ACTH, growth hormone, and antidiuretic hormone deficiency dynamic stimulation tests are usually needed. Repeated pituitary function assessment at regular intervals is needed for diagnosis of the predictable but slowly evolving forms of hypopituitarism. Replacement treatment exists in the form of thyroxine, hydrocortisone, sex steroids, growth hormone, and desmopressin. If onset is acute, cortisol deficiency should be replaced first. Modifications in replacement treatment are needed during the transition from paediatric to adult endocrine care, and during pregnancy.

Psychological or physical stress induces an elevation of corticosteroids in the circulating system. We report here that corticosterone (CT) protects cardiomyocytes from apoptotic cell death induced by doxorubicin (Dox), an antineoplastic drug known to induce cardiomyopathy possibly through reactive oxygen species production. The cytoprotection induced by CT is within the range of physiologically relevant doses. The lowest dose tested, 0.1 microM (or 3.5 microg/dl), inhibited apoptosis by approximately 25% as determined by caspase activity. With 1 microM CT, cardiomyocytes gain a cytoprotective effect after 8 h of incubation and remain protected for at least 72 h. Hydrocortisone, cortisone, dexamethasone, and aldosterone but not androstenedione or cholesterol also induced cytoprotection. Analyses of 20,000 gene expression sequences using Affymetrix high-density oligonucleotide array found that CT caused up-regulation of 140 genes and down-regulation of 108 genes over 1.5-fold. Among the up-regulated genes are bcl-xL, metallothioneins, glutathione peroxidase-3, and glutathione S-transferases. Western blot analyses revealed that CT induced an elevation of bcl-xL but not bcl-2 or proapoptotic factors bax, bak, and bad. Inhibiting the expression of bcl-xL reduced the cytoprotective effect of CT. Our data suggest that CT induces a cytoprotective effect on cardiomyocytes in association with reprogramming gene expression and induction of bcl-xL gene.

Patients with adrenal insufficiency need lifelong glucocorticoid replacement, but many suffer from poor quality of life, and overall there is increased mortality. Moreover, it appears that use of glucocorticoids at the higher end of the replacement dose range is associated with increased risk for cardiovascular and metabolic bone disease. These data highlight some of the inadequacies of current regimes. The cortisol production rate is estimated to be equivalent to 5.7-7.4 mg/m(2) per day, and a major difficulty for replacement regimes is the inability to match the distinct circadian rhythm of circulating cortisol levels, which are low at the time of sleep onset, rise between 0200 and 0400 h, peaking just after waking and then fall during the day. Another issue is that current dose equivalents of glucocorticoids used for replacement are based on anti-inflammatory potency, and few data exist as to doses needed for equivalent cardiovascular and bone effects. Weight-adjusted, thrice-daily dosing using hydrocortisone (HC) reduces glucocorticoid overexposure and represents the most refined regime for current oral therapy, but does not replicate the normal cortisol rhythm. Recently, proof-of-concept studies have shown that more physiological circadian glucocorticoid therapy using HC infusions and newly developed oral formulations of HC have the potential for better biochemical control in patients with adrenal insufficiency. Whether such physiological replacement will have an impact on the complications seen in patients with adrenal insufficiency will need to be analysed in future clinical trials.

The purpose of our studies was to identify factors which regulate the composition of airway secretions produced by normal human tracheobronchial epithelial (NHTBE) cells. Individual factors were removed from the culture media of NHTBE cells grown in air-liquid interface (ALI) cultures (which support mucociliary differentiation) and the effects on mucin, lysozyme (LZ), and secretory leukocyte protease inhibitor (SLPI) secretion and gene expression were examined. Deletion of hydrocortisone, epinephrine, transferrin, or gentamycin-amphotericin from the media had no reproducible effects; deletion of insulin was incompatible with culture growth. We identified 3 factors, namely retinoic acid (RA), triiodothyronine (T3) and collagen gel substratum, which had a major impact on the profile of NHTBE secretions. Removal of RA from the media caused a drastic decrease in mucin secretion and a decrease in expression of the mucin genes MUC2 and MUC5AC.LZ and SLPI secretions were increased in these cultures. Paradoxically LZ mRNA was decreased, while SLPI mRNA levels were increased. Removal of T3 selectively increased mucin secretion, MUC2 gene expression was not affected, but MUC5AC mRNA levels reproducibly increased, suggesting that the expression of these two mucin genes is differentially regulated. LZ and SLPI secretion levels were not significantly affected by deletion of T3 from the culture media; however, LZ mRNA levels were increased in the absence of T3 while SLPI transcript levels were not affected. Omission of the attachment substratum, type I collagen gel, resulted in significant increases in all 3 secretory products. MUC2 and MUC5AC steady state mRNA levels were not consistently affected. In contrast LZ and SLPI gene expression were reproducibly increased. Our studies show that individual factors in the epithelial environment can regulate expression of specific secretory cell gene products in a highly selective manner.

