The transgenic Tg2576 mouse is a widely used animal model that develops some of the cognitive and neuropathological deteriorations observed in patients suffering Alzheimer's disease. The authors investigated 9-month-old Tg2576 mice with respect to behavioral and endocrinological (hypothalamic- pituitary-adrenal [HPA] axis activity) parameters. The locomotor activity test revealed that Tg2576 mice moved almost twice as much as controls. Tg2576 mice spent significantly more time visiting the open arms and performed more entries into these open arms than did controls. However, the amount of time that Tg2576 mice remained in each entry to the open arm was similar to that of controls, and the number of arm entries correlated positively to locomotor activity. In the forced swimming test, Tg2576 mice showed a significant decrease in immobility time, which correlated negatively to locomotor activity. Parameters of the HPA axis, such as plasma level of corticosterone, adrenal gland weight, and noradrenaline or adrenaline release, did not differ between controls and Tg2576 mice. These data suggest that the disinhibitory behavior of Tg2576 mice seems to be related to increased locomotor activity but not to any disturbance of the HPA axis.

Collagen-induced platelet aggregation is a complex process and involves synergistic action of integrins, immunoglobulin (Ig)-like receptors, G-protein-coupled receptors and their ligands, most importantly collagen itself, thromboxane A(2) (TXA(2)), and adenosine diphosphate (ADP). The precise role of each of these receptor systems in the overall processes of activation and aggregation, however, is still poorly defined. Among the collagen receptors expressed on platelets, glycoprotein (GP) VI has been identified to play a crucial role in collagen-induced activation. GPVI is associated with the FcRgamma chain, which serves as the signal transducing unit of the receptor complex. It is well known that clustering of GPVI by highly specific agonists results in platelet activation and irreversible aggregation, but it is unclear whether collagen has the same effect on the receptor. This study shows that platelets from Galphaq-deficient mice, despite their severely impaired response to collagen, normally aggregate on clustering of GPVI, suggesting this not to be the principal mechanism by which collagen activates platelets. On the other hand, dimerization of GPVI by a monoclonal antibody (JAQ1), which by itself did not induce aggregation, provided a sufficient stimulus to potentiate platelet responses to Gi-coupled, but not Gq-coupled, agonists. The combination of JAQ1 and adrenaline or ADP, but not serotonin, resulted in alpha(IIb)beta(3)-dependent aggregation that occurred without intracellular calcium mobilization and shape change in the absence of Galphaq or the P2Y(1) receptor. Together, these results provide evidence for a cross-talk between (dimerized) GPVI and Gi-coupled receptors during collagen-induced platelet aggregation. (Blood. 2001;97:3829-3835)

OBJECTIVE

To evaluate the effect of terlipressin on oxygenation, PaO2/FIO2, heart rate, mean arterial pressure, and mortality in children with septic shock refractory to high doses of dopamine/dobutamine and adrenaline.

METHODS

A randomized, nonblind study in the pediatric intensive care unit of a university hospital.

METHODS

We studied 58 children with septic shock and refractory hypotension despite fluid loading and high doses of catecholamines, randomly enrolled to terlipressin (TP, n=30) or control (n=28). TP was administered as intravenous bolus doses of 20 microg/kg every 6 h for a maximum of 96 h. Hemodynamic changes, PaO2/FIO2 rates, length of stay, and mortality rate in PICU were recorded prospectively.

RESULTS

Mean arterial pressure and PaO2/FIO2 significantly increased, and heart rate significantly decreased 30 min after each TP treatment, but mortality did not differ from control (67.3% vs. 71.4%). Mean stay in the PICU was shorter in the TP group (13.4+/-7.9 vs. 20.2+/-9.7 days and was longer among nonsurvivors of the TP group vs. control (10.4+/-6.9 vs. 6.2+/-3.4 days). Blood urea nitrogen, creatinine, AST, ALT, and urine output of patients in the TP group did not change after terlipressin.

