Serum OPG/TRAIL ratio predicts the presence of cardiovascular disease in people with type 2 diabetes mellitus.

AIMS: Cardiovascular disease (CVD) is the leading cause of mortality in type 2 diabetes mellitus (T2DM). Epidemiological studies suggest serum Osteoprotegrin (OPG)/Tumour-necrosis-factor-related-apoptosis-inducing- ligand (TRAIL) ratio may be a useful marker of cardiovascular risk. This study aimed to compare serum levels of TRAIL, OPG and OPG/TRAIL ratio in people with T2DM, with and without a history of CVD, and controls; and to determine which of these indices, if any, predict cardiovascular risk. METHODS: In this single centre observational study of 133 participants, people with T2DM, with and without a history of a cardiovascular event in the last 5 years, were recruited along with a control cohort without T2DM or CVD. Demographic information and anthropometric measurements were recorded. Blood samples were taken and OPG and TRAIL were measured using ELISA. RESULTS: People with T2DM and CVD had higher OPG/TRAIL ratios compared to controls or those with a new diagnosis of T2DM. After adjustment for potential confounding factors, OPG/TRAIL ratio was significantly associated with the presence of CVD in people with T2DM and an OPG/TRAIL ratio cut-off > 38.6 predicted the presence of CVD in this cohort with a sensitivity of 80% and specificity of 82%. CONCLUSION: This study suggests that OPG/TRAIL ratio may have a role as a biomarker of CVD in people with T2DM.

Hyponatraemia and the syndrome of inappropriate antidiuresis (SIAD) in cancer.

Hyponatraemia is a common electrolyte abnormality seen in a wide range of oncological and haematological malignancies and confers poor performance status, prolonged hospital admission and reduced overall survival, in patients with cancer. Syndrome of inappropriate antidiuresis (SIAD) is the commonest cause of hyponatraemia in malignancy and is characterised by clinical euvolaemia, low plasma osmolality and concentrated urine, with normal renal, adrenal and thyroid function. Causes of SIAD include ectopic production of vasopressin (AVP) from an underlying tumour, cancer treatments, nausea and pain. Cortisol deficiency is an important differential in the assessment of hyponatraemia, as it has an identical biochemical pattern to SIAD and is easily treatable. This is particularly relevant with the increasing use of immune checkpoint inhibitors, which can cause hypophysitis and adrenalitis, leading to cortisol deficiency. Guidelines on the management of acute, symptomatic hyponatraemia recommend 100 mL bolus of 3% saline with careful monitoring of the serum sodium to prevent overcorrection. In cases of chronic hyponatraemia, fluid restriction is recommended as first-line treatment; however, this is frequently not feasible in patients with cancer and has been shown to have limited efficacy. Vasopressin-2 receptor antagonists (vaptans) may be preferable, as they effectively increase sodium levels in SIAD and do not require fluid restriction. Active management of hyponatraemia is increasingly recognised as an important component of oncological management; correction of hyponatraemia is associated with shorter hospital stay and prolonged survival. The awareness of the impact of hyponatraemia and the positive benefits of active restoration of normonatraemia remain challenging in oncology.

Bortezomib-induced hyponatremia: tolvaptan therapy permits continuation of lenalidomide, bortezomib and dexamethasone therapy in relapsed myeloma.

The development of hyponatremia due to syndrome of inappropriate antidiuretic hormone secretion (SIADH) is well recognised in multiple myeloma (MM). SIADH, due to either MM or Bortezomib can be hazardous as severe hyponatremia may develop if large volumes of hypotonic intravenous fluid are used as an adjunct to chemotherapy. We report a case of Bortezomib-induced SIADH, in whom the use of tolvaptan, a vasopressin receptor-2 antagonist, permitted the continuation of triple combination anti-MM therapy with lenalidomide, Bortezomib and dexamethasone (RVD) in a female with aggressive disease, without the development of hyponatremia. Our patient had a rapid relapse, in which the use of Bortezomib as part of an RVD regimen was life-saving. The use of tolvaptan allowed continuation of therapy that is usually halted in other similarly reported cases. This case highlights the possible use of vaptans, which allows an aquaresis to occur by blocking the antidiuretic effects of vasopressin, as a treatment for Bortezomib-induced hyponatremia.

Complexation of novel thiomers and insulin to protect against in vitro enzymatic degradation - towards oral insulin delivery.

