Swollen limbs and bone pain : a case report

A 50 year old man presented with peripheral oedema, abdominal distension and a pulmonary opacity on CXR. He subsequently perforated his sigmoid colon as a complication of diverticulitis with pericolic abscess. After colectomy his postoperative period was marked by severe hypokalaemia, metabolic alkalosis, hyperglycaemia and recurrent chest infections. Paraneoplastic Cushing's syndrome was diagnosed after finding elevated serum cortisol and ACTH levels. CT-guided biopsy of the lung lesion revealed small-cell carcinoma. Bone scan disclosed collapse of numerous thoracic vertebrae possibly due to osteoporosis or oncogenic osteomalacia. Treatment with steroid-synthesis blockers was commenced but the patient died before tumour-directed therapy could be started. Ectopic ACTH syndrome and oncogenic osteomalacia are discussed.peer-reviewe

An audit of the management of diabetic ketoacidosis at St Luke’s Hospital

Aim: To perform an audit of the protocol used in the management of patients with Diabetic Ketoacidosis, in St Lukes Hospital. Methods: Patients admitted with `Diabetes Ketoacidosis', between 14th August 2004 and 14th August 2005, were identified from the Admission book at the Accident and Emergency Department. Data obtained from patients' medical records were collected according to a preset proforma. The criteria assessed by this audit included parameter monitoring, investigations performed, the type and amount of intravenous fluids given, the insulin regime and potassium supplements used. Results: From a total of fifty six patients, forty seven files were traced, of which seventeen satisfied the criteria for Diabetic Ketoacidosis. Two were excluded and fifteen were analysed. In the population studied the mean age was 28 years with a male predominance of 60%. Ten patients suffered from Type 1 Diabetes whilst two patients had Type 2 Diabetes. Three other patients were newly diagnosed. Only one patient had all parameters checked according to protocol. In the majority of patients, fluids given in the first 22 hours, coincided with the amount of fluids stated in the protocol whilst 6/15 (40%) patients were administered the requested amount of insulin via infusion pump. With regards to potassium replacement, 13/15 (87%) patients were started on potassium supplements at a later stage. The factors influencing the total time for conversion to a fixed insulin regime and the duration of stay in hospital were also analysed. Conclusion: Deviations from the protocol were identified in parameter recording, the type of intravenous fluids given and the doses of insulin and potassium supplementation administered. New Diabetic Ketoacidosis guidelines have now been developed.peer-reviewe

Is erectile dysfunction a sentinel symptom for cardiovascular autonomic neuropathy in patients with type 2 diabetes?

The study investigated whether there is a significant association between erectile dysfunction (ED) secondary to autonomic failure, and cardiovascular autonomic neuropathy (CAN) in male patients suffering from type 2 diabetes. Twenty‐two patients suffering from type 2 diabetes were recruited for this study after satisfying the stringent exclusion criteria used in the first stage. They had no evidence of overt cardiovascular disease, hypertension, neurological, renal or thyroid disease. Each subject was assessed for ED and CAN using standardized tests. Six patients were suffering from CAN while 10 patients were suffering from ED. There was no significant association between CAN and autonomic ED (P = 1). Three patients with normal erectile function had CAN, whilst three patients with ED had CAN. Further analysis demonstrates a significant increase in association between ED and CAN with age (P = 0.036). These results show that ED secondary to autonomic neuropathy is not significantly associated with CAN in this specific group of patients. Nonetheless, the study reveals that ED is a sentinel symptom for future development of CAN.peer-reviewe

Book reviews

The books reviewed in this article are: Barton, S., Gonzalez, R., & Tomlinson, P. (2012). Therapeutic residential child care for children and young people: An attachment and trauma-informed model for practice. London: Jessica Kingsley, 287 pp., ISBN 978 1 84905 255 9 (pb), £22.99. Curran, S., Harrison, R., Mackinnon, D. eds. (2013). Working with Young People (2nd ed). Milton Keynes: The Open University. 223pp., ISBN 978-1-4462-7328-9, £24.99. Bettelheim, B. (1950). Love is not enough: the treatment of emotionally disturbed children. Glencoe IL: Free Press 0 02 903280 6 Reissued with the kind permission of Children Webmag - This piece was originally written by Robert Shaw for the August 2009 issue of Children Webmag, which can be accessed on URL: http://www.childrenwebmag.com/2009/0

