Association between pretreatment emotional distress and neoadjuvant immune checkpoint blockade response in melanoma.

Neoadjuvant immune checkpoint blockade (ICB) outperforms adjuvant ICB for treatment of stage IIIB-D melanoma, but potential biomarkers of response, such as interferon-gamma (IFNγ) signature and tumor mutational burden (TMB), are insufficient. Preclinical studies suggest that emotional distress (ED) can negatively affect antitumor immune responses via ß-adrenergic or glucocorticoid signaling. We performed a post hoc analysis evaluating the association between pretreatment ED and clinical responses after neoadjuvant ICB treatment in patients with stage IIIB-D melanoma in the phase 2 PRADO trial ( NCT02977052 ). The European Organisation for Research and Treatment of Cancer scale for emotional functioning was used to identify patients with ED (n = 28) versus those without (n = 60). Pretreatment ED was significantly associated with reduced major pathologic responses (46% versus 65%, adjusted odds ratio 0.20, P = 0.038) after adjusting for IFNγ signature and TMB, reduced 2-year relapse-free survival (74% versus 91%, adjusted hazard ratio 3.81, P = 0.034) and reduced 2-year distant metastasis-free survival (78% versus 95%, adjusted hazard ratio 4.33, P = 0.040) after adjusting for IFNγ signature. RNA sequencing analyses of baseline patient samples could not identify clear ß-adrenergic- or glucocorticoid-driven mechanisms associated with these reduced outcomes. Pretreatment ED may be a marker associated with clinical responses after neoadjuvant ICB in melanoma and warrants further investigation. ClinicalTrials.gov registration: NCT02977052 .

Palbociclib releases the latent differentiation capacity of neuroblastoma cells.

Neuroblastoma is the most common extracranial solid tumor in infants, arising from developmentally stalled neural crest-derived cells. Driving tumor differentiation is a promising therapeutic approach for this devastating disease. Here, we show that the CDK4/6 inhibitor palbociclib not only inhibits proliferation but induces extensive neuronal differentiation of adrenergic neuroblastoma cells. Palbociclib-mediated differentiation is manifested by extensive phenotypic and transcriptional changes accompanied by the establishment of an epigenetic program driving expression of mature neuronal features. In vivo palbociclib significantly inhibits tumor growth in mouse neuroblastoma models. Furthermore, dual treatment with retinoic acid resets the oncogenic adrenergic core regulatory circuit of neuroblastoma cells, further suppresses proliferation, and can enhance differentiation, altering gene expression in ways that significantly correlate with improved patient survival. We therefore identify palbociclib as a therapeutic approach to dramatically enhance neuroblastoma differentiation efficacy that could be used in combination with retinoic acid to improve patient outcomes.

ß2-adrenergic receptor expression in patients receiving bevacizumab therapy for metastatic melanoma.

BACKGROUND: Vascular endothelial growth factor (VEGF) was initially known as vascular permeability factor and identified as a driver of tumour angiogenesis. Recently, its role in supporting an immunosuppressive tumour microenvironment was demonstrated, and anti-VEGF treatment combined with immune checkpoint blockade is currently investigated. Further, beta-adrenergic signalling as a modifier of cancer hallmarks like immune response, angiogenesis and metastasis gained increased attention during past years. METHODS: Focusing on the aspect of immunosuppression in upregulated beta-adrenergic signalling, we investigated predictive markers in patients with metastatic melanoma who received bevacizumab monotherapy, a specific VEGF-A binding antibody. We explored the expression of beta-2 adrenergic receptor (ß2-AR), interleukin 6-receptor (IL6-R), cyclooxygenase 2 (COX2) and VEGF-A by immunohistochemistry in melanoma to assess the correlation between these proteins in melanoma cells and response to treatment. RESULTS: Strong ß2-AR expression in metastases was associated with clinical benefit of bevacizumab. Furthermore, expression of the latter was positively linked to expression of VEGF-A and COX2. ß2-AR expression in melanoma metastasis appears to distinguish a subgroup of patients that might benefit from anti-VEGF treatment. CONCLUSION: Our results strengthen further exploration of anti-VEGF therapy in combination with immune checkpoint blockade in clinical studies and the investigation of ß2-AR as predictive marker.

