Clinical Significance of Pheochromocytoma Size on the Timing and Extent of Surgery.

INTRODUCTION: Elevated metanephrine and catecholamine levels 3-fold upper limit of normal (ULN) are diagnostic for pheochromocytoma. We sought to determine whether size correlates with biochemical activity or symptoms which could guide timing of surgery. METHODS: Data from consecutive patients undergoing adrenalectomy for pheochromocytoma at our institution over a 10-year period were retrospectively collected. These included maximal lesion diameter on preoperative imaging, plasma/urine metanephrine and/or catecholamine levels, demographic variables and presence of typical paroxysmal symptoms. Receiver operating characteristic curves were used to assess predictive accuracy. RESULTS: Sixty-three patients were included in the analysis (41 females and 22 males). Median age was 56 (43, 69) years. Due to various referring practices, 31 patients had documented 24-h urine metanephrine, 26 had 24-h urine catecholamine, and 52 had fractionated plasma metanephrine levels available for review. Values were converted to fold change compared to ULN and the maximum of all measured values was used for logistic regression. Median tumor size was 3.40 (2.25, 4.55) cm in greatest dimension. Tumor size at which pheochromocytoma produced > 3-fold ULN was ≥2.3 cm (AUC of 0.84). Biochemical activity increased with doubling tumor size (odds ratio = 8, P = 0.0004) or ≥ 1 cm increase in tumor size (odds ratio = 3.03, P = 0.001). 40 patients had paroxysmal symptoms, but there was no significant correlation between tumor size/biochemical activity and symptoms. CONCLUSIONS: In our study, tumor size directly correlated with the degree of biochemical activity and pheochromocytomas ≥2.3 cm produced levels 3 times ULN. These findings may allow clinicians to adjust timing of operative intervention.

Biochemical analysis of catecholamine and cortisol for the evaluation of the fetal distress in third trimester stillbirths.

BACKGROUND: Stress hormones like catecholamine and cortisol are thought to reflect the magnitude of physical stress in adults and were studied in relationship to the cause of death and agony time. Intrauterine distress, intrapartum events, and modes of delivery can affect the fetal endocrine stress response, as reflected by biochemical analyses. The aim of the present study was to evaluate the role of catecholamines and cortisol as markers of ante-mortem fetal distress. The role of cortisol as a marker of circadian timing of delivery was also assessed. METHODS: A 2-year prospective cohort-comparison inclusion of stillbirths and newborns took place with collection of antemortem data, labor parameters, neonatal outcome, post-mortem data and blood samples. Stillbirths were classified as acute or chronic on the basis of a multidisciplinary evaluation. Heart blood of stillbirths and cord blood of newborns were analyzed by high pressure liquid chromatography (HPLC) for adrenaline and noradrenaline and by immunoassay for cortisol determination. RESULTS: Fifteen stillbirths and 46 newborns, as a comparison group, delivered by spontaneous vaginal birth, elective, and emergency cesarean sections were included. Stillbirths' main cause of death was cord thrombosis. Levels of adrenaline and noradrenaline (median: 14,188 pg/ml and 230.5 pg/ml, respectively) were significantly higher (p < 0.001) in stillbirths than in newborns and were also higher in acute compared to chronic distress. Cortisol levels were significantly higher (p < 0.05) in spontaneous vaginal delivery (median: 18.2 µg/dl) compared to elective cesarean sections (median: 3.8 µg/dl). No difference in cortisol concentrations was detected between newborns delivered at morning and at afternoon/evening. CONCLUSION: Our results suggest that the biochemical measurement of adrenaline and noradrenaline levels might reflect a marked physical stress response during the process of death in stillbirths. On the contrary, the elevation of cortisol levels could mirror the elevation in maternal cortisol level during vaginal delivery. For the post-mortem evaluation of stillbirths, the analysis of CA levels could provide additional data on the duration of distress, useful to integrate the forensic diagnosis.

Boric Acid Functionalized Hypercrosslinked Polymers for Selective Extraction of Trace Catecholamines and Their Metabolites in Rat Serum.

Abnormal levels of catecholamine (CA) neurotransmitters and their metabolites in biological fluids can lead to various neurological disorders. Herein, a boric acid-functionalized hypercrosslinked polymer was prepared and utilized as a sorbent for the dispersive solid-phase extraction of CAs and their metabolites in rat serum. By combination with a high-performance liquid chromatography-fluorescence detector, the extraction parameters for the seven target analytes were optimized. Under the optimal extraction condition, the methodology for the quantitative analysis of CAs and their metabolites in rat serum samples was established. The limits of detection and limits of quantification were found to be in the ranges of 0.010-0.015 and 0.033-0.050 ng/mL, respectively. The results demonstrated satisfactory recoveries, with values ranging from 88.02% to 113.27%, accompanied by relative standard deviations within the range of 2.69%-9.59%. In addition, the method showed good anti-interference ability (matrix effect ranged from 2.64% to 18.07%). The developed method was validated for the determination of CAs and their metabolites in normal and Alzheimer's disease model rats' serum, which proved the promising application of the method for CAs neurotransmitter analysis in biological samples.