A significant barrier to oral insulin delivery is its enzymatic degradation in the gut. Nano-sized polymer-insulin polyelectrolyte complexes (PECS) have been developed to protect insulin against enzymatic degradation. Poly(allylamine) (Paa) was trimethylated to yield QPaa. Thiolation of Paa and QPaa was achieved by attaching either N-acetylcysteine (NAC) or thiobutylamidine (TBA) ligands (Paa-NAC/QPaa-NAC and Paa-TBA/QPaa-TBA thiomers). PEC formulations were prepared in Tris buffer (pH 7.4) at various polymer: insulin mass ratios (0.2:1-2:1). PECS were characterized by %transmittance of light and photon correlation spectroscopy. Insulin complexation efficiency and enzyme-protective effect of these complexes were determined by HPLC. Complexation with insulin was found to be optimal at mass ratios of 0.4-1:1 for all polymers. PECS in this mass range were positively-charged (20-40 mV), nanoparticles (50-200 nm), with high insulin complexation efficiency (>90%). Complexation with TBA polymers appeared to result in disulfide bridge formation between the polymers and insulin. In vitro enzymatic degradation assays of QPaa, Paa-NAC, and QPaa-NAC PECS showed that they all offered some protection against insulin degradation by trypsin and α-chymotrypsin, but not from pepsin. QPaa-NAC complexes with insulin are the most promising formulation for future work, given their ability to offer protection against intestinal enzymes. This work highlights the importance of optimizing polymer structure in the delivery of proteins.

Patients treated with immunosuppressive steroids are less aware of sick day rules Than those on endocrine replacement therapy and may be at greater risk of adrenal crisis.

BACKGROUND: Patients taking corticosteroids for immune suppression are vulnerable to adrenal crisis during acute illness or if steroids are stopped abruptly. Although patients treated for adrenal failure in endocrine units are routinely provided with sick day guidelines, we wished to ascertain whether patients on immunosuppressive steroids are appropriately advised. AIM: This study sets out to compare patient awareness of steroid sick day rules in endocrine and non-endocrine patients. DESIGN: A short case history is presented to illustrate the clinical impact of adrenal crisis in a patient on immune suppression. Subsequently, we present the results of a 9-point questionnaire, devised to determine knowledge of steroid sick day rules, in two patient cohorts. In group 1, patients on immunosuppressive steroids were recruited from non-endocrine clinics to complete the questionnaire. In group 2, patients on replacement steroids were recruited from endocrine clinics. RESULTS: Endocrine patients exhibited better steroid use awareness; they were more likely to double their steroid dose when ill (89 v/s 23%), to obtain parenteral steroid during vomiting (83 v/s 27%), or during surgery (87 v/s 30%), and were aware of the need to carry a MedicAlert bracelet or a steroid-aware card (82 v/s 21%), (p < 0.001 for all comparisons). CONCLUSION: Endocrine patients exhibited a significantly greater knowledge of sick day rules. The data does highlight the lack of patient awareness of the precautions for steroid use in patients on immunosuppressive steroid therapy for non-endocrine conditions, and the case presentation illustrates the potential hazards of this lack of awareness.

Pituitary tuberculoma: a rare cause of sellar mass.

INTRODUCTION: Pituitary tuberculosis is an uncommon cause of sellar mass [1]; the estimated prevalence worldwide is not known, and there have been no reports of the condition occurring in Ireland. Tuberculosis of the pituitary gland may present as a sellar mass or with symptoms of hypopituitarism. CASE PRESENTATION: A 41-year-old woman, with a short prodromal history without endocrine symptoms, was found to have pituitary tuberculosis after the demonstration of a sellar mass on MRI, and lumbar puncture findings consistent with lymphocytic meningitis. CONCLUSION: To our knowledge, this is the first published case of pituitary tuberculoma in Ireland.

The incidence of anterior pituitary hormone deficiencies in patients with microprolactinoma and idiopathic hyperprolactinaemia.