Role of cardiac ß1-adrenergic and A1-adenosine receptors in severe arrhythmias related to Parkinson's disease.

AIMS: Although reduced life expectancy in Parkinson's Disease (PD) patients has been related to severe cardiac arrhythmias due to autonomic dysfunctions, its molecular mechanisms remain unclear. To investigate the role of cardiac ß1-Adrenergic (ß1AR) and A1-Adenosine (A1R) receptors in these dysfunctions, the pharmacological effects of stimulation of cardiac ß1AR (isoproterenol, ISO), in the absence and presence of cardiac ß1AR (atenolol, AT) or A1R (1,3-dipropyl-8-cyclopentyl xanthine, DPCPX) blockade, on the arrhythmias induced by Ischemia/Reperfusion (CIR) in an animal PD model were studied. METHODS: PD was produced by dopaminergic lesions (confirmed by immunohistochemistry analysis) caused by the injection of 6-hydroxydopamine (6-OHDA, 6 µg) in rat striatum. CIR was produced by a surgical interruption for 10 min followed by reestablishment of blood circulation in the descendent left coronary artery. On the incidence of CIR-Induced Ventricular Arrhythmias (VA), Atrioventricular Block (AVB), and Lethality (LET), evaluated by Electrocardiogram (ECG) analysis, the effects of intravenous treatment with ISO, AT and DPCPX (before CIR) were studied. RESULTS: VA, AVB and LET incidences were significantly higher in 6-OHDA (83%, 92%, 100%, respectively) than in control rats (58%, 67% and 67%, respectively). ISO treatment significantly reduced these incidences in 6-OHDA (33%, 33% and 42%, respectively) and control rats (25%, 25%, 33%, respectively), indicating that stimulation of cardiac ß1AR induced cardioprotection. This response was prevented by pretreatment with AT and DPCPX, confirming the involvement of cardiac ß1AR and A1R. CONCLUSION: Pharmacological modulation of cardiac ß1AR and A1R could be a potential therapeutic strategy to reduce severe arrhythmias and increase life expectancy in PD patients.

Sympathetic modulation of tumor necrosis factor alpha-induced nociception in the presence of oral squamous cell carcinoma.

ABSTRACT: Head and neck squamous cell carcinoma (HNSCC) causes more severe pain and psychological stress than other types of cancer. Despite clinical evidence linking pain, stress, and cancer progression, the underlying relationship between pain and sympathetic neurotransmission in oral cancer is unknown. We found that human HNSCC tumors and mouse tumor tissue are innervated by peripheral sympathetic and sensory nerves. Moreover, ß-adrenergic 1 and 2 receptors (ß-ARs) are overexpressed in human oral cancer cell lines, and norepinephrine treatment increased ß-AR2 protein expression as well as cancer cell proliferation in vitro. We have recently demonstrated that inhibition of tumor necrosis factor alpha (TNFα) signaling reduces oral cancer-induced nociceptive behavior. Norepinephrine-treated cancer cell lines secrete more TNFα which, when applied to tongue-innervating trigeminal neurons, evoked a larger Ca 2+ transient; TNF-TNFR inhibitor blocked the increase in the evoked Ca 2+ transient. Using an orthotopic xenograft oral cancer model, we found that mice demonstrated significantly less orofacial cancer-induced nociceptive behavior during systemic ß-adrenergic inhibitory treatment with propranolol. Furthermore, chemical sympathectomy using guanethidine led to a significant reduction in tumor size and nociceptive behavior. We infer from these results that sympathetic signaling modulates oral cancer pain through TNFα secretion and tumorigenesis. Further investigation of the role of neurocancer communication in cancer progression and pain is warranted.

Tumor microenvironment adrenergic nerves blockade liposomes for cancer therapy.

Adrenergic nerves, which are innervated in the tumor, regulate tumor initiation, angiogenesis, and the establishment of the tumor immunosuppressive microenvironment. The study aimed to evaluate the effectiveness of propranolol liposomes (Lipo pro) in inhibiting adrenergic nerve signaling in cancer therapy. Lipo pro significantly regulated the distribution of tumor microenvironment adrenergic nerves, tumor blood vessels, and immunosuppressive microenvironment. Furthermore, it displayed considerable therapeutic effects on prostatic cancer, pancreatic ductal adenocarcinoma, and melanoma. The combination therapeutic regimen, in which Lipo pro was the primary treatment and was supplemented by chemotherapy, showed significant advantages over any single treatment, effectively restraining tumor growth in situ and metastasis, thereby prolonging the survival of mice. This study established a proof-of-concept by targeting tumor adrenergic nerve signaling for cancer therapy.