Circulating catecholamines, endothelin-1, and nitric oxide releases do not explain the preserved FMD following acute resistance exercise in strength-trained men.

PURPOSE: Acute resistance exercise decreases endothelial function in sedentary individuals but not in strength-trained (ST) individuals. However, the underlying mechanism(s) of vascular protection in ST individuals remains unclear. Herein, we compared catecholamines, endothelin-1 (ET-1), and nitric oxide (NOx) releases after acute resistance exercise between sedentary and ST individuals. METHODS: The untrained (UT) group comprised 12 male individuals with no regular training, while the ST group comprised 12 male individuals. Participants performed a session of resistance exercise, which consisted of 3 sets of 10 repetitions at 75% of one repetition maximum. Heart rate (HR) and blood pressure were measured during resistance exercise. Brachial artery flow-mediated dilation (FMD), blood pressure, HR, and blood collection were undertaken before and 10, 30, and 60 min after the resistance exercise. RESULTS: No significant difference was found in baseline brachial artery FMD between the groups (P > 0.05). Brachial artery FMD was significantly reduced in the UT group (P < 0.05) but it was prevented in the ST group after the resistance exercise. Significant differences were found at 10, 30, and 60 min after the resistance exercise in brachial artery ΔFMD from baseline between groups (P < 0.05). Blood pressure, HR, plasma epinephrine, norepinephrine, dopamine, serum endothelin-1, and plasma NOx responses did not differ between groups throughout the experimental period. CONCLUSION: In conclusion, preserved endothelial function in response to acute resistance exercise in ST male individuals is independent of catecholamines, ET-1, and NOx responses.

A LC-MS/MS method for the simultaneous determination of 6-cyanodopamine, 6-nitrodopamine, 6-nitrodopa, 6-nitroadrenaline and 6-bromodopamine in human plasma and its clinical application in patients with chronic kidney disease.

The aim of this study was to develop a high-performance liquid chromatography-tandem mass spectrometry method for the determination of 6-cyanodopamine, 6-nitrodopamine, 6-nitrodopa, 6-nitroadrenaline and 6-bromodopamine in human plasma samples. Strata-X 33 µm solid-phase extraction cartridges were used for the extraction of the catecholamines from human plasma samples. The catecholamines were separated in a 150 × 3 mm Shim-pack GIST C18-AQ column with 3 µm particle size, placed in an oven at 40°C and perfused with 82% mobile phase A (acetonitrile-H2O; 90:10, v/v) + 0.4% acetic acid and 18% mobile phase B (deionized H2O) + 0.2% formic acid at a flow rate of 340 µl/min in isocratic mode. The injected volume was 4 µl and the run lasted 4 min. The method was linear from 0.1 to 20 ng/ml and the lower limit of quantification was 0.1 ng/ml for all analytes. The method was applied to evaluate the plasma levels of catecholamines in plasma of patients with chronic kidney disease and allowed the detection for the first time of circulating levels of the novel catecholamines 6-bromodopamine and 6-cyanodopamine.

The role of glucose metabolism and insulin resistance in cardiac remodelling induced by cigarette smoke exposure.

The aim of this study is to evaluate whether the alterations in glucose metabolism and insulin resistance are mechanisms presented in cardiac remodelling induced by the toxicity of cigarette smoke. Male Wistar rats were assigned to the control group (C; n = 12) and the cigarette smoke-exposed group (exposed to cigarette smoke over 2 months) (CS; n = 12). Transthoracic echocardiography, blood pressure assessment, serum biochemical analyses for catecholamines and cotinine, energy metabolism enzymes activities assay; HOMA index (homeostatic model assessment); immunohistochemistry; and Western blot for proteins involved in energy metabolism were performed. The CS group presented concentric hypertrophy, systolic and diastolic dysfunction, and higher oxidative stress. It was observed changes in energy metabolism, characterized by a higher HOMA index, lower concentration of GLUT4 (glucose transporter 4) and lower 3-hydroxyl-CoA dehydrogenase activity, suggesting the presence of insulin resistance. Yet, the cardiac glycogen was depleted, phosphofructokinase (PFK) and lactate dehydrogenase (LDH) increased, with normal pyruvate dehydrogenase (PDH) activity. The activity of citrate synthase, mitochondrial complexes and ATP synthase (adenosine triphosphate synthase) decreased and the expression of Sirtuin 1 (SIRT1) increased. In conclusion, exposure to cigarette smoke induces cardiac remodelling and dysfunction. The mitochondrial dysfunction and heart damage induced by cigarette smoke exposure are associated with insulin resistance and glucose metabolism changes.