CONCLUSIONS

Although terlipressin infusion had no effect on mortality, it significantly increases mean arterial pressure, PaO2/FIO2, and survival time in nonsurvivors. Terlipressin seems to cause no adverse effect but warrants further evaluation as a rescue therapy in refractory septic shock.

In spite of more than 100 years of investigations the question of whether a reduced sodium intake improves health is still unsolved.

To estimate the effects of low sodium intake versus high sodium intake on systolic and diastolic blood pressure (SBP and DBP), plasma or serum levels of renin, aldosterone, catecholamines, cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL) and triglycerides.

The Cochrane Hypertension Information Specialist searched the following databases for randomized controlled trials up to March 2016: the Cochrane Hypertension Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL) (2016, Issue 3), MEDLINE (from 1946), Embase (from 1974), the World Health Organization International Clinical Trials Registry Platform, and ClinicalTrials.gov. We also searched the reference lists of relevant articles.

Studies randomising persons to low-sodium and high-sodium diets were included if they evaluated at least one of the above outcome parameters.

Two review authors independently collected data, which were analysed with Review Manager 5.3.

A total of 185 studies were included. The average sodium intake was reduced from 201 mmol/day (corresponding to high usual level) to 66 mmol/day (corresponding to the recommended level).The effect of sodium reduction on blood pressure (BP) was as follows: white people with normotension: SBP: mean difference (MD) -1.09 mmHg (95% confidence interval (CI): -1.63 to -0.56; P = 0.0001); 89 studies, 8569 participants; DBP: + 0.03 mmHg (MD 95% CI: -0.37 to 0.43; P = 0.89); 90 studies, 8833 participants. High-quality evidence. Black people with normotension: SBP: MD -4.02 mmHg (95% CI:-7.37 to -0.68; P = 0.002); seven studies, 506 participants; DBP: MD -2.01 mmHg (95% CI:-4.37 to 0.35; P = 0.09); seven studies, 506 participants. Moderate-quality evidence. Asian people with normotension: SBP: MD -0.72 mmHg (95% CI: -3.86 to 2.41; P = 0.65); DBP: MD -1.63 mmHg (95% CI:-3.35 to 0.08; P =0.06); three studies, 393 participants. Moderate-quality evidence.White people with hypertension: SBP: MD -5.51 mmHg (95% CI: -6.45 to -4.57; P < 0.00001); 84 studies, 5925 participants; DBP: MD -2.88 mmHg (95% CI: -3.44 to -2.32; P < 0.00001); 85 studies, 6001 participants. High-quality evidence. Black people with hypertension: SBP MD -6.64 mmHg (95% CI:-9.00 to -4.27; P = 0.00001); eight studies, 619 participants; DBP -2.91 mmHg (95% CI:-4.52, -1.30; P = 0.0004); eight studies, 619 participants. Moderate-quality evidence. Asian people with hypertension: SBP: MD -7.75 mmHg (95% CI:-11,44 to -4.07; P < 0.0001) nine studies, 501 participants; DBP: MD -2.68 mmHg (95% CI: -4.21 to -1.15; P = 0.0006). Moderate-quality evidence.In plasma or serum, there was a significant increase in renin (P < 0.00001), aldosterone (P < 0.00001), noradrenaline (P < 0.00001), adrenaline (P < 0.03), cholesterol (P < 0.0005) and triglyceride (P < 0.0006) with low sodium intake as compared with high sodium intake. All effects were stable in 125 study populations with a sodium intake below 250 mmol/day and a sodium reduction intervention of at least one week.

Sodium reduction from an average high usual sodium intake level (201 mmol/day) to an average level of 66 mmol/day, which is below the recommended upper level of 100 mmol/day (5.8 g salt), resulted in a decrease in SBP/DBP of 1/0 mmHg in white participants with normotension and a decrease in SBP/DBP of 5.5/2.9 mmHg in white participants with hypertension. A few studies showed that these effects in black and Asian populations were greater. The effects on hormones and lipids were similar in people with normotension and hypertension. Renin increased 1.60 ng/mL/hour (55%); aldosterone increased 97.81 pg/mL (127%); adrenalin increased 7.55 pg/mL (14%); noradrenalin increased 63.56 pg/mL: (27%); cholesterol increased 5.59 mg/dL (2.9%); triglyceride increased 7.04 mg/dL (6.3%).