[Translated article] Spanish Asthma Management Guidelines (GEMA) v.5.1. Highlights and Controversies.

In this fifth phase of development, the contents of the Spanish Asthma Management Guidelines (GEMA), which include versions 5.0 and 5.1, have undergone a thorough review. The aim here is to set the main changes in context. These could be summarized as follows: DIAGNOSIS: new FENO cut-off and severity classification based on treatment needed to maintain control; INTERMITTENT ASTHMA: a more restrictive concept and treatment extended to include a glucocorticoid/adrenergic combination as needed; MILD ASTHMA: glucocorticoid/adrenergic therapy as needed as an alternative in case of low therapeutic adherence to conventional fixed-dose steroids; SEVERE ASTHMA: readjustment of phenotypes, incorporation of triple therapy in a single inhaler, and criteria for selection of a biologic in severe uncontrolled asthma; OTHERS: specific scoring in childhood asthma, incorporation of certain organizational aspects (care circuits, asthma units, telemedicine), new sections on COVID-19 and nasal polyposis.

TH-MYCN tumors, but not tumor-derived cell lines, are adrenergic lineage, GD2+, and responsive to anti-GD2 antibody therapy.

Neuroblastoma is a commonly lethal solid tumor of childhood and intensive chemoradiotherapy treatment cures ~50% of children with high-risk disease. The addition of immunotherapy using dinutuximab, a monoclonal antibody directed against the GD2 disialoganglioside expressed on neuroblasts, improves survival when incorporated into front-line therapy and shows robust activity in regressing relapsed disease when combined with chemotherapy. Still, many children succumb to neuroblastoma progression despite receiving dinutuximab-based immunotherapy, and efforts to counteract the immune suppressive signals responsible are warranted. Animal models of human cancers provide useful platforms to study immunotherapies. TH-MYCN transgenic mice are immunocompetent and develop neuroblastomas at autochthonous sites due to enforced MYCN expression in developing neural crest tissues. However, GD2-directed immunotherapy in this model has been underutilized due to the prevailing notion that TH-MYCN neuroblasts express insufficient GD2 to be targeted. We demonstrate that neuroblasts in TH-MYCN-driven tumors express GD2 at levels comparable to human neuroblastomas but rapidly lose GD2 expression when explanted ex vivo to establish tumor cell lines. This occurs in association with a transition from an adrenergic to mesenchymal differentiation state. Importantly, not only is GD2 expression retained on tumors in situ, treatment with a murine anti-GD2 antibody, 14G2a, markedly extends survival in such mice, including durable complete responses. Tumors in 14G2a-treated mice have fewer macrophage and myeloid-derived suppressor cells in their tumor microenvironment. Our findings support the utility of this model to inform immunotherapy approaches for neuroblastoma and potential opportunities to investigate drivers of adrenergic to mesenchymal fate decisions.

CFTR modulation with elexacaftor-tezacaftor-ivacaftor in people with cystic fibrosis assessed by the ß-adrenergic sweat rate assay.

BACKGROUND: The cystic fibrosis (CF) sweat gland is defective in ß-adrenergically-stimulated sweat secretion in the coil and chloride reabsorption in the duct. Whereas chloride reabsorption is regularly assessed by quantitative pilocarpine iontophoresis (QPIT), the measurement of ß-adrenergic sweat secretion is not yet established in clinical practice. METHODS: A novel sweat bubble imaging protocol was developed that determines sweat secretion rates by automatic recording, processing and quality control of the kinetics of sweat droplet formation. RESULTS: Treatment of CF patients with the CFTR modulators elexacaftor, tezacaftor and ivacaftor reduced the sweat chloride concentration measured in QPIT in the majority of patients to values in the intermediate or normal range. In contrast, the ß-adrenergically-stimulated sweat secretion rate assayed by the automated bubble sweat test was normalized in only 3 patients, slightly increased in 12 patients and remained undetectable in 8 patients. CONCLUSIONS: ß-adrenergic sweat stimulation in the coil is apparently rather stringent in its requirements for a wild type CFTR conformation whereas chloride reabsorption in the duct tolerates residual structural and functional deficits of native or pharmacologically rescued mutant CFTR in the apical membrane.