INTRODUCTION: Patients with microprolactinoma and idiopathic hyperprolactinaemia are not generally considered to be at risk of hypopituitarism and are therefore not routinely screened for this abnormality. In our clinical practice, we have observed a number of patients with nonmacroadenomatous hyperprolactinaemia to have anterior pituitary hormone deficits. AIMS: We aimed to establish the frequency and clinical significance of anterior pituitary hormone deficiencies, comparing patients with radiologically proven microprolactinomas and patients with idiopathic hyperprolactinaemia. STUDY DESIGN: We retrospectively examined the casenotes of 206 patients with hyperprolactinaemia from our centre. Patients who did not fit the profile of surgically naïve microprolactinoma or idiopathic hyperprolactinaemia or who had incomplete data were excluded, resulting in a study group of 56 patients. RESULTS: A total of 35 patients with MRI evidence of microprolactinoma were identified, three (8.57%) of whom had one or more anterior pituitary hormone deficiencies. A total of 21 patients with MRI-negative idiopathic hyperprolactinaemia were identified, nine (42%) of whom had one or more anterior pituitary hormone deficiencies (P<.01). Only one patient in the MRI-positive group had deficiency that required hormone replacement, in contrast six patients in the MRI-negative group had deficiencies that were of clinical significance and which required hormone replacement. SUMMARY: This study shows a clinically significant incidence of anterior pituitary hormone deficiency in patients with idiopathic hyperprolactinaemia. The authors recommend that dynamic pituitary assessment should be considered routinely in this patient group. A prospective study would be required to assess the underlying cause for these abnormalities, as they suggest a nontumour pan-pituitary process.

Predictors of failure to respond to fluid restriction in SIAD in clinical practice; time to re-evaluate clinical guidelines?

BACKGROUND: Fluid restriction is recommended as first line therapy for Syndrome of Inappropriate Antidiuresis (SIAD), despite of lack of good evidence base to support its use, and poor efficacy in clinical practice and in the literature. AIM: We set out to determine how many patients with well-defined SIAD had pre-treatment criteria which would predict failure to fluid restriction. DESIGN AND METHODS: This was a consecutive, prospective evaluation of 183 patients with a diagnosis of SIAD in two different hospitals. Full ascertainment of the diagnostic criteria for SIAD was obtained in all patients. RESULTS: About 47% of patients had a urine volume <1500 ml in 24 h, 41% had initial urine osmolality > 500 mOsm/kg, 26% a Furst-equation ratio > 1. About 59% had one criterion predicting failure to respond to fluid restriction, 37% two criteria, and 3% three criteria. CONCLUSIONS: Our data suggest that up to 60% of patients with SIAD had criteria which recent clinical guidelines suggest would predict nonresponse to fluid restriction. This may explain why the recommended first line therapy for SIAD has been shown to be ineffective.

Diabetes in Patients With Acromegaly.

PURPOSE OF REVIEW: Acromegaly is a clinical syndrome which results from growth hormone excess. Uncontrolled acromegaly is associated with cardiovascular mortality, due to an excess of risk factors including diabetes mellitus, hypertension and cardiomegaly. Diabetes mellitus is a frequent complication of acromegaly with a prevalence of 12-37%. This review will provide an overview of a number of aspects of diabetes mellitus and glucose intolerance in acromegaly including the following: 1. Epidemiology and pathophysiology of abnormalities of glucose homeostasis 2. The impact of different management options for acromegaly on glucose homeostasis 3. The management options for diabetes mellitus in patients with acromegaly RECENT FINDINGS: Growth hormone and IGF-1 have complex effects on glucose metabolism. Insulin resistance, hyperinsulinaemia and increased gluconeogenesis combine to produce a metabolic milieu which leads to the development of diabetes in acromegaly. Treatment of acromegaly should ameliorate abnormalities of glucose metabolism, due to reversal of insulin resistance and a reduction in gluconeogenesis. Recent advances in medical therapy of acromegaly have varying impacts on glucose homeostasis. These adverse effects influence management choices in patients with acromegaly who also have diabetes mellitus or glucose intolerance. The underlying mechanisms of disorders of glucose metabolism in patients with acromegaly are complex. The aim of treatment of acromegaly is normalisation of GH/IGF-1 with reduction of co-morbidities. The choice of therapy for acromegaly should consider the impact of therapy on several factors including glucose metabolism.

Endocrinopathies and renal outcomes in lithium therapy: impact of lithium toxicity.