Pheochromocytoma: a retrospective study from a single center.

Objectives. Pheochromocytoma (PCC) is a neuroendocrine tumor derived from chromaffin tissue more frequently found in the adrenal medulla. Many discoveries over the last decade have significantly improved our understanding of PCC.Methods. We retrospectively reviewed all patients with a histological diagnosis of PCC at the Centro Hospitalar Universitario de Sao Joao, a tertiary and university hospital in Oporto, Portugal, between January 2009 and December 2017.Results. The study group included 33 patients. In most cases the diagnosis was suspected with more than half of patients presenting with hypertension and the third diagnosed during the work-up of an adrenal incidentaloma. About half of the patients was referred for genetic testing and 6 patients had a positive inherited susceptibility genetic pathogenic variant associated with classic cancer predisposition syndromes and also associated with newly described genes. In the incidentaloma group, genetic testing was performed in 3 (9%) patients with only 1 positive result. In the suspected group, 15 (45%) genetic tests were performed.Conclusions. In contrast to other studies, where only a minority of patients with PCC were referred for genetic counselling, in our study 54% of patients was referred for genetic testing. This study suggests that clinicians were correctly recognizing the need to refer young patients and patients with positive family history. However, opportunities for genetic testing are frequently missed due to low referral rates in patients with apparently sporadic PCC, particularly older than 30 years old. It is imperative that all the providers involved in the multidisciplinary care of patients with pheochromocytomas are aware of the genetic disorders associated with these unique tumors.

Study of stability and interference for catecholamines and metanephrines, 3-methoxytyramine: key point of an accurate diagnosis for pheochromocytoma and paraganglioma.

BACKGROUND: Accurate diagnosis of pheochromocytoma and paraganglioma (PPGLs) is highly dependent on the detection of metanephrines and catecholamines. However, the systematic investigation on influencing factors including specimen (plasma or whole blood), anticoagulant, storage conditions, and interference factors need further confirmation. METHODS: Blood with heparin-lithium or EDTA-K2 were collected, stability of epinephrine (EPI), norepinephrine (NE), dopamine (DA), metanephrine (MN), normetanephrine (NMN), 3-methoxytyramine (3-MT) in whole blood and plasma at room temperature and 4 °C for different storage times, stability of plasma MN, NMN and 3-MT at -20 °C and -80 °C were investigated. Plasma with hemoglobin (1 g/L, 2 g/L, 3 g/L, 4 g/L, 6 g/L), TG (<5 mmol/L, 5-8 mmol/L, >8 mmol/L) were prepared. RESULTS: EPI, NE, DA were prone to degrade at room temperature, samples should be centrifuged at 4 °C. EPI and NE were stable in whole blood at 4 °C for 4 h and in plasma for 2 h. For MN, NMN, 3-MT, plasma can be stable at room temperature and 4 °C for at least 6 h, which is better than whole blood; there was no significant difference when stored at -20 °C and -80 °C for 7 days. Heparin-lithium had a slight advantage over EDTA-K2. EPI, NE, DA should not be performed when Hb > 1 g/L or TG > 5 mmol/L. MN, NMN, 3-MT should not be performed when Hb > 2 g/L, whereas TG had no interference. CONCLUSIONS: According to the actual clinical application scenario, this study provided a reliable basis for the accurate diagnosis of PPGLs.

Whey protein preloading can alleviate stress adaptation disorder and improve hyperglycemia in women with gestational diabetes mellitus.

AIMS: To investigate the change of stress hormones, oxidative stress and insulin resistance (IR) in women with gestational diabetes mellitus (GDM) after supplement whey protein, in an attempt to gain insights into the prevention and treatment of GDM. MATERIALS AND METHODS: 60 GDM women were recruited in this study, and 30 women received a preload drink containing 20 g whey protein as group GDM-W, and the other 30 women received control flavoring drink as group GDM, and the trial lasted for 14 days. Plasma epinephrine (E), noradrenaline (NE), and cortisol were detected; we also determined levels of malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione (GSH). Homeostasis model assessment of insulin resistance (HOMA-IR) was used to assess IR. RESULTS: In the GDM-W group, postprandial blood glucose was decreased significantly on 3, 5, 7, and 14 days (all p < .05), plasma 2 h insulin was increased by 7.2, 8.6, and 20.5% on days 5, 7, and 14 (p < .05, .05, .01). HOMA-IR was decreased significantly on day 14 (p < .05). MDA was decreased by 20.7% on day 14 (p < .01), and anti-oxidative enzymes' SOD was decreased by 13.4% on day 14 (p < .05) and GSH was decreased by 16.7 and 29.1% on days 7 and 14 (both p < .05). Stress hormones E and cortisol were decreased by 10.8 and 19.8%, respectively, on day 14 (p < .05). There was no significant difference in NE between the two groups within 14 days. CONCLUSIONS: Whey protein supplementation may improve hyperglycemia by alleviating stress disorder and oxidative stress injury in GDM women. This trial was registered at chictr.org.cn/as ChiCTR1800020413.