Prolonged use of topical corticosteroids causes systemic adverse effects including Cushing's syndrome and hypothalamic-pituitary-adrenal (HPA) axis suppression, which is less common than that of the oral or parenteral route. At least 43 cases with iatrogenic Cushing syndrome from very potent topical steroid usage (Clobetasol) in children and adult have been published over the last 35 years particularly in developing countries. In children group (n = 22), most are infants with diaper dermatitis and two cases who had started topical application at a very early age and died from severe disseminated CMV infection. For the adult group (n = 21), the most common purpose of steroid use was for treatment of Psoriasis. The recovery period of HPA axis suppression was 3.49 ± 2.92 and 3.84 ± 2.51 months in children and adult, respectively. We report on an 8-month-old female infant who developed Cushing's syndrome and adrenal insufficiency after diaper dermatitis treatment through the misuse of Clobetasol without doctor's prescription. Physiologic dose of hydrocortisone was prescribed to prevent an adrenal crisis for 3 months and discontinued when HPA axis recovery was confirmed by normal morning cortisol and ACTH levels.

Context Patients with primary adrenal insufficiency (Addison's disease) receive more glucococorticoids than the normal endogenous production, raising concern about adverse effects on bone.

OBJECTIVE

To determine i) the effects of glucocorticoid replacement therapy on bone, and ii) the impact of glucocorticoid pharmacogenetics.

METHODS

A cross-sectional study of two large Addison's cohorts from Norway (n=187) and from UK and New Zealand (n=105).

METHODS

Bone mineral density (BMD) was measured; the Z-scores represent comparison with a reference population. Blood samples from 187 Norwegian patients were analysed for bone markers and common polymorphisms in genes that have been associated with glucocorticoid sensitivity.

RESULTS

Femoral neck BMD Z-scores were significantly reduced in the patients (Norway: mean -0.28 (95% confidence intervals (CI) -0.42, -0.16); UK and New Zealand: -0.21 (95% CI -0.36, -0.06)). Lumbar spine Z-scores were reduced (Norway: -0.17 (-0.36, +0.01); UK and New Zealand: -0.57 (-0.78, -0.37)), and significantly lower in males compared with females (P=0.02). The common P-glycoprotein (ABCB1) polymorphism C3435T was significantly associated with total BMD (CC and CT>TT P=0.015), with a similar trend at the hip and spine.

CONCLUSIONS

BMD at the femoral neck and lumbar spine is reduced in Addison's disease, indicating undesirable effects of the replacement therapy. The findings lend support to the recommendations that 15-25 mg hydrocortisone daily is more appropriate than the higher conventional doses. A common polymorphism in the efflux transporter P-glycoprotein is associated with reduced bone mass and might confer susceptibility to glucocorticoid induced osteoporosis.

The mucus layer covering the surface of the gastrointestinal tract may act as a barrier to drug absorption. The aim of this investigation was to study the self-diffusion coefficients of model drugs with different physicochemical properties in gastrointestinal mucus. An in vitro method was used to determine the self-diffusion coefficients of radiolabeled model drugs in different diffusion media. Glucosamine, mannitol, glucuronic acid, glucose, metoprotol, antipyrine, propranolol, hydrocortisone, and testosterone, which display large differences in charge and octanol/water distribution ratios (K), were used as model drugs. The diffusion coefficients of model drugs were compared in phosphate buffer (PB), native pig intestinal mucus (PIM), and purified pig gastric much (PPGM). PIM was not purified and therefore contained all the original components of native mucus, whereas PPGM contained only high molecular weight mucin molecules. Charge had only minor effects on the diffusion coefficients of the model drugs. Lipophilicity, however, had a much larger effect, the largest decrease in diffusion coefficient, 58%, was observed for testosterone in PIM. A negative relationship between the diffusion coefficient and log K was observed in PIM, but no relationship was observed in PPGM and PB. In contrast, the diffusion coefficients for two larger molecules of comparable size, the lipophilic peptide cyclosporin and the hydrophilic peptide D-arginine vasopressin, were markedly reduced in PIM. In conclusion, the most important physicochemical characteristic influencing the diffusion coefficient of most drugs in gastrointestinal mucus appears to be lipophilicity, whereas molecular size appears to have more influence for larger peptide drugs.

