Treatment options in the young patient with Graves' disease.

The treatment options in the young patient with Graves' disease are the same as in adults, namely antithyroid drug (ATD), surgery (partial or total thyroidectomy) and radioiodine. However, the emphasis and expectation is different in the young person, reflecting a range of considerations including age, pubertal status, disease natural history, likely impact of ATD on disease course and the implications of radiation exposure. New therapeutic strategies that could increase the likelihood of long-term remission are being explored.

Adrenal surgery in England: better outcomes in high-volume practices.

AIMS AND BACKGROUND: Adrenal surgery is performed by a variety of surgical specialities in differing environments and volumes. International data suggest that there is a correlation between adrenal surgery volume and outcomes but there are no UK data to support this or UK surgical guidelines. A multidisciplinary team representing the stakeholders in adrenal disease is preparing a national guidance on adrenal surgery. A review of the outcomes for adrenal surgery in England was performed to correlate outcomes with the volume of surgeon practice. METHODS: Hospital Episode Statistics (HES) data for the National Health Service (NHS) in England in the tax year 2013-2014 were examined for adrenal surgery. Length of hospital stay and rate of postoperative readmission were assessed as surrogate quality markers and a comparison made between 'high-' and 'low-' volume surgeons. RESULTS: A total of 795 adult adrenalectomies were performed by 222 different surgeons with a range of between 1 and 34 adrenalectomies performed per surgeon. Only thirty-six (16%) adrenal surgeons performed 6 or more adrenalectomies. A total of 186 surgeons (84%) performed a median of one adrenalectomy a year. Length of stay and readmission rate within thirty days of operation was 60% longer and 47% higher, respectively, when performed by low-volume surgeons. CONCLUSION: The current provision of adrenal surgery in the UK is not in the best interests of patients and is not cost-effective for the NHS. Adrenal surgery is best performed by higher volume surgeons in centres with dedicated adrenal multidisciplinary teams expert in all aspects of care of the adrenal patient.

Phaeochromocytoma and ACTH-dependent cushing's syndrome: tumour crf secretion can mimic pituitary cushing's disease.

INTRODUCTION: 10% of corticotrophin (ACTH)-dependent Cushing's syndrome arises from secretion by extrapituitary tumours, with phaeochromocytoma implicated in a few cases. Ectopic secretion by phaeochromocytoma of corticotropin-releasing hormone (CRF), with secondary corticotroph hyperplasia, is even rarer, with only five cases in the literature hitherto. However, such cases may be classified as 'ectopic ACTH' due to incomplete verification. CLINICAL CASES: We describe three patients with phaeochromocytoma and ACTH-dependent Cushing's syndrome in whom biochemical cure was achieved following unilateral adrenalectomy. Although unable to access a validated CRF assay within the timeframe for sample storage, we nevertheless inferred CRF secretion in 2 of 3 cases by tumour immunostaining (positive for CRF; negative for ACTH), supported in one case by pre-operative inferior petrosal sinus sampling (IPSS) indicative of pituitary ACTH source. Both cases were characterized by rapid postoperative wean off glucocorticoids, presumed to reflect the pituitary stimulatory-effect of CRF outweighing central negative feedback inhibition by hypercortisolaemia. By contrast, the tumour excised in a third case exhibited positive immunostaining for ACTH - negative for CRF - and postoperative recovery of hypothalamic-pituitary-adrenal axis took significantly longer. DISCUSSION: Ectopic CRF production is biochemically indistinguishable from ectopic ACTH secretion, except that IPSS mimics pituitary Cushing's disease and cortisol dynamics may normalize rapidly postadrenalectomy. CRF secretion can be inferred through tumour immunohistochemistry, even if no CRF assay is available. Unrecognized phaeochromocytoma ACTH secretion may underpin some cases of cardiovascular collapse postadrenalectomy through acute hypocortisolaemia. Despite advances in phaeochromocytoma genetics since previous reports, we were unable to identify somatic DNA defects associated with either ACTH or CRF secretion.

Parafibromin, galectin-3, PGP9.5, Ki67, and cyclin D1: using an immunohistochemical panel to aid in the diagnosis of parathyroid cancer.