BACKGROUND

The effect of venom immunotherapy (VIT) is well documented, but fear of systemic side-effects (SE) may prevent its use. The study aimed to analyze the character and frequency of SE and risk factors.

METHODS

In a prospective study, 19 European centers included patients starting on VIT for systemic reactions to insect stings. Various dose regimens were applied.

RESULTS

Data from 840 patients with a total of 26 601 injections were obtained. Seventy-one percent were treated with Vespula-venom extract and 27% with honeybee-venom extract. Twenty percent of patients had SE corresponding to 1.9% of injections during dose increase and 0.5% during the maintenance phase. The vast majority of the 280 reactions were mild: only one-third required medical treatment. Injected or inhaled adrenaline was applied in six patients, of whom only one had a drop in blood pressure and collapse. Female sex, bee-venom extract, and rapid dose increase, but not severity of insect sting reactions, increased the risk of SE. The severity of SE was less in males but was not related to age, treatment phase, species of insect, or severity of insect sting reactions.

CONCLUSIONS

The frequency of SE was low, and the majority of these could be managed without treatment. Risk was increased in females, in bee-venom-treated patients, and in those with rapid dose increase.

1. The effect of hyperketonaemia on counter-regulatory hormone responses to hypoglycaemia has been examined in six healthy subjects. 2. A controlled, step-wise reduction in blood glucose concentration was achieved by adjusting the rate of glucose infusion during a primed-continuous infusion of soluble insulin (1.5 m-units min-1 kg-1 body weight, plasma insulin concentration approximately 90 m-units/l). Simultaneous infusion of either saline or beta-hydroxybutyrate (3 mg min-1 kg-1 body weight) was administered in a single-blind fashion, in random order. Despite a need for 40% more glucose during the ketone infusion, an identical fall in blood glucose concentration was achieved in each study. 3. The glycaemic threshold for stimulating an adrenaline response of 0.41 nmol/l was reduced from 3.1 to 2.8 mmol/l (P less than 0.05) during ketone infusion, and that for stimulating a response of more than 50% of basal from 3.6 to 3.1 mmol/l (P less than 0.001). The peak adrenaline response fell from 7.97 to 2.6 nmol/l (P less than 0.04). Peak noradrenaline, cortisol and growth hormone responses were also significantly lower during ketone infusion (P = 0.04, 0.001 and 0.006, respectively). Glucagon responses alone were unaffected by hyperketonaemia. 4. The provision of an alternate metabolic fuel thus produced immediate changes in the neurohumoral responses to hypoglycaemia. This is consistent with the hypothesis that human nervous tissue can metabolize ketones acutely.

OBJECTIVE

To assess whether plasma endothelin, adrenaline, noradrenaline, arginine vasopressin, adrenocorticotropin, and cortisol concentrations were higher during cardiopulmonary resuscitation in patients in whom resuscitation was successful than in those in whom it failed, and to measure the concentrations of these hormones in the immediate post-resuscitation phase.

METHODS

Prospective, descriptive study.

METHODS

Emergency medical service at a university hospital.

METHODS

60 patients with cardiac arrest out of hospital.

METHODS

Blood samples were drawn and blood pressure and heart rate were measured during cardiopulmonary resuscitation, before and after the first dose of adrenaline was given and at 5, 15, 30, and 60 minutes after the restoration of spontaneous circulation. Plasma hormone concentrations were measured by radio-immunoassays.