BACKGROUND: Lithium is the mainstay of treatment for bipolar disorder, mania and an augmentation therapy in patients with treatment resistant depression. It has a narrow therapeutic index, with recognized adverse multi-system and endocrine side effects. AIM: To assess the impact of lithium therapy, in particular lithium toxicity, on the development of endocrine and renal disorders in a cohort of patients in a single tertiary referral centre in Ireland. STUDY DESIGN: A retrospective analysis was performed of the prevalence of lithium toxicity and renal, thyroid and parathyroid dysfunction in our study population. METHODS: We collected laboratory data from the Clinical Chemistry department of the Adelaide and Meath Hospital incorporating the National Children's Hospital (AMNCH), Dublin, Ireland. Our study population included all patients who had at least one serum lithium measurement from January 1st 2000 to December 31st 2014 inclusive. RESULTS: A total of 580 patients were included in the study. Among our study group, 70 patients (12.1%) had 1 toxic lithium measurement (lithium level >1.2 mmol/l). 27.8% (n > 161) of patients developed stage 3 Chronic kidney Disease (CKD) or higher, which was commoner in those patients who developed toxic lithium levels (P < 0.0001) and in those who developed hypernatraemia (P > 0.0001). 16.2% of patients (n > 94) had one serum sodium >145 mmol/l during follow up. 60 patients(10.3%) had a TSH >10 mU/l, while complete suppression of TSH (<0.05 mU/l) was observed in 22 patients (3.8%) during follow-up. 4% (n > 37) of the study population had ≥1 serum corrected calcium level > 2.55 mmol/l, and 4 patients had biochemical confirmation of primary hyperparathyroidism but PTH levels were only performed in 2.8% (n > 16) of the studypopulation. CONCLUSION: Stage 3 CKD is common in patients receiving lithium therapy. Lithium toxicity is associated with CKD and hypernatraemia. Thyroid dysfunction and hypercalcaemia are common in patients receiving lithium therapy. Patients receiving lithium therapy require surveillance of renal, thyroid and bone biochemistry.

MR-compatibility of a high-resolution small animal PET insert operating inside a 7 T MRI.

A full-ring PET insert consisting of 16 PET detector modules was designed and constructed to fit within the 114 mm diameter gradient bore of a Bruker 7 T MRI. The individual detector modules contain two silicon photomultiplier (SiPM) arrays, dual-layer offset LYSO crystal arrays, and high-definition multimedia interface (HDMI) cables for both signal and power transmission. Several different RF shielding configurations were assessed prior to construction of a fully assembled PET insert using a combination of carbon fibre and copper foil for RF shielding. MR-compatibility measurements included field mapping of the static magnetic field (B 0) and the time-varying excitation field (B 1) as well as acquisitions with multiple pulse sequences: spin echo (SE), rapid imaging with refocused echoes (RARE), fast low angle shot (FLASH) gradient echo, and echo planar imaging (EPI). B 0 field maps revealed a small degradation in the mean homogeneity (+0.1 ppm) when the PET insert was installed and operating. No significant change was observed in the B 1 field maps or the image homogeneity of various MR images, with a 9% decrease in the signal-to-noise ratio (SNR) observed only in EPI images acquired with the PET insert installed and operating. PET detector flood histograms, photopeak amplitudes, and energy resolutions were unchanged in individual PET detector modules when acquired during MRI operation. There was a small baseline shift on the PET detector signals due to the switching amplifiers used to power MRI gradient pulses. This baseline shift was observable when measured with an oscilloscope and varied as a function of the gradient duty cycle, but had no noticeable effect on the performance of the PET detector modules. Compact front-end electronics and effective RF shielding led to minimal cross-interference between the PET and MRI systems. Both PET detector and MRI performance was excellent, whether operating as a standalone system or a hybrid PET/MRI.

The syndrome of inappropriate antidiuresis (SIAD).

Hyponatraemia is the commonest electrolyte disturbance encountered in clinical practice and the syndrome of inappropriate antidiuresis (SIADH) is the most frequent underlying disorder. There is a well-recognized relationship between hyponatraemia and increased morbidity and mortality, though it is unknown whether SIADH confers the same mortality as other causes of hyponatraemia. SIADH is the biochemical manifestation of a wide variety of diseases, and the pathophysiology of SIADH is sometimes multiple. There have been significant advances in the treatment of SIADH over the last 10 years, in particular since the introduction of the vasopressin-2 receptor antagonists, which provide a potent, disease-specific tool which targets the underlying pathophysiology of SIADH. The mechanisms and the evidence base recommendations of the available therapies for SIADH are discussed in this article. The various guidelines and recommendations for treatment of hyponatraemia all emphasise that fluid restriction is first line therapy for SIADH, but we feel that it is ineffective or unfeasible in many patients. A number of key points relevant to the use of fluid restriction are presented in the manuscript. The clinical efficacy of tolvaptan in SIADH supported by good quality randomized, placebo controlled, clinical trials. However, the cost of the therapy and the need for long term safety data may limit its widespread use. Finally, new recommendations for the management of acute hyponatraemia, with a focus on the use of bolus therapy with 3% hypertonic sodium chloride is described.