BACKGROUND: Parathyroid cancer is rare. Differentiating parathyroid carcinoma from degenerative changes at histopathology can be difficult and studies investigating the value of single immunohistochemical markers have had variable results. In this study we aimed to investigate whether a panel of immunohistochemistry markers could aid the diagnosis of parathyroid cancer. METHODS: All cases of parathyroid cancer at our institution from 1998 to 2012 were identified retrospectively. Cases were classified as definite cancers (those with evidence of metastatic spread) or histological cancers (those with features of carcinoma without evidence of metastasis). Controls with benign parathyroid disease were included for comparison. Immunohistochemistry for parafibromin, galectin-3, PGP9.5, Ki67, and cyclin D1 was analysed by an experienced endocrine pathologist. RESULTS: There were 24 cases and 14 benign adenomas. Four cases had evidence of metastatic spread and 20 were diagnosed on histological criteria alone. Sixteen of the 24 cases had further surgery with ipsilateral thyroid lobectomy and 15 also had a prophylactic level VI lymph node dissection. Apart from one patient with distant metastases at presentation, none developed recurrence at follow-up (median = 38 months). Immunohistochemistry results associated with parathyroid cancer were seen in 11/24 parafibromin, 13/24 galectin-3, 8/24 PGP9.5, 5/24 Ki67, and 2/24 cyclin D1. None of the controls had immunohistochemical staining suggestive of cancer. Nineteen of the 24 patients had at least one immunohistochemical result associated with parathyroid cancer (sensitivity 79 %, specificity 100 %). Cyclin D1 did not suggest malignancy in any case that did not already have another abnormal marker, and so did not add value to the panel in this study. CONCLUSION: A panel of immunohistochemistry (PGP9.5, galectin-3, parafibromin, and Ki67) is better than any single marker and can be used to supplement classical histopathology in diagnosing parathyroid cancer.

Three dimensional reconstruction of coronary artery stents from optical coherence tomography: experimental validation and clinical feasibility.

The structural morphology of coronary stents (e.g. stent expansion, lumen scaffolding, strut apposition, tissue protrusion, side branch jailing, strut fracture), and the local hemodynamic environment after stent deployment are key determinants of procedural success and subsequent clinical outcomes. High-resolution intracoronary imaging has the potential to enable the geometrically accurate three-dimensional (3D) reconstruction of coronary stents. The aim of this work was to present a novel algorithm for 3D stent reconstruction of coronary artery stents based on optical coherence tomography (OCT) and angiography, and test experimentally its accuracy, reproducibility, clinical feasibility, and ability to perform computational fluid dynamics (CFD) studies. Our method has the following steps: 3D lumen reconstruction based on OCT and angiography, stent strut segmentation in OCT images, packaging, rotation and straightening of the segmented struts, planar unrolling of the segmented struts, planar stent wireframe reconstruction, rolling back of the planar stent wireframe to the 3D reconstructed lumen, and final stent volume reconstruction. We tested the accuracy and reproducibility of our method in stented patient-specific silicone models using micro-computed tomography (µCT) and stereoscopy as references. The clinical feasibility and CFD studies were performed in clinically stented coronary bifurcations. The experimental and clinical studies showed that our algorithm (1) can reproduce the complex spatial stent configuration with high precision and reproducibility, (2) is feasible in 3D reconstructing stents deployed in bifurcations, and (3) enables CFD studies to assess the local hemodynamic environment within the stent. Notably, the high accuracy of our algorithm was consistent across different stent designs and diameters. Our method coupled with patient-specific CFD studies can lay the ground for optimization of stenting procedures, patient-specific computational stenting simulations, and research and development of new stent scaffolds and stenting techniques.

Neuroprotective effects of leptin following kainic acid-induced status epilepticus.

We investigated the potential neuroprotective effects of leptin (LEP) against cellular damage, long-term recurrent spontaneous seizures, and behavioral changes associated with kainate (KA)-induced status epilepticus (SE). Adult Sprague-Dawley rats were sacrificed 24 hours after KA injections, and hippocampi were subjected to histological analysis. In the acute condition, one group received 12 mg/kg KA intraperitoneally (KAac group), and another group received 12 mg/kg KA intraperitoneally, followed by two intraperitoneal LEP injections of 4 mg/kg each, 1 and 13 hours after KA (KALEPac group). For long-term outcomes, one group received KA (KA group), and the other group received three intraperitoneal LEP injections (4 mg/kg at 1 hour, and 2mg/kg at 13 and 24 hours) after KA (KALEP group). Controls were sham manipulated. Behavioral tests started 6 weeks after SE. All rats that received KA underwent behavioral seizures of comparable severity. Compared with the KAac group, the KALEPac group had significantly larger pyramidal cell surface areas and fewer black-stained degenerating neurons with silver stain. The KALEP and KA groups were comparable with respect to recurrent spontaneous seizures, aggression, hyperactivity, and impaired memory. We show that leptin reduces cellular injury associated with KA-induced SE, but does not prevent long-term recurrent spontaneous seizures and behavioral deficits.

AMPA-induced dark cell degeneration is associated with activation of caspases in pyramidal neurons of the rat hippocampus.