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. Objectives: Our objectives were to define key variables of physiological cortisol rhythm, and by pharmacokinetic modeling test whether modified-release hydrocortisone (MR-HC) can provide circadian cortisol profiles. Setting: The study was performed at a Clinical Research Facility. Design and Methods: Using data from a cross-sectional study in healthy reference subjects (n = 33), we defined parameters for the cortisol rhythm. We then tested MR-HC against immediate-release hydrocortisone in healthy volunteers (n = 28) in an open-label, randomized, single-dose, cross-over study. We compared profiles with physiological cortisol levels, and modeled an optimal treatment regimen. Results: The key variables in the physiological cortisol profile included: peak 15.5 mu g/dl (95% reference range 11.7-20.6), acrophase 0832 h(95% confidence interval 0759-0905), nadir less than 2 mu g/dl (95% reference range 1.5-2.5), time of nadir 0018 h (95% confidence interval 2339-0058), and quiescent phase (below the mesor) 1943-0531 h. MR-HC 15 mg demonstrated delayed and sustained release with a mean (SEM) maximum observed concentration of 16.6 (1.4) mu g/dl at 7.41 (0.57) h after drug. Bioavailability of MR-HC 5, 10, and 15 mg was 100, 79, and 86% that of immediate-release hydrocortisone. Modeling suggested that MR-HC 15-20 mg at 2300 h and 10 mg at 0700 h could reproduce physiological cortisol levels. Conclusion: By defining circadian rhythms and using modern formulation technology, it is possible to allow a more physiological circadian replacement of cortisol. (J Clin Endocrinol Metab 94: 1548-1554, 2009

Outcomes after urgent thyroidectomy following rapid control of thyrotoxicosis in Graves’ disease are similar to those after elective surgery in well-controlled disease

Background Surgery for Graves’ disease (GD) is usually performed after adequate control with medical treatment. Occasionally, rapid pre-operative optimization is required. The primary objective was to compare the outcomes of patients undergoing elective surgery for well-controlled GD with those undergoing rapid pre-operative treatment. We also propose a formal treatment protocol for future use. Methods A retrospective cohort study in a tertiary referral centre included 247 patients with well-controlled GD undergoing elective surgery and 19 patients with poorly controlled disease undergoing surgery after rapid optimization. The latter group did not respond well to thionamides (carbimazole and/or propylthiouracil) or had intolerance or side effects to thionamides and were treated with a range of non-thionamide drugs, including Lugol’s iodine, cholestyramine, beta blockers and steroids (with or without thionamides), and closely monitored for 1–2 weeks before surgery. Outcome measures included thyroid storm, hypoparathyroidism and recurrent laryngeal nerve palsy. Results In total, 266 patients with male-to-female ratio of 1:6 and median (interquartile range) age of 39 (31–51) were included. Overall, long-term recurrent laryngeal palsy and hypoparathyroidism occurred in 1 (0.38%) and 13 (4.9%) patients, respectively. No patient had thyroid storm. There was no significant difference in hypoparathyroidism (p = 1), vocal cord palsy (p = 0.803) and post-operative bleeding (p = 0.362), between elective surgery and rapid optimization groups. Conclusion Rapid pre-operative treatment is effective, safe and is associated with similar outcomes compared to usual treatment. A rapid pre-operative optimization protocol is proposed