Changes in sympathetic nervous system activity after renal denervation: results from the randomised Oslo RDN study.

PURPOSE: Sympathetic nervous system (SNS) over-activity is associated with essential hypertension. Renal sympathetic denervation (RDN) possibly lowers office- and ambulatory blood pressure (BP) in patients with treatment-resistant hypertension (TRH). We aimed to assess the effect of RDN compared to drug adjustment on SNS activity among patients with TRH by measuring plasma catecholamines and heart rate variability (HRV) during stress tests. MATERIALS AND METHODS: Patients with TRH were randomised to RDN (n = 9) or Drug Adjustment (DA) (n = 10). We measured continuous HRV and beat-to-beat-BP using FinaPres® and obtained plasma catecholamines during standardised orthostatic- and cold-pressor stress tests (CPT) before- and six months after randomisation. RESULTS: CPT revealed no differences between groups at baseline in peak adrenaline concentration (69.3 pg/mL in the DA group vs. 70.0 pg/mL in the RDN group, p = 0.38) or adrenaline reactivity (Δ23.1 pg/mL in the DA group vs. Δ29.3 pg/mL in the RDN group, p = 0.40). After six months, adrenaline concentrations were statistically different between groups after one minute (66.9 pg/mL in the DA group vs. 55.3 pg/mL in the RDN group, p = 0.03), and six minutes (62.4 pg/mL in the DA group vs. 50.1 pg/mL in the RDN group, p = 0.03). There was a tendency of reduction in adrenaline reactivity after six months in the RDN group (Δ26.3 pg/mL at baseline vs. Δ12.8 pg/ml after six months, p = 0.08), while it increased in the DA group (Δ13.6 pg/mL at baseline vs. Δ19.9 pg/mL after six months, p = 0.53). We also found a difference in the Low Frequency band at baseline following the CPT (667µs2 in the DA group vs. 1628µs2 in the RDN group, p = 0.03) with a clear tendency of reduction in the RDN group to 743µs2 after six months (p = 0.07), compared to no change in the DA group (1052µs2,p = 0.39). CONCLUSION: Our data suggest that RDN reduces SNS activity after six months. This finding warrants investigation in a larger study. Clinical Trial Number registered at www.clinicaltrials.gov: NCT01673516.

Impaired counterregulatory responses to hypoglycaemia following oral glucose in adults with cystic fibrosis.

AIMS/HYPOTHESIS: The aim of this study was to determine the mechanism(s) for hypoglycaemia occurring late following oral glucose loading in patients with cystic fibrosis (CF). METHODS: A 3 h 75 g OGTT was performed in 27 non-diabetic adults with CF who were classified based on this test as experiencing hypoglycaemia (glucose <3.3 mmol/l with or without symptoms or glucose <3.9 mmol/l with symptoms, n = 14) or not (n = 13). Beta cell function, incretin (glucagon-like peptide-1 [GLP-1] and glucose-dependent insulinotropic peptide [GIP]) and counterregulatory hormone responses (glucagon, catecholamines, growth hormone and cortisol) were assessed. RESULTS: The two groups did not differ in age, weight or BMI. There were more male participants and individuals with pancreatic exocrine insufficiency in the hypoglycaemia group. Fasting plasma glucose did not differ between the two groups (5.3 ± 0.16 vs 5.3 ± 0.10 mmol/l). Both fasting insulin (20.7 ± 2.9 vs 36.5 ± 4.8 pmol/l; p = 0.009) and C-peptide (0.38 ± 0.03 vs 0.56 ± 0.05 nmol/l; p = 0.002) were lower in those who experienced hypoglycaemia. Following glucose ingestion, glucose concentrations were significantly lower in the hypoglycaemia group from 135 min onwards, with a nadir of 3.2 ± 0.2 vs 4.8 ± 0.3 mmol/l at 180 min (p < 0.001). The test was terminated early in three participants because of a glucose level <2.5 mmol/l. Insulin and C-peptide concentrations were also lower in the hypoglycaemia group, while incretin hormone responses were not different. Modelling demonstrated that those experiencing hypoglycaemia were more insulin sensitive (439 ± 17.3 vs 398 ± 13.1 ml min-1 m-2, p = 0.074 based on values until 120 min [n = 14]; 512 ± 18.9 vs 438 ± 15.5 ml min-1 m-2, p = 0.006 based on values until 180 min [n = 11]). In line with their better insulin sensitivity, those experiencing hypoglycaemia had lower insulin secretion rates (ISRfasting: 50.8 ± 3.2 vs 74.0 ± 5.9 pmol min-1 m-2, p = 0.002; ISROGTT: 44.9 ± 5.0 vs 63.4 ± 5.2 nmol/m2, p = 0.018) and beta cell glucose sensitivity (47.4 ± 4.5 vs 79.2 ± 7.5 pmol min-1 m-2 [mmol/l]-1, p = 0.001). Despite the difference in glucose concentrations, there were no significant increases in glucagon, noradrenaline, cortisol or growth hormone levels. Adrenaline increased by only 66% and 61% above baseline at 165 and 180 min when glucose concentrations were 3.8 ± 0.2 and 3.2 ± 0.2 mmol/l, respectively. CONCLUSIONS/INTERPRETATION: Hypoglycaemia occurring late during an OGTT in people with CF was not associated with the expected counterregulatory hormone response, which may be a consequence of more advanced pancreatic dysfunction/destruction.