Various neurons in the central nervous system (CNS) exhibit selective vulnerability to AMPA-induced delayed neurotoxicity known as dark cell degeneration. Hippocampal pyramidal neurons in the CA1 and CA3 regions display such vulnerability that encompasses morphological changes including cytoplasmic and nuclear condensation, neuronal shrinkage, formation of cytoplasmic vacuoles, and general failure of physiology. The present study was undertaken to ascertain the potential involvement of initiator (caspase-9) and executor (caspase-3) caspases in AMPA-receptor-induced dark cell degeneration in pyramidal neurons. Immunohistochemical analyses revealed that immunoreactivity of the active form of caspase-9 and -3 was increased in pyramidal neurons in CA1 and CA3 regions of the hippocampus following AMPA (100 microM). Elevated levels of active caspase-9 immunoreactivity generally preceded elevations in active caspase-3 immunoreactivity. The pan caspase inhibitor FK011 effectively attenuated AMPA-induced dark cell degeneration in both CA1 and CA3 regions. Collectively, the data suggest a role for these caspases in mediating AMPA-induced toxicity in pyramidal neurons of the rat hippocampus.

Involvement of calpain in AMPA-induced toxicity to rat cerebellar Purkinje neurons.

AMPA receptor-elicited excitotoxicity is manifested as both a type of programmed cell death termed dark cell degeneration and edematous necrosis, both of which are linked to increased intracellular Ca2+ concentration. The appearance of marked cytoskeletal changes in response to abusive AMPA receptor activation, coupled with increased intracellular Ca2+ concentration suggests activation of various destructive enzymes such as calpains, a family of Ca2+-dependent cysteine proteases. Since calpains and AMPA have been linked to both necrotic cell death and programmed cell death, we sought to determine the role of calpains in mediating both types of AMPA-mediated toxicity in Purkinje neurons of the cerebellum. These studies employed immunohistochemistry for cytoskeletal breakdown products of calpain activity coupled with confocal microscopy and pharmacological interventions with calpain and AMPA receptor antagonists. The present study identifies an early involvement of calpains in mediating AMPA-induced dark cell degeneration, but not edematous necrosis, based upon the effectiveness of AMPA to generate calpain-derived alpha-spectrin cleavage products in cerebellar Purkinje neurons that express dark cell degeneration, and the effectiveness of calpain antagonists, PD150606 and MDL28170, to attenuate AMPA-induced dark cell degeneration. Moreover, the AMPA receptor antagonist CNQX, a proven inhibitor of AMPA-elicited dark cell degeneration, also blocked AMPA-induced increases in alpha-spectrin, further suggesting interplay between abusive AMPA receptor activation, calpain activation and dark cell degeneration. Since AMPA-induced dark cell degeneration possesses morphological changes that resemble those that occur following brain ischemia in vivo, hypoglycemia, or extended seizure episodes, the involvement of calpains as mediators of cell death is potentially far reaching and has widespread therapeutic implications in numerous CNS disorders.

"Non-trivial pursuit of physiology".

This article describes a novel way to conduct a review session that combines interactivity, team learning, and peer-to-peer instruction. It uses the format of the familiar game "Trivial Pursuit." To facilitate the game process and to encourage its use by others, we have developed custom software. It allows an instructor to run the game from the podium and to input questions/answers for a particular block or other area to be reviewed. In addition to the software itself, the online supplement (http://advan.physiology.org/cgi/content/full/00031.2004/DC1) contains 100 sample questions and answers written for the cardiovascular physiology review session. The developed game format and its software add to the arsenal of educational tools that can be used to enrich students' learning experiences.

Tumor necrosis factor-α (TNF-α) augments AMPA-induced Purkinje neuron toxicity.

It is well recognized that exposure of neurons to excessive levels of the excitatory neurotransmitter glutamate, termed glutamate excitotoxicity, contributes to the damage and degeneration seen in many acute and chronic neurological diseases. However, it is becoming increasingly evident that inflammation also can play a role in certain neurodegenerative diseases and inflammatory mediators, such as tumor necrosis factor-α (TNF-α), may directly interact with excitotoxic processes. In a postnatal rat cerebellar slice model, we found that TNF-α exacerbated AMPA-induced excitotoxicity in Purkinje neurons in a dose-dependent manner beyond the toxicity caused by AMPA alone. It also was shown that combinations of TNF-α and AMPA increased the mean intracellular activity of calpains, calcium-activated cysteine proteases that are known to contribute to cell death in Purkinje neurons. Additionally, these combinations augmented colbalt influx, a marker for calcium entry that selectively occurs through calcium permeable AMPA receptors only. Pharmacologic blockade of calcium permeable AMPA receptors with a specific antagonist, 1-naphthyl acetyl spermine (NASPM), reversed the apparent increase in AMPA receptor calcium permeability caused by TNF-α as measured by cobalt influx; caused a reduction in the Purkinje neuron calpain activity; and reversed the enhanced neurodegeneration induced by the combination of TNF-α and AMPA. From these studies we concluded that TNF-α augmented AMPA-induced toxicity in Purkinje neurons by increasing intracellular calcium flux through calcium permeable AMPA receptors, and this increase in calcium was directly involved in enhanced activation of calpains and a greater percentage of Purkinje neuron loss.