OBJECTIVE

To assess the effects of stress doses of hydrocortisone (HC) on clinical parameters and neutrophil functions in patients with septic shock.

METHODS

Prospective, double-blind, randomized, placebo-controlled study.

METHODS

Intensive care units of a university hospital.

METHODS

30 adult patients with septic shock.

METHODS

Patients were allocated to receive either HC (intravenous bolus of 100 mg preceding a continuous infusion 10 mg/h, n = 15) or placebo (n = 15), respectively. The effects of HC were assessed at baseline and after 24 h.

RESULTS

As compared with placebo-treated patients, administration of HC significantly decreased norepinephrine requirements (from 1.5 to 0.8 mg/h; p < 0.001), interleukin-6 serum concentrations (from 388.8 to 88.8 pg/ml; p < 0.02), and the spontaneous release of hydrogen peroxide (H2O2) by neutrophils (-33.0%; p < 0.05). Additionally, HC treatment preserved the autologous plasma-induced amplification of phagocytosis of zymosan particles [factor of opsonin-induced amplification of phagocytosis of unopsonized particles: 1.80 for placebo vs. 1.75 for HC at baseline (not significant between groups) and 0.50 for placebo vs. 1.75 for HC after 24 h of treatment (p < 0.05)]. These effects were paralleled by respective changes in the phagocytosis-associated H2O2 production.

CONCLUSIONS

In patients with septic shock stress doses of HC exert beneficial effects in terms of improvements in hemodynamics, decrease in pro-inflammatory mediators, and oxidative stress without the compromise of opsonization-dependent phagocytic neutrophil functions; thus, HC treatment does not aggravate non-specific immunosuppression but instead improves innate immunity in the early stage of septic shock.

Nitric oxide (NO) has been implicated in the etiopathology of multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), and inhibition of NO synthesis has been proposed to be a possible mechanism of action of drugs to treat MS. In the present study, we investigated the inhibitory effect on NO synthesis of various steroids, cytokines and drugs used or proposed for the treatment of MS. As a model system, we used primary rat microglial cells which produce NO synthase and subsequently release NO upon stimulation with lipopolysaccharide (LPS). Among the substances tested, the glucocorticoids prednisone, hydrocortisone, dexamethasone and progesterone as well as transforming growth factor-beta (TGF-beta) dose-dependently inhibited LPS-induced nitric oxide synthase (iNOS) and NO synthesis. In contrast, COP-1, the phosphodiesterase inhibitors rolipram and pentoxifylline, the cytokines interleukin-10 (IL-10) and interferon-beta (IFN-beta) as well as the steroids beta-estradiol, testosterone, and dehydroepiandrosterone (DHEA) showed no inhibitory effect. Cholesterol slightly, but not significantly, increased LPS-induced nitric oxide synthesis. We conclude from the present study that with respect to treatment of MS, inhibition of NO synthesis may be an important mechanism of action of glucocorticoids and transforming growth factor-beta, but not of other drugs used or proposed to treat MS.

OBJECTIVE

To update the 2008 consensus statements for the diagnosis and management of critical illness-related corticosteroid insufficiency (CIRCI) in adult and pediatric patients.

METHODS

A multispecialty task force of 16 international experts in critical care medicine, endocrinology, and guideline methods, all of them members of the Society of Critical Care Medicine and/or the European Society of Intensive Care Medicine.

METHODS

The recommendations were based on the summarized evidence from the 2008 document in addition to more recent findings from an updated systematic review of relevant studies from 2008 to 2017 and were formulated using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology. The strength of each recommendation was classified as strong or conditional, and the quality of evidence was rated from high to very low based on factors including the individual study design, the risk of bias, the consistency of the results, and the directness and precision of the evidence. Recommendation approval required the agreement of at least 80% of the task force members.

RESULTS

The task force was unable to reach agreement on a single test that can reliably diagnose CIRCI, although delta cortisol (change in baseline cortisol at 60 min of < 9 μg/dL) after cosyntropin (250 μg) administration and a random plasma cortisol of < 10 μg/dL may be used by clinicians. We suggest against using plasma-free cortisol or salivary cortisol level over plasma total cortisol (conditional, very low quality of evidence). For treatment of specific conditions, we suggest using IV hydrocortisone < 400 mg/day for ≥ 3 days at full dose in patients with septic shock that is not responsive to fluid and moderate- to high-dose vasopressor therapy (conditional, low quality of evidence). We suggest not using corticosteroids in adult patients with sepsis without shock (conditional recommendation, moderate quality of evidence). We suggest the use of IV methylprednisolone 1 mg/kg/day in patients with early moderate to severe acute respiratory distress syndrome (PaO2/FiO2 < 200 and within 14 days of onset) (conditional, moderate quality of evidence). Corticosteroids are not suggested for patients with major trauma (conditional, low quality of evidence).