RESULTS

24 of the 60 patients were successfully resuscitated and admitted to hospital: 36 were not. During cardiopulmonary resuscitation before adrenaline was given, the plasma concentration of endothelin (mean (SEM)) in resuscitated and in not resuscitated patients was 4.3 (0.9) pg/ml and 5.5 (0.4) pg/ml respectively (NS), adrenaline was 14.1 (2.0) ng/ml and 25.3 (3.6) ng/ml (P < 0.01), noradrenaline was 5.0 (0.9 ng/ml) and 8.4 (1.1 ng/ml) (P < 0.05), arginine vasopressin was 193 (28) pg/ml and 70 (9) pg/ml (P < 0.001), adrenocorticotropin was 128 (34) pg/ml and 57 (6) pg/ml (P < 0.05), and cortisol was 18 (3) microgram/dl and 15 (2) microgram/dl (NS). During cardiopulmonary resuscitation after adrenaline was given endothelin in resuscitated and in not resuscitated patients was 4.0 (1.0) pg/ml and 5.3 (0.5) pg/ml (NS), adrenaline was 145 (16) ng/ml and 201 (21) ng/ml (P < 0.05), noradrenaline was 3.9 (0.9) ng/ml and 8.3 (1.1) ng/ml (P < 0.01), arginine vasopressin was 177 (27) pg/ml and 58 (9) pg/ml (P < 0.001), adrenocorticotropin was 234 (92) pg/ml and 85 (9) pg/ml (P < 0.001), and cortisol was 17 (2) microgram/dl and 13 (2) microgram/dl (NS).

CONCLUSIONS

Despite a tremendous adrenosympathetic response, the lower arginine vasopressin and adrenocorticotropin concentrations during cardiopulmonary resuscitation in patients in whom resuscitation failed may influence vital organ perfusion and hence the success of resuscitation. Plasma concentrations of arginine vasopressin and adrenocorticotropin may have a more important effect on outcome than previously thought.

Sympatho-adrenal activation induced by stress contributes to the development of pathological states such as hypertension and anxiety disorders. The Stroop Color Word Test (CWT) is evaluated as a test for the study of stress-induced sympathetic effects, on the basis of psychological, physiological and biochemical responses. The CWT induced increases in plasma and urinary adrenaline, heart rate, respiration rate, electrodermal activity, electromyography, feelings of anxiety, and decreased finger pulse amplitude.

OBJECTIVE

To evaluate and compare the efficacy and safety of bronchodilators and steroids, alone or combined, for the acute management of bronchiolitis in children aged less than 2 years.

METHODS

Systematic review and meta-analysis.

METHODS

Medline, Embase, Central, Scopus, PubMed, LILACS, IranMedEx, conference proceedings, and trial registers. Inclusion criteria Randomised controlled trials of children aged 24 months or less with a first episode of bronchiolitis with wheezing comparing any bronchodilator or steroid, alone or combined, with placebo or another intervention (other bronchodilator, other steroid, standard care).

METHODS

Two reviewers assessed studies for inclusion and risk of bias and extracted data. Primary outcomes were selected by clinicians a priori based on clinical relevance: rate of admission for outpatients (day 1 and up to day 7) and length of stay for inpatients. Direct meta-analyses were carried out using random effects models. A mixed treatment comparison using a Bayesian network model was used to compare all interventions simultaneously.

RESULTS

48 trials (4897 patients, 13 comparisons) were included. Risk of bias was low in 17% (n = 8), unclear in 52% (n = 25), and high in 31% (n = 15). Only adrenaline (epinephrine) reduced admissions on day 1 (compared with placebo: pooled risk ratio 0.67, 95% confidence interval 0.50 to 0.89; number needed to treat 15, 95% confidence interval 10 to 45 for a baseline risk of 20%; 920 patients). Unadjusted results from a single large trial with low risk of bias showed that combined dexamethasone and adrenaline reduced admissions on day 7 (risk ratio 0.65, 0.44 to 0.95; number needed to treat 11, 7 to 76 for a baseline risk of 26%; 400 patients). A mixed treatment comparison supported adrenaline alone or combined with steroids as the preferred treatments for outpatients (probability of being the best treatment based on admissions at day 1 were 45% and 39%, respectively). The incidence of reported harms did not differ. None of the interventions examined showed clear efficacy for length of stay among inpatients.

CONCLUSIONS

Evidence shows the effectiveness and superiority of adrenaline for outcomes of most clinical relevance among outpatients with acute bronchiolitis, and evidence from a single precise trial for combined adrenaline and dexamethasone.

