Abstract-Bulbospinal neurons in the rostral ventrolateral medulla (RVLM) are critical for the maintenance of sympathetic vasomotor tone and normal cardiovascular reflex function. So far, selectively eliminating/inhibiting distinct subpopulations of RVLM neurons has not significantly altered arterial pressure. Here we show that RVLM presympathetic neurons that express somatostatin 2A receptors are essential for maintaining and potentially generating sympathetic vasomotor tone. Combined immunocytochemistry and in situ hybridization were used to map the expression of somatostatin receptors 1, 2A, 2B, 3, and 4 (sst1 through 4, respectively) in the rat RVLM. sst1 and sst2B were absent; sst3 and sst4 were sparse. However, sst2A was found postsynaptically and detected in 35Ϯ5% of bulbospinal RVLM neurons a population that included 54Ϯ4% of catecholaminergic and 30Ϯ3% of enkephalinergic neurons. Bilateral microinjection into the RVLM of either somatostatin or the receptor-selective agonist lanreotide evoked dramatic, dose-dependent sympathoinhibition, hypotension, and bradycardia that were blocked by the sst2 receptor antagonist BIM-23627 in anesthetized rats. Bilateral RVLM microinjection of somatostatin also attenuated chemoreceptor and somatosympathetic reflex function. Somatostatin only eliminated the first sympathoexcitatory peak evoked by somatosympathetic reflex activation, whereas muscimol abolished both excitatory peaks providing functional evidence that the activity of only a subpopulation of RVLM presympathetic neurons is inhibited by somatostatin. We suggest that the subpopulation of bulbospinal RVLM neurons that expresses the sst2A receptor sets sympathetic vasomotor output. These neurons are essential for maintaining resting blood pressure under anesthesia and contribute to adaptive reflexes mediated through the RVLM. Key Words: cardiovascular Ⅲ sympathetic vasomotor tone Ⅲ catecholamine Ⅲ enkephalin Ⅲ respiration P resympathetic neurons within the rostral ventrolateral medulla (RVLM) contain catecholamines and/or preproenkephalin (PPE) and are critical for the tonic and reflex control of arterial pressure (AP). [1][2][3] Inputs regulating RVLM presympathetic neuronal activity release amino acids and/or a range of modulatory neurochemicals, including peptides. [2][3][4][5][6] These underlie the ability to provide a differentiated sympathetic drive to the various vascular beds, 6 alter the responses to reflex activation, 5 and set the level of AP. 1,3,5 Identification of neurons responsible for generating and maintaining sympathetic vasomotor tone and, therefore, setting the level of AP would be a major breakthrough in understanding circulatory control.The inhibitory neuropeptide somatostatin (SST) is distributed widely in regions of the central nervous system involved in motor, cognitive, autonomic, and neuroendocrine processes. 7,8 Two biologically active forms of SST, SST 14 and SST 28, are cleaved from preprosomatostatin and bind to all of the SST receptors with similar affinity. 8 Six G protein-couple...

Background: Amiodarone-induced thyrotoxicosis (AIT) is associated with significant morbidity and mortality, particularly in patients with cardiac failure. The aim of the study was to evaluate the management of AIT at a tertiary hospital specialising in cardiac failure and transplantation.Methods: Retrospective audit of 66 patients treated for AIT by Endocrinology (2007–2016), classified as type 1 (T1) or type 2 (T2) based on radiological criteria. Main outcome measurements were response rate to initial treatment, time to euthyroidism, and frequency/safety of thyroidectomy.Results: Mean age was 60 ± 2 years; 80% were male. Sixty-four patients commenced medical treatment: thionamides (THIO) in 23, glucocorticoids (GC) in 17 and combination (COMB) in 24. Median thyroxine (fT4) was 35.1 (31.2–46.7) in THIO, 43.1 (30.4 –60.7) in GC, and 60.0 (39.0 –>99.9) pmol/L in COMB (p = 0.01). Initial therapy induced euthyroidism in 52%: 70% THIO, 53% GC, and 33% COMB (p = 0.045) by 100 (49–167), 47 (35–61), and 53 (45–99) days, respectively (p = 0.02). A further 11% became euthyroid after transitioning from monotherapy to COMB. Thyroidectomy was undertaken in 33%. Patients who underwent thyroidectomy were younger (54 ± 3 vs. 63 ± 2 years; p = 0.03), with higher prevalence of severely impaired left ventricular function prior to diagnosis of AIT (38 vs. 18%; p = 0.08). Despite median American Society of Anaesthesiologists classification 4, no thyroidectomy patient experienced cardiorespiratory complications/death.Conclusions: Patients with AIT had limited response to medical treatment. The poorest response was observed in COMB group, likely related to greater hyperthyroidism severity. Thyroidectomy is safe in patients with severe cardiac failure if performed in a centre with cardiac anaesthetic expertise. There should be low threshold for proceeding to thyroidectomy in patients with severe AIT and/or cardiac failure.

Objectives To determine the clinical utility of assessment of tumour invasion, markers of proliferation and the French clinicopathological classification in pituitary tumour prognostication. Methods Retrospective evaluation of adult patients undergoing pituitary surgery at Oxford University and St Vincent’s Hospitals, between 1989 and 2016, with at least 12 months of clinical data. Invasion was assessed radiologically, proliferative markers (Ki67, mitotic count, p53) by immunohistochemistry. Tumours were graded according to the clinicopathological classification. Intra- and inter-laboratory variability of histopathology reporting were evaluated. Outcomes (1) Tumour recurrence (radiological or re-intervention ≥12 months post-operatively) and/or (2) “Aggressive behaviour” (≥4 interventions and/or invasive tumour with recurrence/re-intervention between 12-24 months post-operatively). Results 386 patients were included, age at surgery was 56 (IQR 41-67) years, 54% were male and median follow up was 90 months (range 44-126). Tumours were predominantly clinically non-functioning (252, 65%), with overall 53% invasive, and 10% that demonstrated ≥2 proliferative marker positivity. Recurrence was predicted by invasiveness (HR 1.6 [1.10-2.37], p 0.02), elevated mitotic count (HR 2.17 [1.21-3.89], p 0.01), grade (2b v 1a HR 2.32 [1.06-5.03], p 0.03) and absence of gross total resection (HR 3.70 [1.72-8.00], p 0.01). Clinically defined aggressiveness was associated with elevated Ki67, mitotic count and invasiveness. Ki67 reporting methodologies showed moderate correlation across laboratories (Phi 0.620), whereas p53 reporting reproducibility was poor (Phi 0.146). Conclusions Proliferative markers, including Ki67 and mitotic count, but not p53, are important in predicting the development of aggressive pituitary tumour behaviour.