Rho-kinase pathway activation and apoptosis in circulating leucocytes in patients with heart failure with reduced ejection fraction.

BACKGROUND: Increased Rho-kinase activity in circulating leucocytes is observed in heart failure with reduced ejection fraction (HFrEF). However, there is little information in HFrEF regarding other Rho-kinase pathway components an on the relationship between Rho-kinase and apoptosis. Here, Rho-kinase activation levels and phosphorylation of major downstream molecules and apoptosis levels were measured for the first time both in HFrEF patients and healthy individuals. METHODS: Cross-sectional study comparing HFrEF patients (n = 20) and healthy controls (n = 19). Rho-kinase activity in circulating leucocytes (peripheral blood mononuclear cells, PBMCs) was determined by myosin light chain phosphatase 1 (MYPT1) and ezrin-radixin-moesin (ERM) phosphorylation. Rho-kinase cascade proteins phosphorylation p38-MAPK, myosin light chain-2, JAK and JNK were also analysed along with apoptosis. RESULTS: MYPT1 and ERM phosphorylation were significantly elevated in HFrEF patients, (3.9- and 4.8-fold higher than in controls, respectively). JAK phosphorylation was significantly increased by 300% over controls. Phosphorylation of downstream molecules p38-MAPK and myosin light chain-2 was significantly higher by 360% and 490%, respectively, while JNK phosphorylation was reduced by 60%. Catecholamine and angiotensin II levels were significantly higher in HFrEF patients, while angiotensin-(1-9) levels were lower. Apoptosis in circulating leucocytes was significantly increased in HFrEF patients by 2.8-fold compared with controls and significantly correlated with Rho-kinase activation. CONCLUSION: Rho-kinase pathway is activated in PMBCs from HFrEF patients despite optimal treatment, and it is closely associated with neurohormonal activation and with apoptosis. ROCK cascade inhibition might induce clinical benefits in HFrEF patients, and its assessment in PMBCs could be useful to evaluate reverse remodelling and disease regression.

In Matrix Derivatization Combined with LC-MS/MS Results in Ultrasensitive Quantification of Plasma Free Metanephrines and Catecholamines.

Plasma-free metanephrines and catecholamines are essential markers in the biochemical diagnosis and follow-up of neuroendocrine tumors and inborn errors of metabolism. However, their low circulating concentrations (in the nanomolar range) and poor fragmentation characteristics hinder facile simultaneous quantification by liquid chromatography and tandem mass spectrometry (LC-MS/MS). Here, we present a sensitive and simple matrix derivatization procedure using propionic anhydride that enables simultaneous quantification of unconjugated l-DOPA, catecholamines, and metanephrines in plasma by LC-MS/MS. Dilution of propionic anhydride 1:4 (v/v) in acetonitrile in combination with 50 µL of plasma resulted in the highest mass spectrometric response. In plasma, derivatization resulted in stable derivatives and increased sensitivity by a factor of 4-30 compared with a previous LC-MS/MS method for measuring plasma metanephrines in our laboratory. Furthermore, propionylation increased specificity, especially for 3-methoxytyramine, by preventing interference from antihypertensive medication (ß-blockers). The method was validated according to international guidelines and correlated with a hydrophilic interaction LC-MS/MS method for measuring plasma metanephrines (R2 > 0.99) and high-performance liquid chromatography with an electrochemical detection method for measuring plasma catecholamines (R2 > 0.85). Reference intervals for l-DOPA, catecholamines, and metanephrines in n = 115 healthy individuals were established. Our work shows that analytes in the subnanomolar range in plasma can be derivatized in situ without any preceding sample extraction. The developed method shows improved sensitivity and selectivity over existing methods and enables simultaneous quantification of several classes of amines.

Circulating catecholamines partially regulate T-wave morphology but not heart rate variability during repeated umbilical cord occlusions in fetal sheep.

