Adaptor protein-2 sigma subunit mutations causing familial hypocalciuric hypercalcaemia type 3 (FHH3) demonstrate genotype-phenotype correlations, codon bias and dominant-negative effects.

The adaptor protein-2 sigma subunit (AP2σ2) is pivotal for clathrin-mediated endocytosis of plasma membrane constituents such as the calcium-sensing receptor (CaSR). Mutations of the AP2σ2 Arg15 residue result in familial hypocalciuric hypercalcaemia type 3 (FHH3), a disorder of extracellular calcium (Ca(2+) o) homeostasis. To elucidate the role of AP2σ2 in Ca(2+) o regulation, we investigated 65 FHH probands, without other FHH-associated mutations, for AP2σ2 mutations, characterized their functional consequences and investigated the genetic mechanisms leading to FHH3.

A seven-day diabetes service for inpatients and the emergency department in an acute hospital setting - the East and North Herts Diabetes Outreach Team (DOT).

There is evidence that all hospital-based care needs to improve across 7 days. Inpatients with diabetes require better specialist attention and improved clinical outcomes. The East and North Herts inpatient diabetes service has responded to this challenge with care now delivered by consultants and diabetes nurses, 365 days per year.

Radiation-induced hypopituitarism.

Purpose Of Review: Progressive and irreversible neuro-endocrine dysfunction following radiation-induced damage to the hypothalamic-pituitary (h-p) axis is the most common complication in cancer survivors with a history of cranial radiotherapy involving the h-p axis and in patients with a history of conventional or stereotactic pituitary radiotherapy for pituitary tumours. This review examines the controversy about the site and pathophysiology of radiation damage while providing an epidemiological perspective on the frequency and pattern of radiation-induced hypopituitarism.

Recent Findings: Contrary to the previously held belief that h-p axis irradiation with doses less than 40 Gy result in a predominant hypothalamic damage with time-dependent secondary pituitary atrophy, recent evidence in survivors of nonpituitary brain tumours suggests that cranial radiation causes direct pituitary damage with compensatory increase in hypothalamic release activity.

A case of severe staphylococcal septicaemia: septic arthritis and a mediastinal abscess following leflunamide therapy for rheumatoid arthritis.

This highly unusual case illustrates how a potentially life-threatening complication may develop insidiously in the context of immunosuppression. A 46-year-old woman presented with increasing malaise and a marked inflammatory response in the context of immunosuppressive therapy for rhueumatoid arthritis. On the basis of microbiological findings, the patient was treated for systemic staphylococcal infection with a prolonged antibiotic course.

Hypopituitarism following Radiotherapy Revisited.

Neuroendocrine disturbances in anterior pituitary hormone secretion are common following radiation damage to the hypothalamic-pituitary (H-P) axis, the severity and frequency of which correlate with the total radiation dose delivered to the H-P axis and the length of follow-up. The somatotropic axis is the most vulnerable to radiation damage and GH deficiency remains the most frequently seen endocrinopathy. Compensatory hyperstimulation of a partially damaged somatotropic axis may restore normality of spontaneous GH secretion in the context of reduced but normal stimulated responses in adults.

Modified-release hydrocortisone to provide circadian cortisol profiles.

Context: Cortisol has a distinct circadian rhythm regulated by the brain's central pacemaker. Loss of this rhythm is associated with metabolic abnormalities, fatigue, and poor quality of life. Conventional glucocorticoid replacement cannot replicate this rhythm.

Radiation-induced hypopituitarism after cancer therapy: who, how and when to test.

Subtle to frank abnormalities in hypothalamic-pituitary axis function are frequently seen in cancer survivors who have received prophylactic or therapeutic cranial irradiation. The growth hormone (GH) axis is the most vulnerable to radiation damage, and isolated GH deficiency can occur after doses as low as 18 Gy. Furthermore, the frequency of GH deficiency can reach 50-100% within 3-5 years of cranial irradiation with doses of 30-50 Gy.

Cranially irradiated adult cancer survivors may have normal spontaneous GH secretion in the presence of discordant peak GH responses to stimulation tests (compensated GH deficiency).

Context: We have previously demonstrated that spontaneous (physiological) GH secretion was entirely normal in cranially irradiated patients who had normal individual peak GH responses to the insulin tolerance test (ITT) but reduced maximal somatotroph reserve as indicated by substantially reduced group GH responses to the GHRH + arginine stimulation test (AST). The normality of spontaneous GH secretion was attributed to a compensatory increase in hypothalamic stimulatory input within a partially damaged hypothalamic-pituitary (h-p) axis. It is unknown, however, if such compensatory stimulation can also maintain normality of GH secretion in those who fail the ITT but pass the GHRH + AST.

Hypopituitarism following radiotherapy.