Blood glucose, glucose tolerance, serum insulin, free fatty acids in serum, plasma noradrenaline, and plasma adrenaline were measured in 10 patients with acute myocardial infarction (AMI) as well as in healthy subjects. Both noradrenaline and adrenaline in plasma were elevated in patients with AMI, the level being fairly constant in the individual patients and dependent on their degree of illness. In the fasting state, blood glucose, serum insulin, and free fatty acids were elevated in patients with AMI. Plasma noradrenaline showed a highly significant correlation with the fasting blood glucose concentration, but not with serum insulin or free fatty acids. The concentration of free fatty acids in serum could be predicted only if both plasma noradrenaline and the basal insulin concentration were known. Intravenous glucose tolerance was reduced in patients with AMI, especially in patients with high plasma noradrenaline and a low initial rise in insulin. There was a significant negative correlation between the initial rise in insulin expressed in percentage of the basal insulin concentration and the plasma noradrenaline level. The statistical effects of serum insulin and plasma noradrenaline on the glucose tolerance could not be separated from each other. The decline in free fatty acids after intravenous injection of glucose showed a negative correlation with plasma noradrenaline and a positive correlation with the initial rise in insulin. Plasma adrenaline did not correlate with any of the metabolic parameters mentioned above. The plasma noradrenaline concentration was elevated to such a degree in patients with AMI that the observed changes in metabolism might have been caused directly by the circulating noradrenaline. During the glucose tolerance tests, the effects of noradrenaline was probably carried out indirectly via a suppression of insulin secretion. It is conceivable that any effect of plasma noradrenaline on the basal insulin secretion was neutralized by the fasting hyperglycemia.

BACKGROUND

Different additives have been used to prolong brachial plexus block. We performed a prospective, randomised, double-blind study to evaluate the effect of dexamethasone added to lidocaine on the onset and duration of supraclavicular brachial plexus block as this is the most common type of brachial block performed in our institute.

METHODS

Sixty American Society of Anaesthesiologist's physical status I and II patients undergoing elective hand, forearm and elbow surgery under brachial plexus block were randomly allocated to receive either 1.5% lidocaine (7 mg/kg) with adrenaline (1:200,000) and 2 ml of normal saline (group C, n=30) or 1.5% lidocaine (7 mg/kg) with adrenaline (1:200,000) and 2 ml of dexamethasone (8 mg) (group D, n=30). The block was performed using a nerve stimulator. Onset and duration of sensory and motor blockade were assessed. The sensory and motor blockade of radial, median, ulnar and musculocutaneous nerves were evaluated and recorded at 5, 10, 20, 120 min, and at every 30 min thereafter.

RESULTS

Two patients were excluded from the study because of block failure. The onset of sensory and motor blockade (13.4±2.8 vs. 16.0±2.3 min and 16.0±2.7 vs. 18.7±2.8 min, respectively) were significantly more rapid in the dexamethasone group than in the control group (P=0.001). The duration of sensory and motor blockade (326±58.6 vs. 159±20.1 and 290.6±52.7 vs. 135.5±20.3 min, respectively) were significantly longer in the dexamethasone group than in the control group (P=0.001).

CONCLUSIONS

Addition of dexamethasone to 1.5% lidocaine with adrenaline in supraclavicular brachial plexus block speeds the onset and prolongs the duration of sensory and motor blockade.