CONCLUSIONS

Evidence-based recommendations for the use of corticosteroids in critically ill patients with sepsis and septic shock, acute respiratory distress syndrome, and major trauma have been developed by a multispecialty task force.

Adrenal crisis is a life-threatening emergency contributing to the excess mortality of patients with adrenal insufficiency. Studies in patients on chronic replacement therapy for adrenal insufficiency have revealed an incidence of 5-10 adrenal crises/100 patient years and suggested a mortality rate from adrenal crisis of 0.5/100 patient years. Patients with adrenal crisis typically present with profoundly impaired well-being, hypotension, nausea and vomiting, and fever responding well to parenteral hydrocortisone administration. Infections are the major precipitating causes of adrenal crisis. Lack of increased cortisol concentrations during infection enhances pro-inflammatory cytokine release and sensitivity to the toxic effects of these cytokines (e.g. tumour necrosis factor alpha). Furthermore, pro-inflammatory cytokines may impair glucocorticoid receptor function aggravating glucocorticoid deficiency. Treatment of adrenal crisis is simple and highly effective consisting of i.v. hydrocortisone (initial bolus of 100 mg followed by 200 mg over 24 h as continuous infusion) and 0.9% saline (1000 ml within the first hour). Prevention of adrenal crisis requires appropriate hydrocortisone dose adjustments to stressful medical procedures (e.g. major surgery) and other stressful events (e.g. infection). Patient education is a key for such dose adjustments but current education concepts are not sufficiently effective. Thus, improved education strategies are needed. Every patient should carry an emergency card and should be provided with an emergency kit for parenteral hydrocortisone self-administration. A hydrocortisone pen would hold a great potential to lower the current barriers to hydrocortisone self-injection. Improved patient education and measures to facilitate parenteral hydrocortisone self-administration in impending crisis are expected to significantly reduce morbidity and mortality from adrenal crisis.

Bronchopulmonary dysplasia remains a major problem in neonatal intensive care units. Persistent inflammation in the lungs is the most likely underlying pathogenesis. Corticosteroids have been used to prevent or treat bronchopulmonary dysplasia because of their potent anti-inflammatory effects.

To examine the relative benefits and adverse effects of systemic postnatal corticosteroids commenced within the first seven days of life for preterm infants at risk of developing bronchopulmonary dysplasia.

For the 2017 update, we used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 1); MEDLINE via PubMed (January 2013 to 21 February 2017); Embase (January 2013 to 21 February 2017); and the Cumulative Index to Nursing and Allied Health Literature (CINAHL) (January 2013 to 21 February 2017). We also searched clinical trials databases, conference proceedings, and reference lists of retrieved articles for randomised controlled trials (RCTs) and quasi-randomised trials.

For this review, we selected RCTs examining systemic postnatal corticosteroid treatment within the first seven days of life (early) in high-risk preterm infants. Most studies evaluated the use of dexamethasone, but we also included studies that assessed hydrocortisone, even when used primarily for management of hypotension.

We used the GRADE approach to assess the quality of evidence.We extracted and analysed data regarding clinical outcomes that included mortality, bronchopulmonary dysplasia, death or bronchopulmonary dysplasia, failure to extubate, complications during primary hospitalisation, and long-term health outcomes.

