Transcriptional regulation of episodic glucocorticoid secretion.

Circadian and ultradian variations of basal glucocorticoid secretion and transient elevations during stress are essential for homeostasis. Using intronic qRT-PCR to measure changes in primary transcript (hnRNA) we have shown that secretory events induced by stress or ACTH injection are followed by episodic increases in transcription of rate limiting steroidogenic proteins, such as steroidogenic acute regulatory protein (StAR), cytochrome P450 side chain cleavage and melanocortin receptor associated protein. These transcriptional episodes imply rapid turnover of steroidogenic proteins and the need of de novo synthesis following each secretory event.

GPR54-dependent stimulation of luteinizing hormone secretion by neurokinin B in prepubertal rats.

Kisspeptin, neurokinin B (NKB) and dynorphin A (Dyn) are coexpressed within KNDy neurons that project from the hypothalamic arcuate nucleus (ARC) to GnRH neurons and numerous other hypothalamic targets. Each of the KNDy neuropeptides has been implicated in regulating pulsatile GnRH/LH secretion. In isolation, kisspeptin is generally known to stimulate, and Dyn to inhibit LH secretion.

Clinical and molecular features associated with cystic visceral lesions in von hippel-lindau disease.

Background: Von Hippel-Lindau (VHL) is an uncommon oncogenic disorder which occurs as a result of genetic mutations on chromosome 3p. Retinal capillary haemangiomas and CNS haemangioblastomas have been well-characterised in genotypic-phenotypic analyses, but cystic visceral lesions are less common and have been less frequently studied. The aim of this study was to perform genotypic and phenotypic analysis of a cohort of VHL patients that developed cystic visceral lesions to determine whether their genotype differs from that seen in other manifestations of VHL and whether the ocular manifestations differ.

Histopathological features predictive of a clinical diagnosis of ophthalmic granulomatosis with polyangiitis (GPA).

Background: The limited form of Granulomatosis with Polyangiitis (GPA), formerly known as Wegener's Granulomatosis (WG) primarily involves the head and neck region, including the orbit, but is often a diagnostic challenge, particularly as it commonly lacks positive anti-neutrophil cytoplasm antibody (ANCA) titres or classical features on diagnostic orbital biopsies. The purpose of this study was to relate biopsy findings with clinical outcome and to determine which histopathological features are predictive of a clinical diagnosis of GPA.

Methods: Retrospective case series of 234 patients identified from the database of the UCL Institute of Ophthalmology Department of Eye Pathology as having had orbital biopsies of orbital inflammatory disorders performed between 1988 and 2009.

Valacyclovir in the treatment of acute retinal necrosis.

Background: To report the outcome of oral valacyclovir as the sole antiviral therapy for patients with acute retinal necrosis (ARN).

Methods: This study reports a retrospective, interventional case series of nine consecutive patients with ten eyes with newly diagnosed ARN treated with oral valacyclovir as the sole antiviral agent. Eight patients received oral valacyclovir 2 g tid (Valtrex, GlaxoSmithKline) and one patient with impaired renal function received oral 1 g tid.

Topical prostaglandin analogues and conjunctival inflammation in uveitic glaucoma.

Purpose: A pilot study to determine whether topical prostaglandin analogues alter the expression of conjunctival inflammatory markers in patients with uveitic glaucoma.

Methods: Prospective, single-masked case series of 20 patients with uveitis and secondary raised intraocular pressure. Participants were divided into four groups of five patients dependent on their use of topical medication: (1) prostaglandin analogues only, (2) corticosteroids only, (3) both prostaglandin analogues and corticosteroids, (4) no topical medication.

Suppression of the GnRH pulse generator by neurokinin B involves a κ-opioid receptor-dependent mechanism.

Neurokinin B (NKB) and its receptor (NK3R) are coexpressed with kisspeptin, Dynorphin A (Dyn), and their receptors [G-protein-coupled receptor-54 (GPR54)] and κ-opioid receptor (KOR), respectively] within kisspeptin/NKB/Dyn (KNDy) neurons in the hypothalamic arcuate nucleus (ARC), the proposed site of the GnRH pulse generator. Much previous research has employed intracerebroventricular (icv) administration of KNDy agonists and antagonists to address the functions of KNDy neurons. We performed a series of in vivo neuropharmacological experiments aiming to determine the role of NKB/NK3R signaling in modulating the GnRH pulse generator and elucidate the interaction between KNDy neuropeptide signaling systems, targeting our interventions to ARC KNDy neurons.

Ultradian corticosterone secretion is maintained in the absence of circadian cues.

Plasma levels of corticosterone exhibit both circadian and ultradian rhythms. The circadian component of these rhythms is regulated by the suprachiasmatic nucleus (SCN). Our studies investigate the importance of the SCN in regulating ultradian rhythmicity.

Circadian and ultradian rhythms of free glucocorticoid hormone are highly synchronized between the blood, the subcutaneous tissue, and the brain.

Total glucocorticoid hormone levels in plasma of various species, including humans, follow a circadian rhythm that is made up from an underlying series of hormone pulses. In blood most of the glucocorticoid is bound to corticosteroid-binding globulin and albumin, resulting in low levels of free hormone. Although only the free fraction is biologically active, surprisingly little is known about the rhythms of free glucocorticoid hormones.

The origin of glucocorticoid hormone oscillations.