SIAD: practical recommendations for diagnosis and management.

Hyponatremia is the commonest electrolyte disturbance encountered in hospitalized patients, and the syndrome of inappropriate antidiuresis (SIAD) is the most frequent underlying disorder. There is a well-recognized relationship between hyponatremia and increased morbidity and mortality. Therefore, to provide appropriate treatment is critical to improve the clinical outcome related to SIAD-hyponatremia. There have been important advances in the treatment of SIAD over the last decade, leading to the publication of several clinical guidelines. In particular, the introduction of the vasopressin-2 receptor antagonists provides a potent pharmacological tool to target the underlying pathophysiology of SIAD. The evidence base recommendations of the available therapies for SIAD are discussed in this study. Fluid restriction is considered the first-line therapy by the recent published guidelines, but it is certainly ineffective or unfeasible in many patients with SIAD. We discuss a number of relevant points to the use of fluid restriction in this study, including the lack of good evidence-based recommendations to support its use. Conversely, the clinical efficacy of oral tolvaptan in SIAD supported by good quality randomized, placebo controlled, clinical trials. However, the cost of the therapy and the need for long-term safety data may limit its widespread use. Finally, new recommendations for the management of acute hyponatremia with a focus on the use of bolus therapy with 3 % hypertonic sodium chloride are described in this study.

Heterogenous patterns of recovery of thirst in adult patients with adipsic diabetes insipidus.

BACKGROUND: The natural history of adipsic diabetes insipidus (ADI) is not well described, and reports of recovery of thirst are rare. DESIGN AND METHODS: Case histories presentation. ADI was identified by demonstrating absent thirst and arginine vasopressin (AVP) responses to hypertonic saline infusion. RESULTS: Twelve patients with ADI were identified (craniopharyngioma 5, anterior communicating artery aneurysm (ACOM) repair 4, congenital 1, neurosarcoidosis 1, prolactinoma 1). Three patients died. Six patients had permanent ADI. Three patients had recovery of thirst, with a heterogenous pattern of recovery. In the first case, ADI had developed after clipping of an ACOM aneurysm. Ten years after surgery; he sensed the return of thirst; repeated hypertonic saline infusion showed recovery of thirst and AVP secretion. In the second case, a 41-year-old female with an intrasellar craniopharyngioma developed post-operative ADI with persistent hypernatremia. Two years post-operatively, she complained of thirst, and hypertonic saline infusion showed normalization of thirst but absent AVP responses, confirming recovery of thirst, but with persistent diabetes insipidus (DI). In the third case, a 29-year-old Caucasian had craniotomy and radiotherapy for craniopharyngioma and developed ADI post-operatively. Eight years post-op, she presented with thirst, seizures and pNa of 112 mmol/l. Hypertonic saline infusion showed persistent DI but thirst responses typical of compulsive water drinking; she has had recurrent hyponatraemia since then. CONCLUSIONS: We report that 3/12 patients with ADI recovered thirst after longstanding adipsia with heterogenous pattern of recovery. Both the mortality of 25% and the recovery rate of 25% should be considered when planning long-term surveillance.

In-vitro evaluation of the effect of polymer structure on uptake of novel polymer-insulin polyelectrolyte complexes by human epithelial cells.

The biocompatibility and cellular uptake of polymer, insulin polyelectrolyte complexes (PECs) prepared using polyallylamine-based polymers was evaluated in-vitro using Caco-2 cell monolayers as a predictive model for human small intestinal epithelial cells. Poly(allyl amine) (PAA) and Quaternised PAA (QPAA) were thiolated using either carbodiimide mediated conjugation to N-acetylcysteine (NAC) or reaction with 2-iminothiolane hydrochloride yielding their NAC and 4-thiobutylamidine (TBA) conjugates, respectively. The effect of polymer quaternisation and/or thiolation on the IC50 of PAA was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay carried out on Caco-2 cells (with and without a 24 h recovery period after samples were removed). Uptake of PECs by Caco-2 cells was monitored by microscopy using fluorescein isothiocyanate (FITC) labelled insulin and rhodamine-labelled polymers at polymer:insulin ratios (4:5) after 0.5, 1, 2 and 4 h incubation in growth media (±calcium) and following pre-incubation with insulin. MTT results indicated that quaternisation of PAA was associated with an improvement in IC50 values; cells treated with QPAA (0.001-4 mg mL(-1)) showed no signs of toxicity following a 24 h cell recovery period, while thiolation of QPAA resulted in a decrease in the IC50. Cellular uptake studies showed that within 2-4 h, QPAA and QPAA-TBA insulin PECs were taken up intracellularly, with PECs being localised within the perinuclear area of cells. Further investigation showed that uptake of PECs was unaffected when calcium-free media was used, while presaturating insulin receptors affected the uptake of QPAA, insulin PECs, but not QPAA-TBA PECs. The biocompatibility of PAA and uptake of insulin was improved by both thiol and quaternary substitution.