Deficiencies in anterior pituitary hormones secretion ranging from subtle to complete occur following radiation damage to the hypothalamic-pituitary (h-p) axis, the severity and frequency of which correlate with the total radiation dose delivered to the h-p axis and the length of follow up. Selective radiosensitivity of the neuroendocrine axes, with the GH axis being the most vulnerable, accounts for the high frequency of GH deficiency, which usually occurs in isolation following irradiation of the h-p axis with doses less than 30 Gy. With higher radiation doses (30-50 Gy), however, the frequency of GH insufficiency substantially increases and can be as high as 50-100%.

Cranial irradiation and growth hormone neurosecretory dysfunction: a critical appraisal.

Context: It has been suggested that radiation-induced GH neurosecretory dysfunction exists in children; however, the pathophysiology is poorly understood, and it is unknown if such a phenomenon exists in adult life.

Study Subjects: Twenty-four-hour spontaneous GH secretion was studied by 20-min sampling both in the fed state (n = 16; six women) and the last 24 h of 33-h fast (n = 10; three women) in adult cancer survivors of normal GH status defined by two GH provocative tests, 13.1 +/- 1.

Pathophysiology of radiation-induced growth hormone deficiency: efficacy and safety of GH replacement.

Radiation-induced growth hormone deficiency (GHD) is primarily due to hypothalamic damage. GH secretion by the pituitary may be affected either secondary to some degree of quantitative deprivation of hypothalamic input or, if the radiation dose is high enough, by direct pituitary damage. As a consequence, the neurosecretory profile of GH secretion in an irradiated patient remains pulsatile and qualitatively intact.

Hypopituitarism as a consequence of brain tumours and radiotherapy.

Radiation-induced damage to the hypothalamic-pituitary (h-p) axis is associated with a wide spectrum of subtle and frank abnormalities in anterior pituitary hormones secretion. The frequency, rapidity of onset and the severity of these abnormalities correlate with the total radiation dose delivered to the h-p axis, as well as the fraction size, younger age at irradiation, prior pituitary compromise by tumour and/or surgery and the length of follow up. Whilst, the hypothalamus is the primary site of radiation-induced damage, secondary pituitary atrophy evolves with time due to impaired secretion of hypothalamic trophic factors and/or time-dependent direct radiation-induced damage.

The impact of short-term fasting on the dynamics of 24-hour growth hormone (GH) secretion in patients with severe radiation-induced GH deficiency.

Context: In patients with severe radiation-induced GH deficiency, we previously demonstrated that pulsatile GH secretion and diurnal rhythm are maintained in the fed state, albeit with great attenuation of the pulse amplitude. However, it remained unclear whether stressing the hypothalamic-pituitary axis could unmask neurosecretory dysregulation that is not seen under basal conditions. In addition, the impact of fasting on GH pulsatility and diurnal variation in GH-deficient patients has not been studied in detail before.

Circadian and stimulated thyrotropin secretion in cranially irradiated adult cancer survivors.

Context: It has been claimed that with the use of the TRH test and knowledge of the nocturnal TSH surge, the diagnosis of so-called hidden central hypothyroidism might be uncovered in a substantial proportion of euthyroid cranially irradiated children.

Study Subjects: We conducted 24-h TSH profiles and TRH tests in 37 euthyroid adult cancer survivors 2-29 yr (median, 11.5) after irradiation (18-64 Gy) and in 33 matched normal controls.

Absence of adrenocorticotropin (ACTH) neurosecretory dysfunction but increased cortisol concentrations and production rates in ACTH-replete adult cancer survivors after cranial irradiation for nonpituitary brain tumors.

Context: For the first time, physiological cortisol secretion has been studied in ACTH-replete adult cancer survivors to explore any discrepancy between stimulated (during insulin-induced hypoglycemia) and spontaneous cortisol secretion and, in particular, the possible existence of ACTH neurosecretory dysfunction that might explain the excessive fatigue suffered by some cancer survivors.

Study Subjects: Cortisol profiling at 20-min intervals over 24 h during the fed state was undertaken in 34 patients (10 females), aged 17-53.7 yr (median, 21.

The dynamics of growth hormone (GH) secretion in adult cancer survivors with severe GH deficiency acquired after brain irradiation in childhood for nonpituitary brain tumors: evidence for preserved pulsatility and diurnal variation with increased secretory disorderliness.

Dynamics of GH secretion in patients with GH deficiency due to radiation damage of the hypothalamic-pituitary (h-p) axis acquired in childhood has rarely been studied. Thus, we used a sensitive chemiluminescence GH assay to analyze 24-h GH profiles (20-min sampling) from 10 adult cancer survivors with severe GH deficiency acquired after brain irradiation in childhood for nonpituitary brain tumors. An age- and sex-matched control group of 30 normal healthy volunteers, eight of whom were matched for body mass index with the patients, were also studied.

Late endocrine, metabolic and skeletal sequelae following treatment of childhood cancer.

With an ever increasing adult population of childhood cancer survivors there is a need to focus on the late effects of cancer therapy. It is essential that, after discharge from the paediatric oncologists, the patients are not lost from the health system but are under continued surveillance with access to the appropriate physicians. Endocrine and metabolic consequences may affect a patient's life both soon after cancer treatment and also for many years in the future.