Rapid response to the alpha-1 adrenergic agent phenylephrine in the perioperative period is impacted by genomics and ancestry.

The emergence of genomic data in biobanks and health systems offers new ways to derive medically important phenotypes, including acute phenotypes occurring during inpatient clinical care. Here we study the genetic underpinnings of the rapid response to phenylephrine, an α1-adrenergic receptor agonist commonly used to treat hypotension during anesthesia and surgery. We quantified this response by extracting blood pressure (BP) measurements 5 min before and after the administration of phenylephrine. Based on this derived phenotype, we show that systematic differences exist between self-reported ancestry groups: European-Americans (EA; n = 1387) have a significantly higher systolic response to phenylephrine than African-Americans (AA; n = 1217) and Hispanic/Latinos (HA; n = 1713) (31.3% increase, p value < 6e-08 and 22.9% increase, p value < 5e-05 respectively), after adjusting for genetic ancestry, demographics, and relevant clinical covariates. We performed a genome-wide association study to investigate genetic factors underlying individual differences in this derived phenotype. We discovered genome-wide significant association signals in loci and genes previously associated with BP measured in ambulatory settings, and a general enrichment of association in these genes. Finally, we discovered two low frequency variants, present at ~1% in EAs and AAs, respectively, where patients carrying one copy of these variants show no phenylephrine response. This work demonstrates our ability to derive a quantitative phenotype suited for comparative statistics and genome-wide association studies from dense clinical and physiological measures captured for managing patients during surgery. We identify genetic variants underlying non response to phenylephrine, with implications for preemptive pharmacogenomic screening to improve safety during surgery.

Treatments for priapism in boys and men with sickle cell disease.

BACKGROUND: Sickle cell disease comprises a group of genetic haemoglobin disorders. The predominant symptom associated with sickle cell disease is pain resulting from the occlusion of small blood vessels by abnormally 'sickle-shaped' red blood cells. There are other complications, including chronic organ damage and prolonged painful erection of the penis, known as priapism. Severity of sickle cell disease is variable, and treatment is usually symptomatic. Priapism affects up to half of all men with sickle cell disease, however, there is no consistency in treatment. We therefore need to know the best way of treating this complication in order to offer an effective interventional approach to all affected individuals. This is an update of a previously published review. OBJECTIVES: To assess the benefits and risks of different treatments for stuttering (repeated short episodes) and fulminant (lasting for six hours or more) priapism in sickle cell disease. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Haemoglobinopathies Trials Register, which comprises references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. We also searched trial registries. Date of the most recent search of the Group's Haemoglobinopathies Trials Register: 09 September 2019. Date of most recent search of trial registries and of Embase: 01 October 2019. SELECTION CRITERIA: All randomised or quasi-randomised controlled trials comparing non-surgical or surgical treatment with placebo or no treatment, or with another intervention for stuttering or fulminant priapism. DATA COLLECTION AND ANALYSIS: The authors independently extracted data and assessed the risk of bias of the trials. MAIN RESULTS: Three trials with 102 participants were identified and met the criteria for inclusion in this review. These trials compared stilboestrol to placebo, sildenafil to placebo and a four-arm trial which compared ephedrine or etilefrine to placebo and ranged in duration from two weeks to six months. All of the trials were conducted in an outpatient setting in Jamaica, Nigeria and the UK. None of the trials measured our first primary outcome, detumescence. However, all three trials reported on the reduction in frequency of stuttering priapism, our second primary outcome; and from the evidence included in this review, we are uncertain whether stilboestrol, etilefrine or ephedrine reduce the frequency of stuttering priapism as the certainty of the evidence has been assessed as very low. Additionally, we conclude that sildenafil may make little or no difference (low-certainty evidence). Two trials reported on immediate side effects and we are uncertain whether etilefrine or ephedrine reduce the occurrence of these (very low-certainty of evidence) and also conclude that sildenafil may make little or no difference in side effects (low-quality evidence). Given that all of the trials were at risk of bias and all had low participant numbers, we considered the certainty of the evidence to be low to very low. AUTHORS' CONCLUSIONS: There is a lack of evidence for the benefits or risks of the different treatments for both stuttering and fulminant priapism in sickle cell disease. This systematic review has clearly identified the need for well-designed, adequately-powered, multicentre randomised controlled trials assessing the effectiveness of specific interventions for priapism in sickle cell disease.