Abnormal plasma sodium concentrations in patients treated with desmopressin for cranial diabetes insipidus: results of a long-term retrospective study.

CONTEXT AND OBJECTIVE: Patients with cranial diabetes insipidus (CDI) are at risk of developing both hypernatraemia and hyponatraemia, due to the condition itself or secondary to treatment with vasopressin-analogues or during administration of i.v. fluids. We aimed to assess the frequency and impact of dysnatraemias in the inpatient (INPT) and outpatient (OPT) setting in desmopressin-treated CDI, comparing those with normal thirst with those with abnormal thirst. DESIGN: The study included 192 patients with cranial diabetes, who were identified from the Beaumont Pituitary Database, a tertiary referral centre. Retrospective case note audit was performed and the clinical and biochemical information of 147 patients with CDI were available for analysis. RESULTS: A total of 4142 plasma sodium measurements for 137 patients with normal thirst, and 385 plasma sodium measurements for ten patients with abnormal thirst were analysed. In those with normal thirst, the most common OPT abnormality was mild hyponatraemia (pNa(+) 131-134  mmol/l) in 27%, while 14.6% had more significant hyponatraemia (pNa(+) ≤130  mmol/l). Of those patients with normal thirst, 5.8% were admitted due to complications directly related to hyponatraemia. Compared with patients with normal thirst, those with abnormal thirst were more likely to develop significant OPT hypernatraemia (20% vs 1.4%, P=0.02) and significant INPT hyponatraemia (50% vs 11.1%, P 0.02). CONCLUSION: OPT management of CDI is complicated by a significant incidence of hyponatraemia. In contrast, OPT hypernatraemia is almost exclusively a complication seen in adipsic CDI, who also had more frequent INPT hyponatraemia. CDI associated with thirst disorder requires increased physician attention and patient awareness of potential complications.

Chronic hypopituitarism is uncommon in survivors of aneurysmal subarachnoid haemorrhage.

OBJECTIVE: The incidence of hypopituitarism after aneurysmal subarachnoid haemorrhage (SAH) is unclear from the conflicting reports in the literature. As routine neuroendocrine screening for hypopituitarism for all patients would be costly and logistically difficult, there is a need for precise data on the frequency of hypopituitarism and on factors which might predict the later development of pituitary dysfunction. We aimed to: (i) Establish the incidence of long-term hypopituitarism in patients with aneurysmal SAH. (ii) Determine whether data from patients' acute admission with SAH could predict the occurrence of long-term hypopituitarism. DESIGN: One hundred patients were studied prospectively from the time of presentation with acute SAH. Plasma cortisol, plasma sodium and a variety of clinical and haemodynamic parameters were sequentially measured for the first 12 days of their acute admission. Forty-one patients then underwent dynamic pituitary testing at median 15 months following SAH (range 7-30 months), with insulin tolerance test (ITT) or, if contraindicated, a glucagon stimulation test (GST) plus short synacthen test (SST). If symptoms of cranial diabetes insipidus (CDI) were present, a water deprivation test was also performed. RESULTS: Forty-one patients attended for follow-up dynamic pituitary testing. Although 14 of 100 had acute glucocorticoid deficiency immediately following SAH, only two of 41 had long-term adrenocorticotrophic hormone (ACTH) deficiency and four of 41 had growth hormone (GH) deficiency. None were hypothyroid or gonadotrophin deficient. None had chronic CDI or hyponatraemia. There was no association between acute glucocorticoid deficiency, acute CDI or acute hyponatraemia and long-term pituitary dysfunction. CONCLUSION: Both anterior and posterior hypopituitarism are very uncommon following SAH and are not predicted by acute clinical, haemodynamic or endocrinological parameters. Routine neuroendocrine screening is not justified in SAH patients.

Species distributions and area relationships.

The well-known species-area relationship is one of many scaling laws, or allometries, in ecology and biology that have received much attention over the years. We present a new derivation of this relationship based on Yule׳s theory of evolution of species. Using definitions of mutation rates, our analysis yields species-area exponents that are in close agreement with previously observed values.