Ligand-induced activation of the glucocorticoid receptor (GR) is not well understood. The GR ligand-binding domain was modeled, based on homology with the progesterone receptor. Tyrosine 735 interacts with the D ring of dexamethasone, and substitution of D ring functional groups results in partial agonist steroids with reduced ability to direct transactivation. Loss of the Tyr735 hydroxyl group by substitution to phenylalanine (Tyr735Phe) did not reduce ligand binding affinity [dissociation constant (Kd) 4.3 nM compared with Kd 4.6 nM for wild-type] and did not alter transrepression of an nuclear factor-kappaB (NF-kappaB reporter. But, there was a significant 30% reduction in maximal transactivation of a mouse mammary tumor virus (MMTV) reporter, although with an unchanged EC50 (8.6 nM compared with 6 nM). Substitution to a nonaromatic hydrophobic amino acid, valine (Tyr735Val), retained high-affinity ligand binding for dexamethasone (Kd 6 nM compared with 4.6 nM) and did not alter transrepression of NF-kappaB. However, there was a 36% reduction in MMTV activity with a right shift in EC50 (14.8 nM). The change to serine, a small polar amino acid (Tyr735Ser), caused significantly lower affinity for dexamethasone (10.4 nM). Maximal transrepression of NF-kappaB was unaltered, but the IC50 for this effect was increased. Tyr735Ser had a major shift in EC50 (118 nM) for transactivation of an MMTV reporter. Maximal transactivation of MMTV induced by the natural ligand cortisol was reduced to 60% by Tyr735Phe and Tyr735Val and was completely absent by Tyr735Ser. These data suggest that tyrosine 735 is important for ligand interpretation and transactivation.

The route of migration and development of Ancylostoma ceylanicum, when given orally, has been described for the first time in hamsters. A predominant feature of the migration is the absence of any lung journey. This is unlike A. caninum, A. duodenale and A, brazilicnse when larvae are similarly given to an abnormal host. The larvae of A. ceylanicum apparently had no submucosal migration

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Complete development ofAncylostoma ceylanicum(Hamster strain) is reported for the first time in mice. A patent infection (viz. ova in faeces) could be established only under the influence of hydrocortisone acetate. Cultures made from the faeces containing eggs produced viable larvae which were infective to mice.

SummaryTo assess continuous subcutaneous hydrocortisone infusion (CSHI) in patients with adrenocortical insufficiency (AI) and difficulties with oral replacement. Three patients with AI and frequent hospital admissions attributed to adrenal crises were treated with CSHI, which was delivered via a continuous subcutaneous infusion. All three patients preferred CSHI and remained on it long term, which permitted prolonged follow-up analysis. All three patients reported symptomatic improvement, and in two cases, reduced hospital admission rates and inpatient stay lengths were observed. The cost of hospital admissions and overall treatment was reduced in all cases. CSHI offers a practical and acceptable alternative to oral replacement in a subset of patients with AI. The cost of initiating and maintaining the pump is offset in the long term by reduced frequency and duration of emergency admissions. CSHI can therefore be considered in a select group of patients who are resistant to treatment with conventional oral glucocorticoids.Learning points Continuous subcutaneous infusion of cortisol is a viable alternative in patients unable to take oral steroids.Patient acceptability was high, with three out of three patients preferring to remain on pump treatment.Hospital admissions were reduced in response to pump therapy, which compensated for the increased treatment cost.The daily dosage of hydrocortisone can be reduced by using pump therapy.