Fetal heart rate (FHR) variability (FHRV) and ST segment morphology are potential clinical indices of fetal well-being during labor. ß-Adrenergic stimulation by circulating catecholamines has been hypothesized to contribute to both FHRV and ST segment morphology during labor, but this has not been tested during brief repeated fetal hypoxemia that is characteristic of labor. Near-term fetal sheep (0.85 gestation) received propranolol (ß-adrenergic blockade; n = 10) or saline (n = 7) 30 min before being exposed to three 2-min complete umbilical cord occlusions (UCOs) separated by 3-min reperfusions. T/QRS ratio was calculated throughout UCOs and reperfusion periods, and measures of FHRV (RMSSD, SDNN, and STV) were calculated between UCOs. During the baseline period, before the start of UCOs, propranolol was associated with reduced FHR, SDNN, and STV but did not affect RMSSD or T/QRS ratio. UCOs were associated with rapid FHR decelerations and increased T/QRS ratio; propranolol significantly reduced FHR during UCOs and was associated with a slower rise in T/QRS ratio during the first UCOs, without affecting the maximal rise or T/QRS ratio during the second and third UCO. Between UCOs propranolol reduced FHR and T/QRS ratio but did not affect any measure of FHRV. These data demonstrate that circulating catecholamines do not contribute to FHRV during labor-like hypoxemia. Furthermore, circulating catecholamines did not contribute to the major rise in T/QRS ratio during labor-like hypoxemia but may regulate T/QRS ratio between brief hypoxemia.

Update on Pheochromocytoma and Paraganglioma from the SSO Endocrine/Head and Neck Disease-Site Work Group. Part 1 of 2: Advances in Pathogenesis and Diagnosis of Pheochromocytoma and Paraganglioma.

This first part of a two-part review of pheochromocytoma and paragangliomas (PPGLs) addresses clinical presentation, diagnosis, management, treatment, and outcomes. In this first part, the epidemiology, prevalence, genetic etiology, clinical presentation, and biochemical and radiologic workup are discussed. In particular, recent advances in the genetics underlying PPGLs and the recommendation for genetic testing of all patients with PPGL are emphasized. Finally, the newer imaging methods for evaluating of PPGLs are discussed and highlighted.

Effects of ß-adrenoceptor activation on haemodynamics during hypoxic stress in rats.

NEW FINDINGS: What is the central question of this study? The acute hypoxic compensatory reaction is based on haemodynamic changes, and ß-adrenoceptors are involved in haemodynamic regulation. What is the role of ß-adrenoceptors in haemodynamics during hypoxic exposure? What is the main finding and its importance? Activation of ß2 -adrenoceptors attenuates the increase in pulmonary artery pressure during hypoxic exposure. This compensatory reaction activated by ß2 -adrenoceptors during hypoxic stress is very important to maintain the activities of normal life. ABSTRACT: The acute hypoxic compensatory reaction is accompanied by haemodynamic changes. We monitored the haemodynamic changes in rats undergoing acute hypoxic stress and applied antagonists of ß-adrenoceptor (ß-ARs) subtypes to reveal the regulatory role of ß-ARs on haemodynamics. Sprague-Dawley rats were randomly divided into control, atenolol (ß1 -AR antagonist), ICI 118,551 (ß2 -AR antagonist) and propranolol (non-selective ß-AR antagonist) groups. Rats were continuously recorded for changes in haemodynamic indexes for 10 min after administration. Then, a hypoxic ventilation experiment [15% O2 , 2200 m a.sl., 582 mmHg (0.765 Pa), PO2 87.3 mmHg; Xining, China] was conducted, and the indexes were monitored for 5 min after induction of hypoxia. Plasma catecholamine concentrations were also measured. We found that, during normoxia, the mean arterial pressure, heart rate, ascending aortic blood flow and pulmonary artery pressure were reduced in the propranolol and atenolol groups. Catecholamine concentrations were increased significantly in the atenolol group compared with the control group. During hypoxia, mean arterial pressure and total peripheral resistance were decreased in the control, propranolol and ICI 118,551 groups. Pulmonary arterial pressure and pulmonary vascular resistance were increased in the propranolol and ICI 118,551 groups. During hypoxia, catecholamine concentrations were increased significantly in the control group, but decreased in ß-AR antagonist groups. In conclusion, the ß2 -AR is involved in regulation of pulmonary haemodynamics in the acute hypoxic compensatory reaction, and the activation of ß2 -ARs attenuates the increase in pulmonary arterial pressure during hypoxic stress. This compensatory reaction activated by ß2 -ARs during hypoxic stress is very important to maintain activities of normal life.

Dexmedetomidine-Mediated Prevention of Renal Ischemia-Reperfusion Injury Depends in Part on Cholinergic Anti-Inflammatory Mechanisms.