Oscillating levels of adrenal glucocorticoid hormones are essential for optimal gene expression, and for maintaining physiological and behavioural responsiveness to stress. The biological basis for these oscillations is not known, but a neuronal "pulse generator" within the hypothalamus has remained a popular hypothesis. We demonstrate that pulsatile hypothalamic activity is not required for generating ultradian glucocorticoid oscillations.

Dysregulation of the hypothalamic pituitary adrenal (HPA) axis and physical performance at older ages: an individual participant meta-analysis.

The association between functioning of the hypothalamic pituitary adrenal (HPA) axis and physical performance at older ages remains poorly understood. We carried out meta-analyses to test the hypothesis that dysregulation of the HPA axis, as indexed by patterns of diurnal cortisol release, is associated with worse physical performance. Data from six adult cohorts (ages 50-92 years) were included in a two stage meta-analysis of individual participant data.

Organ-specific management and supportive care in chronic graft-versus-host disease.

A joint working group established by the Haemato-oncology subgroup of the British Committee for Standards in Haematology and the British Society for Bone Marrow Transplantation has reviewed the available literature and made recommendations for the supportive care and management of organ-specific complications of chronic graft-versus-host disease (cGvHD). This guideline includes recommendations for the specific therapy of skin, oral, liver, gut, lung, ocular and genital manifestations of cGvHD and for the supportive care of these patients, including vaccinations and prophylaxis against infection. The goal of treatment should be effective control of GvHD while minimizing the risk of toxicity and relapse.

The impact of macular edema on visual function in intermediate, posterior, and panuveitis.

Purpose: To evaluate the impact of macular edema on visual acuity and visual field sensitivity in uveitis.

Design: This study utilized baseline data from the Multicenter Uveitis Steroid Treatment (MUST) Trial, a randomized, parallel treatment clinical trial comparing alternative treatments for intermediate, posterior and panuveitis.

Patients & Methods: 255 patients (481 eyes with uveitis) recruited at 23 subspecialty centers.

Corticosteroid-sparing agents: new treatment options.

Corticosteroids form the cornerstone of treatment for noninfectious uveitis, but their safety profile and adverse effects render their use a double-edged sword. As a result, the local benefits of treating ocular inflammation may be outweighed by systemic adverse effects, and it is mainly for this reason that steroid-sparing agents are used. Most of these systemic immunomodulatory drugs used in ophthalmology have been adopted from other specialties, such as rheumatology and, while their safety profiles make them valid alternatives to long-term high-dose corticosteroids, systemic side effects still prove problematic for a significant proportion of patients.

Should intranasal corticosteroids be used for the treatment of ocular symptoms of allergic rhinoconjunctivitis? A review of their efficacy and safety profile.

Allergic rhinoconjunctivitis (ARC) presents as nasal symptoms, eye watering and additional signs of ocular allergy (e.g. itchy/burning eyes).

Activation of the orexin 1 receptor is a critical component of CO2-mediated anxiety and hypertension but not bradycardia.

Acute hypercapnia (elevated arterial CO(2)/H(+)) is a suffocation signal that is life threatening and rapidly mobilizes adaptive changes in breathing and behavioral arousal in order to restore acid-base homeostasis. Severe hypercapnia, seen in respiratory disorders (eg, asthma or bronchitis, chronic obstructive pulmonary disease (COPD)), also results in high anxiety and autonomic activation. Recent evidence has demonstrated that wake-promoting hypothalamic orexin (ORX: also known as hypocretin) neurons are highly sensitive to local changes in CO(2)/H(+), and mice lacking prepro-ORX have blunted respiratory responses to hypercapnia.

Maternal mood and neuroendocrine programming: effects of time of exposure and sex.

Adverse exposures that influence growth in prenatal and early postnatal periods are considered to influence vulnerability to chronic diseases via their effects on the neuroendocrine system. In humans, the assessment of the underlying mechanisms has been restricted. The present study aimed to investigate the effects of adverse early-life exposures, specifically maternal mood, on hypothlamic-pituitary-adrenal (HPA) axis, sympathetic nervous system (SNS) and parasympathetic nervous system (PNS) responses to an acute physiological stressor.

Symptoms of depression during pregnancy are associated with increased systolic blood pressure responses towards infant distress.

A mother's response towards her infant's distress is important for the mother-infant relationship and infant development. There is evidence that maternal responses are impaired in depressed mothers. Further understanding of how depression disrupts maternal responses is important to direct treatment strategies.

Characterizing dynamic interactions between ultradian glucocorticoid rhythmicity and acute stress using the phase response curve.

The hypothalamic-pituitary-adrenal (HPA) axis is a dynamic oscillatory hormone signalling system that regulates the pulsatile secretion of glucocorticoids from the adrenal glands. In addition to regulation of basal levels of glucocorticoids, the HPA axis provides a rapid hormonal response to stress that is vitally important for homeostasis. Recently it has become clear that glucocorticoid pulses encode an important biological signal that regulates receptor signalling both in the central nervous system and in peripheral tissues.

Factors determining visual outcome in endogenous Candida endophthalmitis.

Purpose: To determine factors affecting the visual outcome of eyes with endogenous Candida endophthalmitis.

Methods: Retrospective cohort study of 44 eyes from 36 patients diagnosed with candida endophthalmitis at 2 tertiary referral uveitis centers. Outcome measures included the development of retinal detachment and the occurrence of visual loss (visual acuity of <20/40) and severe visual loss (visual acuity of ≤ 20/200).