We included 32 RCTs enrolling a total of 4395 participants. The overall risk of bias of included studies was probably low, as all were RCTs, and most trials used rigorous methods. Investigators reported significant benefits for the following outcomes overall: lower rates of failure to extubate, decreased risks of bronchopulmonary dysplasia both at 28 days of life and at 36 weeks' postmenstrual age, death or bronchopulmonary dysplasia at 28 days of life and at 36 weeks' postmenstrual age, patent ductus arteriosus, and retinopathy of prematurity (ROP), including severe ROP. Researchers found no significant differences in rates of neonatal or subsequent mortality; they noted that gastrointestinal bleeding and intestinal perforation were important adverse effects, and that risks of hyperglycaemia, hypertension, hypertrophic cardiomyopathy, and growth failure were increased. The 13 trials that reported late outcomes described several adverse neurological effects at follow-up examination, including cerebral palsy. However, study authors indicated that major neurosensory disability was not significantly increased, either overall in the eight studies for which this outcome could be determined, or in the two individual studies in which rates of cerebral palsy or abnormal neurological examination were significantly increased. Moreover, data show that rates of the combined outcomes of death or cerebral palsy, or of death or major neurosensory disability, were not significantly increased. Two-thirds of studies used dexamethasone (n = 21). Subgroup analyses by type of corticosteroid revealed that most of the beneficial and harmful effects of treatment were attributable to dexamethasone. However, as with dexamethasone, hydrocortisone was associated with reduced rates of patent ductus arteriosus, mortality, and the combined outcome of mortality or chronic lung disease, but with increased occurrence of intestinal perforation. Results showed that hydrocortisone was not associated with obvious longer-term problems.Use of the GRADE approach revealed that the quality of evidence was high for the major outcomes considered, but review authors downgraded quality one level for several outcomes (mortality at latest age, bronchopulmonary dysplasia at 36 weeks, and death or bronchopulmonary dysplasia at 36 weeks) because of weak evidence of publication bias or moderate heterogeneity (death or cerebral palsy).

Benefits of early postnatal corticosteroid treatment (≤ 7 days), particularly dexamethasone, may not outweigh adverse effects associated with this treatment. Although early corticosteroid treatment facilitates extubation and reduces risk of bronchopulmonary dysplasia and patent ductus arteriosus, it causes short-term adverse effects including gastrointestinal bleeding, intestinal perforation, hyperglycaemia, hypertension, hypertrophic cardiomyopathy, and growth failure. Long-term follow-up studies report increased risk of abnormal findings on neurological examination and increased risk of cerebral palsy. However, the methodological quality of studies examining long-term outcomes is limited in some cases: Surviving children have been assessed predominantly before school age; no study has been sufficiently powered to detect important adverse long-term neurosensory outcomes; and no study has been designed with survival free of adverse long-term neurodevelopmental disability as the primary outcome. There is a compelling need for long-term follow-up and reporting of late outcomes, especially neurological and developmental outcomes, among surviving infants who participated in all randomised trials of early postnatal corticosteroid treatment. Hydrocortisone reduced rates of patent ductus arteriosus, of mortality, and of the combined outcome of mortality or bronchopulmonary dysplasia, without causing any obvious long-term harm. However, gastrointestinal perforation was more frequent in the hydrocortisone group. Longer-term follow-up into late childhood is vital for assessment of important effects or other effects that cannot be assessed in early childhood, such as effects of early hydrocortisone treatment on higher-order neurological functions, including cognitive function, academic performance, behaviour, mental health, and motor function. Further randomised controlled trials of early hydrocortisone should include longer-term survival free of neurodevelopmental disability as the main outcome.

It is well known that applications of a single dose of 12-O-tetradecanoylphorbol-13-acetate (TPA) to mouse ears induces an acute inflammatory reaction consisting of erythema, edema and polymorphonuclear leukocyte (PMN) infiltration. We report here that multiple topical applications of TPA to mouse ears produce a prolonged inflammatory reaction characterized by increases in ear weight, inflammatory cell infiltration and epidermal hyperplasia. TPA was applied 5 times over 10 days to mouse ears. Epidermal thickness and PMN infiltration (myeloperoxidase content) increased 3- and 160-fold, respectively, by day 3 and remained elevated over control values throughout the test period. Ear weight was elevated from day 1 and remained high. Hydrocortisone 17-valerate and betamethasone dipropionate significantly reduced all three parameters of inflammation. Indomethacin and two other cyclo-oxygenase inhibitors, and an antihistamine had little or no effect on any of the parameters. This chronic skin inflammation model may be more relevant for evaluating anti-inflammatory compounds than the acute TPA model because the test compounds are applied after the inflammatory lesion is established, which mirrors the use of clinical anti-inflammatory drugs. Also this model may be more selective than the acute TPA model for compounds which affect leukotriene production since other pharmacological agents which are active in the acute model are not active in the multiple-application model.