Dopaminergic and Adrenergic Pathways as Targets for Drug Repurposing in the Neuroimmune Network.

Dopamine, noradrenaline and adrenaline are catecholamines, and are all produced along the same metabolic pathway. Their discovery dates back to the early 1900s, and they were appreciated until the second half of the century mainly for their role in the brain and in the regulation of autonomic functions. Nonetheless, in the 1970s characterization of the key role of sympathoadrenergic nerve fibers in the cross-talk between the brain and the immune system paved the way to the raise of modern neuroimmunology, and understanding the immune effects of dopamine occurred in the subsequent decades. Both adrenergic and dopaminergic transmission offer a possibly unparalleled wealth of therapeutic targets, and most of them have been already successfully exploited for cardiovascular, respiratory, neurologic and even psychiatric diseases, however so far the therapeutic potential of adrenergic and dopaminergic agents in the neuroimmune network remains relatively unexploited. This special issue provides a unique collection of expert contributions from some of the most prominent researchers currently studying dopaminergic and adrenergic agents in major diseases like cancer, autoimmunity, neurodegeneration, and even in emerging areas like hematology and metabolism. It is strongly hoped that these reviews will be not only helpful for researchers already working on topics related to the neuroimmune pharmacology of catecholamines, but will also attract novel researchers as much work is still needed to fully exploit the therapeutic potential of dopaminergic and adrenergic drugs for the benefit of patients.

Acute, but not Chronic, Exposure to Arsenic Provokes Glucose Intolerance in Rats: Possible Roles for Oxidative Stress and the Adrenergic Pathway.

OBJECTIVES: Health problems due to heavy metals have become a worldwide concern. Along with its carcinogenicity, arsenic exposure results in impairment of glucose metabolism and insulin secretion as well as altered gene expression and signal transduction. However, the exact mechanism behind the behaviour of arsenic on glucose homeostasis and insulin secretion has not yet been fully understood. METHODS: Fasting blood sugar and glucose tolerance tests were evaluated. RESULTS: In this study, we demonstrated that arsenic, when acutely administered, induced glucose intolerance in rats, although its chronic oral exposure did not provoke any glucose intolerance or hyperglycemia in rats. The protective activity of N-acetylcysteine, carvedilol and propranolol in male rats exposed to arsenic were also assessed, and N-acetylcysteine, particularly at 40 and 80 mg/kg, prevented the glucose intolerance induced in rats by arsenic. CONCLUSIONS: The present study showed that acute, but not chronic, contact with arsenic generates significant changes in the normal glucose tolerance pattern that may be due fundamentally to overproduction of reactive oxygen species and oxidative stress and is preventable by using N-acetylcysteine, a thiol-containing antioxidant.

Complete prevention of radiation-induced dermatitis using topical adrenergic vasoconstrictors.

Radiation dermatitis is a commonly occurring, painful, side effect of cancer radiotherapy that causes some patients to withdraw from the radiotherapy course. Our goal was to test and optimize topical application of an adrenergic vasoconstrictor to rat skin in a preclinical test to prevent radiation-induced dermatitis. A radiation dermatitis assay was developed in which 17.2 Gy to a 1.5 × 3.0 cm rectangle on the clipped dorsal back of rats yielded Grade 3 radiation dermatitis over the irradiated area 13 days later. Single, topical applications of each of three adrenergic vasoconstrictors, epinephrine, norepinephrine, or phenylephrine, in various vehicle formulations, doses, and application schedules, were tested to determine their efficacy in preventing radiation dermatitis. Each of the three adrenergic agonists conferred 100 % prevention of radiation dermatitis in linear, dose-dependent manners and their EC50 potencies in preventing radiation dermatitis correlated well with their individual K d association constants for binding to mammalian α-adrenergic receptors. Topical vasoconstrictor application as little as 3-12 min before irradiation gave 80-100 % prevention, respectively, of radiation dermatitis. There was a strong correlation between the extent (0-100 %) of skin blanch present in skin immediately before irradiation and prevention of radiation dermatitis scored 13 days after irradiation. The data presented here demonstrate that topical application of adrenergic vasoconstrictors to rat skin before a large, 17.2 Gy, radiation insult confers 100 % protection against radiation dermatitis and support ongoing clinical trials and commercial development of a vasoconstrictor-based product to prevent radiotherapy-induced dermatitis.