BACKGROUND: Organ ischemia-reperfusion injury often induces local and systemic inflammatory responses, which in turn worsen organ injury. These inflammatory responses can be regulated by the central nervous system, particularly by the vagal nerve and nicotinic acetylcholine receptors, which are the key components of cholinergic anti-inflammatory pathway. Activation of the cholinergic anti-inflammatory pathway can suppress excessive inflammatory responses and be a potential strategy for prevention of ischemia-reperfusion injury of organs including the kidney. METHODS: Vagal nerve activity, plasma acetylcholine, catecholamine and inflammatory mediators, renal tissue injury, and cell death were measured in mice with bilateral renal ischemia/reperfusion with or without treatment with dexmedetomidine (Dex), an α2-adrenergic receptor agonist. RESULTS: Dex significantly increased the discharge frequency of the cervical vagal nerve by up to 142 Hz (mean) (P < .001), and preserved kidney gross morphology and structure and attenuated cell apoptosis after ischemia-reperfusion. Furthermore, Dex also significantly increased acetylcholine release to 135.8 pmol/L (median) when compared to that (84.7 pmol/L) in the sham group (P < .001) and reduced the levels of several inflammatory mediators induced by renal ischemia/reperfusion. All the effects were abolished by vagotomy, splenectomy, or combinative administration of atipamezole, an α2-adrenergic receptor antagonist. CONCLUSIONS: Our findings suggest that Dex provides renoprotection, at least in part, through anti-inflammatory effects of the parasympathetic nervous system activation in addition to its direct actions on α2-adrenergic receptors.

Effects of low sodium diet versus high sodium diet on blood pressure, renin, aldosterone, catecholamines, cholesterol, and triglyceride.

BACKGROUND: Recent cohort studies show that salt intake below 6 g is associated with increased mortality. These findings have not changed public recommendations to lower salt intake below 6 g, which are based on assumed blood pressure (BP) effects and no side-effects. OBJECTIVES: To assess the effects of sodium reduction on BP, and on potential side-effects (hormones and lipids) SEARCH METHODS: The Cochrane Hypertension Information Specialist searched the following databases for randomized controlled trials up to April 2018 and a top-up search in March 2020: the Cochrane Hypertension Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (from 1946), Embase (from 1974), the World Health Organization International Clinical Trials Registry Platform, and ClinicalTrials.gov. We also contacted authors of relevant papers regarding further published and unpublished work. The searches had no language restrictions. The top-up search articles are recorded under "awaiting assessment." SELECTION CRITERIA: Studies randomizing persons to low-sodium and high-sodium diets were included if they evaluated at least one of the outcome parameters (BP, renin, aldosterone, noradrenalin, adrenalin, cholesterol, high-density lipoprotein, low-density lipoprotein and triglyceride,. DATA COLLECTION AND ANALYSIS: Two review authors independently collected data, which were analysed with Review Manager 5.3. Certainty of evidence was assessed using GRADE. MAIN RESULTS: Since the first review in 2003 the number of included references has increased from 96 to 195 (174 were in white participants). As a previous study found different BP outcomes in black and white study populations, we stratified the BP outcomes by race. The effect of sodium reduction (from 203 to 65 mmol/day) on BP in white participants was as follows: Normal blood pressure: SBP: mean difference (MD) -1.14 mmHg (95% confidence interval (CI): -1.65 to -0.63), 5982 participants, 95 trials; DBP: MD + 0.01 mmHg (95% CI: -0.37 to 0.39), 6276 participants, 96 trials. Hypertension: SBP: MD -5.71 mmHg (95% CI: -6.67 to -4.74), 3998 participants,88 trials; DBP: MD -2.87 mmHg (95% CI: -3.41 to -2.32), 4032 participants, 89 trials (all high-quality evidence). The largest bias contrast across studies was recorded for the detection bias element. A comparison of detection bias low-risk studies versus high/unclear risk studies showed no differences. The effect of sodium reduction (from 195 to 66 mmol/day) on BP in black participants was as follows: Normal blood pressure: SBP: mean difference (MD) -4.02 mmHg (95% CI:-7.37 to -0.68); DBP: MD -2.01 mmHg (95% CI:-4.37, 0.35), 253 participants, 7 trials. Hypertension: SBP: MD -6.64 mmHg (95% CI:-9.00, -4.27); DBP: MD -2.91 mmHg (95% CI:-4.52, -1.30), 398 participants, 8 trials (low-quality evidence). The effect of sodium reduction (from 217 to 103 mmol/day) on BP in Asian participants was as follows: Normal blood pressure: SBP: mean difference (MD) -1.50 mmHg (95% CI: -3.09, 0.10); DBP: MD -1.06 mmHg (95% CI:-2.53 to 0.41), 950 participants, 5 trials. Hypertension: SBP: MD -7.75 mmHg (95% CI:-11.44, -4.07); DBP: MD -2.68 mmHg (95% CI: -4.21 to -1.15), 254 participants, 8 trials (moderate-low-quality evidence).   During sodium reduction renin increased 1.56 ng/mL/hour (95%CI:1.39, 1.73) in 2904 participants (82 trials); aldosterone increased 104 pg/mL (95%CI:88.4,119.7) in 2506 participants (66 trials); noradrenalin increased 62.3 pg/mL: (95%CI: 41.9, 82.8) in 878 participants (35 trials); adrenalin increased 7.55 pg/mL (95%CI: 0.85, 14.26) in 331 participants (15 trials); cholesterol increased 5.19 mg/dL (95%CI:2.1, 8.3) in 917 participants (27 trials); triglyceride increased 7.10 mg/dL (95%CI: 3.1,11.1) in 712 participants (20 trials); LDL tended to increase 2.46 mg/dl (95%CI: -1, 5.9) in 696 participants (18 trials); HDL was unchanged -0.3 mg/dl (95%CI: -1.66,1.05) in 738 participants (20 trials) (All high-quality evidence except the evidence for adrenalin). AUTHORS' CONCLUSIONS: In white participants, sodium reduction in accordance with the public recommendations resulted in mean arterial pressure (MAP) decrease of about 0.4 mmHg in participants with normal blood pressure and a MAP decrease of about 4 mmHg in participants with hypertension. Weak evidence indicated that these effects may be a little greater in black and Asian participants. The effects of sodium reduction on potential side effects (hormones and lipids) were more consistent than the effect on BP, especially in people with normal BP.