Late complications of pelvic radiotherapy occur in 5-20% of patients, particularly chronic radiation proctitis (CRP). Rectal bleeding is the most common symptom. Other symptoms include difficulty in defaecation or tenesmus because of loss of distensibility of the rectum or rectal structuring. Treatment options of CRP include oral therapy (5-aminosalicylates, metronidazole), rectal instillation therapy (hydrocortisone, sucralfate, 5-aminosalicylates, formalin), thermal therapy (argon plasma coagulation, heater probe or laser) and hyperbaric oxygen. It is difficult to recommend evidence-based therapy. There are no adequately powered studies of the treatment of CRP and most data are uncontrolled, non-blinded observation studies from single sites. There are no standard evaluation tools (including endoscopic grading, symptom scores and quality-of-life scores), adequate description of preceding radiotherapy dose or adequate follow-up in most studies. Many studies have poor documentation of complications and few are carried out prospectively. A pragmatic approach is to use sucralfate enemas and oral metronidazole. Thermal methods seem to be effective and safe. Simple heater probe treatment or argon plasma coagulation are the preferred methods due to their better safety profile. Intra-rectal formalin seems to be effective, but possibly has a higher rate of complications. For resistant disease, hyperbaric oxygen may be an option.

BACKGROUND

Natural corticosteroids (e.g. hydrocortisone) and synthetic selective glucocorticoid (GC) agonists have been used by ophthalmologists for decades to treat various forms of ocular inflammation. More recently, increased clinical use of locally delivered GC has shown significant benefit for the treatment of multiple retinal indications including macular edema associated with uveitis, retinal vascular occlusions and diabetes. Our current understanding of the clinical utility of specific intraocular GC far surpasses our knowledge of their biologic and pharmacologic activities in the eye.

OBJECTIVE

To present an update on GC receptor (GR) biology in general and as it applies to the eye, and discuss the pharmacokinetics, delivery and pharmacology of the commonly used intraocular GC dexamethasone (DEX), triamcinolone acetonide (TA) and fluocinolone acetonide (FA).

RESULTS

DEX, TA and FA are structurally similar but significantly differentiated by their aqueous and lipid solubility, delivery system requirements, pharmacokinetics and interactions with functional GR. Culture of human trabecular meshwork cells and full transcriptome microarray analysis reveals that DEX, TA and FA generate unique gene transactivation and repression profiles as well as potentially distinct biologic responses that are not only steroid structure dependent, but also dose and time dependent. Finally, DEX and FA markedly protect photoreceptors from degenerating in animal models of excessive light and retinitis pigmentosa, respectively.

CONCLUSIONS

It is tempting to speculate that the unique pharmacokinetic and pharmacologic profiles of the commonly used intraocular steroids and novel future drugs may reveal significant differences in their therapeutic value in patients with macular edema or other inflammatory disease, in their ocular adverse side effect profile, and their ability to normalize glial and neuronal function in diseased retina.

Ten patients with life-threatening attacks of asthma (status asthmatiucus') were treated with salbutamol inhaled by intermittent positive pressure breathing, and their response in terms of rise in peak flow rate was measured. They were then given intravenous salbutamol and any further increment in peak flow was measured. Hydrocortisone treatment was started simultaneously and the responses to salbutamol were re-measured on each of the next three days. Only two patients initially responded to the aerosol, whereas all save one responded to the intravenous drug. The two who responded initially to the aerosol were the two who were able to produce sputum at the time of admission. All patients subsequently responded to the aerosol, and the onset of this response correlated closely with the beginning of sputum production. Sympathominetics should be given parenterally to patients in severe asthma if the response to inhaled drug is reduced or absent.

A study of 23 patients admitted to hospital with severe acute asthma is reported in which plasma cortisol level on admission was significantly correlated with the degree of acidaemia and pulse rate. Patients who had not previously received treatment with corticosteroids responded satisfactorily to repeated daily injections of tetracosactrin depot, the rate of improvement being comparable to that observed in other patients treated with intravenous hydrocortisone hemisuccinate. A prompt and sustained rise in plasma cortisol was also seen following tetracosactrin. The total daily dose of hydrocortisone required to achieve plasma cortisol levels above 100 mug/100 ml was less when given by continuous intravenous infusion compared with intermittent injections, and a regime of 3 mg/kg body weight every six hours by infusion appeared satisfactory. Most patients reported subjective improvement by about four hours after starting treatment but objective evidence did not appear until about six hours from the start. Measurements of FEV1 and FVC proved to be the most reliable indices of the beginning of improvement although pulse rate was the first index to show maximum improvement. Previous maintenance treatment with corticosteroids in patients with asthma did not appear materially to affect the plasma half-life of intravenous hydrocortisone (4 mgm/kg body weight) when compared with healthy subjects or other patients with asthma who had not previously been treated with corticosteroids.