Curcumin pretreatment mediates antidiabetogenesis via functional regulation of adrenergic receptor subtypes in the pancreas of multiple low-dose streptozotocin-induced diabetic rats.

Lifestyle modification pivoting on nutritional management holds tremendous potential to meet the challenge of management of diabetes. The current study hypothesizes that regular uptake of curcumin lowers the incidence of diabetes by functional regulation of pancreatic adrenergic receptor subtypes. The specific objective of the study was to identify the regulatory pathways implicated in the antidiabetogenesis effect of curcumin in multiple low-dose streptozotocin (MLD-STZ)-induced diabetic Wistar rats. Administration of MLD-STZ to curcumin-pretreated rats induced a prediabetic condition. Scatchard analysis, real-time polymerase chain reaction, and confocal microscopic studies confirmed a significant increase in α2-adrenergic receptor expression in the pancreas of diabetic rats. Pretreatment with curcumin significantly decreased α2-adrenergic receptor expression. The diabetic group showed a significant decrease in the expression of ß-adrenergic receptors when compared with control. Pretreatment significantly increased ß-adrenergic receptor expression to near control. When compared with the diabetic rats, a significant up-regulation of CREB, phospholipase C, insulin receptor, and glucose transporter 2 were observed in the pretreated group. Curcumin pretreatment was also able to maintain near control levels of cyclic adenosine monophosphate, cyclic guanosine monophosphate, and inositol triphosphate. These results indicate that a marked decline in α2-adrenergic receptor function relents sympathetic inhibition of insulin release. It also follows that escalated signaling through ß-adrenergic receptors mediates neuronal stimulation of hyperglycemia-induced ß-cell compensatory response. Curcumin-mediated functional regulation of adrenergic receptors and modulation of key cell signaling molecules improve pancreatic glucose sensing, insulin gene expression, and insulin secretion.

Catecholamine excess: pseudopheochromocytoma and beyond.

Symptoms of catecholamine excess or pseudopheochromocytoma can be clinically indistinguishable from pheochromocytoma. Patients usually present with paroxysmal or episodic hypertension and have a negative evaluation for pheochromocytoma. It is important to exclude other causes of catecholamine excess that can be induced by stress, autonomic dysfunction due to baroreflex failure, medications, and drugs. Patients with pseudopheochromocytoma appear to have an amplified cardiovascular responsiveness to catecholamines with enhanced sympathetic nervous stimulation. The exact mechanism is not well understood and increased secretion of dopamine, epinephrine, and norepinephrine, and their metabolites have been identified as potentiating this clinical scenario leading to differing hemodynamic presentations depending on which catecholamine is elevated. Management of this condition is often difficult and frustrating for both the physician and the patient. Most patients respond reasonably well to medications that reduce sympathetic nervous system activity. Anxiolytics, antidepressants, and psychotherapy also play an important role in managing these patients' symptoms.

Ephedrine for myasthenia gravis, neonatal myasthenia and the congenital myasthenic syndromes.