The use of whole-body cryotherapy: time- and dose-response investigation on circulating blood catecholamines and heart rate variability.

PURPOSE: A predominance of parasympathetic drive is observed following cold exposure. Such modulation of the autonomic nervous system (ANS) is associated with faster post-exercise recovery. Within this context, whole-body cryotherapy (WBC) has been spreading in sport medicine, though the optimal temperature and frequency are unclear. The aim of this study was to examine the effects of different cryotherapy conditions on the sympathovagal balance. METHODS: Forty healthy males were randomly assigned into five different groups (- 110 °C, - 60 °C, - 10 °C, control temperature [≃ 24 °C]) and undertook 5 WBC sessions over 5 consecutive days. Cardiac autonomic activity was assessed through heart rate variability (HRV) using power density of high frequency (HF), root-mean square difference of successive R-R intervals (RMSSD) and sympathovagal balance (LF/HF). Systemic sympathetic activity was assessed via circulating blood catecholamines. RESULTS: Mean weekly RMSSD (pre: 48 ± 22 ms, post: 68 ± 29 ms) and HF (pre: 607 ± 692 ms2, post: 1271 ± 1180 ms2) increased (p < 0.05) from pre to post WBC, only in the - 110 °C condition. A rise in plasma norepinephrine was found after the first - 110 °C WBC session only (pre: 173 ± 98, post: 352 ± 231 ng L-1, p < 0.01); whereas, it was not significant after the 5th session (pre: 161 ± 120, post: 293 ± 245 ng L-1, p = 0.15). CONCLUSION: These results suggest that one - 110 °C WBC exposure is required to stimulate the ANS. After five daily exposures, a lower autonomic response was recorded compared to day one, therefore suggesting the development of physiological habituation to WBC.

LC-MS/MS determination of plasma catecholamines after selective extraction by borated zirconia.

For the first time, boronate affinity chromatography and metal oxide affinity chromatography mechanisms for cis-diol-compounds extraction are simultaneously realized on a single material, termed borated zirconia. This material was prepared by hydrolyzing zirconium butoxide with boric acid under non-aqueous environment. The diameter of formed particles is around 200 nm. By extracting catechol under different pH conditions or with phosphate ion competition, the dual affinity mechanisms of borated zirconia are confirmed. Benefiting from such unique feature, borated zirconia can function well under neutral condition. By using borated zirconia for dispersive solid phase extraction, specific capture of cis-diol-containing catecholamines, including epinephrine (E), norepinephrine (NE) and dopamine (DA), was achieved. A reliable LC-MS/MS method was established and validated for quantification of these target analytes in plasma samples after derivatisation with benzoyl chloride. The linear ranges are 0.010-0.200 ng·mL-1 for E and DA, and 0.050-1.000 ng·mL-1 for NE. The limits of quantification are 0.008, 0.020 and 0.004 ng·mL-1 for E, NE and DA respectively. By analyzing samples from healthy volunteers and schizophrenia patients, the plasma concentrations of E, NE and DA were found to be higher for the latter. Graphical AbstractSchematic representation of boronate combined metal oxide affinity chromatography (BMOAC) extraction of cis-diol catecholamines from human plasma by borated zirconia following with benzoyl chloride derivatization and LC-MS determination.