A prospective longitudinal study of Pasireotide in Nelson's syndrome

PURPOSE: Nelson's syndrome is a challenging condition that can develop following bilateral adrenalectomy for Cushing's disease, with high circulating ACTH levels, pigmentation and an invasive pituitary tumor. There is no established medical therapy. The aim of the study was to assess the effects of pasireotide on plasma ACTH and tumor volume in Nelson's syndrome. METHODS: Open labeled multicenter longitudinal trial in three steps: (1) a placebo-controlled acute response test; (2) 1 month pasireotide 300-600 μg s.c. twice-daily; (3) 6 months pasireotide long-acting-release (LAR) 40-60 mg monthly. RESULTS: Seven patients had s.c. treatment and 5 proceeded to LAR treatment. There was a significant reduction in morning plasma ACTH during treatment (mean ± SD; 1823 ± 1286 ng/l vs. 888.0 ± 812.8 ng/l during the s.c. phase vs. 829.0 ± 1171 ng/l during the LAR phase, p < 0.0001). Analysis of ACTH levels using a random intercept linear mixed-random effects longitudinal model showed that ACTH (before the morning dose of glucocorticoids) declined significantly by 26.1 ng/l per week during the 28-week of treatment (95% CI - 45.2 to - 7.1, p < 0.01). An acute response to a test dose predicted outcome in 4/5 patients. Overall, there was no significant change in tumor volumes (1.4 ± 0.9 vs. 1.3 ± 1.0, p = 0.86). Four patients withdrew during the study. Hyperglycemia occurred in 6 patients. CONCLUSIONS: Pasireotide lowers plasma ACTH levels in patients with Nelson's syndrome. A longer period of treatment may be needed to assess the effects of pasireotide on tumor volume. TRIAL REGISTRATION: Clinical Trials.gov ID, NCT01617733

Berry Flesh and Skin Ripening Features in Vitis vinifera as Assessed by Transcriptional Profiling

Background Ripening of fleshy fruit is a complex developmental process involving the differentiation of tissues with separate functions. During grapevine berry ripening important processes contributing to table and wine grape quality take place, some of them flesh- or skin-specific. In this study, transcriptional profiles throughout flesh and skin ripening were followed during two different seasons in a table grape cultivar ‘Muscat Hamburg’ to determine tissue-specific as well as common developmental programs. Methodology/Principal Findings Using an updated GrapeGen Affymetrix GeneChip® annotation based on grapevine 12×v1 gene predictions, 2188 differentially accumulated transcripts between flesh and skin and 2839 transcripts differentially accumulated throughout ripening in the same manner in both tissues were identified. Transcriptional profiles were dominated by changes at the beginning of veraison which affect both pericarp tissues, although frequently delayed or with lower intensity in the skin than in the flesh. Functional enrichment analysis identified the decay on biosynthetic processes, photosynthesis and transport as a major part of the program delayed in the skin. In addition, a higher number of functional categories, including several related to macromolecule transport and phenylpropanoid and lipid biosynthesis, were over-represented in transcripts accumulated to higher levels in the skin. Functional enrichment also indicated auxin, gibberellins and bHLH transcription factors to take part in the regulation of pre-veraison processes in the pericarp, whereas WRKY and C2H2 family transcription factors seems to more specifically participate in the regulation of skin and flesh ripening, respectively. Conclusions/Significance A transcriptomic analysis indicates that a large part of the ripening program is shared by both pericarp tissues despite some components are delayed in the skin. In addition, important tissue differences are present from early stages prior to the ripening onset including tissue-specific regulators. Altogether, these findings provide key elements to understand berry ripening and its differential regulation in flesh and skin.This study was financially supported by GrapeGen Project funded by Genoma España within a collaborative agreement with Genome Canada. The authors also thank The Ministerio de Ciencia e Innovacion for project BIO2008-03892 and a bilateral collaborative grant with Argentina (AR2009-0021). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Peer reviewe

Review: Replication of cortisol circadian rhythm: new advances in hydrocortisone replacement therapy

Cortisol has one of the most distinct and fascinating circadian rhythms in human physiology. This is regulated by the central clock located in the suprachiasmatic nucleus of the hypothalamus. It has been suggested that cortisol acts as a secondary messenger between central and peripheral clocks, hence its importance in the synchronization of body circadian rhythms. Conventional immediate-release hydrocortisone, either at twice- or thrice-daily doses, is not capable of replicating physiological cortisol circadian rhythm and patients with adrenal insufficiency or congenital adrenal hyperplasia still suffer from a poor quality of life and increased mortality. Novel treatments for replacement therapy are therefore essential. Proof-of-concept studies using hydrocortisone infusions suggest that the circadian delivery of hydrocortisone may improve biochemical control and life quality in patients lacking cortisol with an impaired cortisol rhythm. Recently oral formulations of modified-release hydrocortisone are being developed and it has been shown that it is possible to replicate cortisol circadian rhythm and also achieve better control of morning androgen levels. These new drug therapies are promising and potentially offer a more effective treatment with less adverse effects. Definite improvements clearly need to be established in future clinical trials