BACKGROUND: Myasthenia is a condition in which neuromuscular transmission is affected by antibodies against neuromuscular junction components (autoimmune myasthenia gravis, MG; and neonatal myasthenia gravis, NMG) or by defects in genes for neuromuscular junction proteins (congenital myasthenic syndromes, CMSs). Clinically, some individuals seem to benefit from treatment with ephedrine, but its effects and adverse effects have not been systematically evaluated. OBJECTIVES: To assess the effects and adverse effects of ephedrine in people with autoimmune MG, transient neonatal MG, and the congenital myasthenic syndromes. SEARCH METHODS: On 17 November 2014, we searched the Cochrane Neuromuscular Disease Group Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and EMBASE. We also searched reference lists of articles, conference proceedings of relevant conferences, and prospective trial registers. In addition, we contacted manufacturers and researchers in the field. SELECTION CRITERIA: We considered randomised controlled trials (RCTs) and quasi-RCTs comparing ephedrine as a single or add-on treatment with any other active treatment, placebo, or no treatment in adults or children with autoimmune MG, NMG, or CMSs. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed study design and quality, and extracted data. We contacted study authors for additional information. We collected information on adverse effects from included articles, and contacted authors. MAIN RESULTS: We found no RCTs or quasi-RCTs, and therefore could not establish the effect of ephedrine on MG, NMG and CMSs. We describe the results of 53 non-randomised studies narratively in the Discussion section, including observations of endurance, muscle strength and quality of life. Effects may differ depending on the type of myasthenia. Thirty-seven studies were in participants with CMS, five in participants with MG, and in 11 the precise form of myasthenia was unknown. We found no studies for NMG. Reported adverse effects included tachycardia, sleep disturbances, nervousness, and withdrawal symptoms. AUTHORS' CONCLUSIONS: There was no evidence available from RCTs or quasi-RCTs, but some observations from non-randomised studies are available. There is a need for more evidence from suitable forms of prospective RCTs, such as series of n-of-one RCTs, that use appropriate and validated outcome measures.

Magnetic resonance imaging (MRI) to study striatal iron accumulation in a rat model of Parkinson's disease.

Abnormal accumulation of iron is observed in neurodegenerative disorders. In Parkinson's disease, an excess of iron has been demonstrated in different structures of the basal ganglia and is suggested to be involved in the pathogenesis of the disease. Using the 6-hydroxydopamine (6-OHDA) rat model of Parkinson's disease, the edematous effect of 6-OHDA and its relation with striatal iron accumulation was examined utilizing in vivo magnetic resonance imaging (MRI). The results revealed that in comparison with control animals, injection of 6-OHDA into the rat striatum provoked an edematous process, visible in T2-weighted images that was accompanied by an accumulation of iron clearly detectable in T2*-weighted images. Furthermore, Prussian blue staining to detect iron in sectioned brains confirmed the existence of accumulated iron in the areas of T2* hypointensities. The presence of ED1-positive microglia in the lesioned striatum overlapped with this accumulation of iron, indicating areas of toxicity and loss of dopamine nerve fibers. Correlation analyses demonstrated a direct relation between the hyperintensities caused by the edema and the hypointensities caused by the accumulation of iron.

Anesthetic considerations and management of a patient with unsuspected carcinoid crisis during hepatic tumor resection.

Anesthetic management for massive blood loss in liver surgery concomitant with hemodynamic instability secondary to carcinoid crisis can be challenging in the perioperative setting. Hypotension, diarrhea, facial flushing, bronchospasm, and tricuspid and pulmonic valvular diseases are the common manifestations of carcinoid syndrome. This report illustrates the importance of early recognition and treatment for signs and symptoms of carcinoid syndrome not only in the preoperative setting but also in the intraoperative phase to prevent undue cardiovascular collapse.

Effects of berberine on rat jejunal motility.

OBJECTIVES: The aim of the study was to evaluate berberine-induced bidirectional regulation on the contractility of jejunum. METHODS: Different low and high contractile states of isolated jejunal segment from rat were established to investigate the effects of berberine. KEY FINDINGS: Stimulatory effects on jejunal segment were exerted by berberine in six low contractile states and inhibitory effects were produced on jejunal segment in six high contractile states. The effects of berberine on myosin light chain kinase (MLCK) mRNA expression, MLCK protein content, and myosin phosphorylation in jejunum were also bidirectional. Bidirectional regulation was not observed in the presence of tetrodotoxin. No regulatory effects of berberine on jejunal contractility were observed in the presence of verapamil. The stimulatory effects of berberine on jejunal contractility were blocked by atropine. The inhibitory effects of berberine on jejunal contractility were abolished by phentolamine, propranolol and L-NG-nitro-arginine, respectively. CONCLUSIONS: Berberine-induced bidirectional regulation needed the presence of the enteric nervous system, and depended on the influx of extracellular Ca(2+) , related to the cholinergic system while jejunum was in low contractile states, and related to the adrenergic system and nitric oxide relaxing mechanism while jejunum was in high contractile states. The results suggested the potential clinical implication of berberine for alternating-type irritable bowel syndrome.