The sarcoplasmic reticulum (SR) is central to intracellular Ca2+ regulation during excitation­contraction (E-C) coupling in mammalian cardiac tissue. The importance of the SR to E-C coupling in lower vertebrates is less certain. This uncertainty can be attributed, in part, to the temperature-dependency of the SR Ca2+-release channel and to interspecific differences in the ryanodine-sensitivity of ectotherm cardiac muscle. Furthermore, the relative importance of the SR in contributing intracellular Ca2+ to force development may be influenced by adrenergic stimulation, which increases trans-sarcolemmal (extracellular) Ca2+ influx. The objective of this study was to assess the relative importance of SR (intracellular) and sarcolemmal (SL; extracellular) Ca2+ fluxes during the isometric contraction of isolated ventricular trabeculae from rainbow trout Oncorhynchus mykiss. To approximate in vivo Ca2+ availability to the muscle better, a tonic level (10 nmol l-1) of adrenaline was used in all control experiments, and SL Ca2+ influx was stimulated with high levels (10 µmol l-1) of adrenaline. Ryanodine, a noted blocker of SR Ca2+ release in mammals, was used to assess SR involvement. To examine the role of temperature on the relative Ca2+ contribution from each source, experiments were performed at two temperatures (12 and 22 °C), using ventricular trabeculae from fish acclimated to both 12 and 22 °C. Under all test conditions studied, SL Ca2+ influx was the primary source of activator Ca2+, as assessed by the change in isometric force after ryanodine application. Even so, the SR contribution of activator Ca2+ was significantly greater at a test temperature of 22 °C than at 12 °C. We attribute this observation to the temperature-dependent nature of the SR Ca2+-release channel. At 22 °C and under control conditions, ryanodine reduced peak tension at all pacing frequencies (by approximately 50 % at 0.2 Hz, approximately 25 % at 1.2 Hz and approximately 20 % at 2.0 Hz), regardless of acclimation temperature. Therefore, the SR is a significant, but secondary, contributor of activator Ca2+ for tension development at warm temperatures. The magnitude of SR Ca2+ contribution was inversely related to pacing frequency, but remained significant at physiological pacing frequencies. This was a novel finding. The degree of ryanodine-sensitivity in the present study was greater than that reported previously for the rainbow trout. We attribute this difference to the use of tonic adrenergic stimulation in the present study. In contrast to the experiments at the warmer test temperature, at 12 °C and under control conditions, ryanodine significantly reduced peak tension only at low frequencies (by approximately 25 % at 0.2 Hz), regardless of acclimation temperature. These findings suggest that at cold temperatures, and at physiologically relevant pacing frequencies, the SR may not be important in supplying Ca2+ to the contractile elements of the trout heart. At both test temperatures and regardless of acclimation temperature, stimulation with 10 µmol l-1 adrenaline caused positive inotropy of sufficient magnitude to ameliorate the negative inotropic effect of ryanodine completely, with the exception of high pacing frequencies (>1.2 Hz) at 22 °C, where adrenergic stimulation did not fully compensate for the effects of ryanodine. This exception is discussed in relation to the reduced adrenergic sensitivity of the trout myocardium at warm temperatures. The adrenergically mediated compensation for the loss of the SR Ca2+ supply is a novel finding for fish hearts. Therefore, while our study clearly demonstrates that the relative importance of SR Ca2+ release is subject to temperature and frequency, adrenaline-mediated increases in SL Ca2+ influx decrease the importance of the SR in contributing Ca2+ to E-C coupling in trout ventricular myofilaments.

Bacterial sensing of environmental signals plays a key role in regulating virulence and mediating bacterium-host interactions. The sensing of the neuroendocrine stress hormones epinephrine (adrenaline) and norepinephrine (noradrenaline) plays an important role in modulating bacterial virulence. We used MudJ transposon mutagenesis to globally screen for genes regulated by neuroendocrine stress hormones in Salmonella enterica serovar Typhimurium. We identified eight hormone-regulated genes, including yhaK, iroC, nrdF, accC, yedP, STM3081, and the virulence-related genes virK and mig14. The mammalian alpha-adrenergic receptor antagonist phentolamine reversed the hormone-mediated effects on yhaK, virK, and mig14 but did not affect the other genes. The beta-adrenergic receptor antagonist propranolol had no activity in these assays. The virK and mig14 genes are involved in antimicrobial peptide resistance, and phenotypic screens revealed that exposure to neuroendocrine hormones increased the sensitivity of S. Typhimurium to the antimicrobial peptide LL-37. A virK mutant and a virK mig14 double mutant also displayed increased sensitivity to LL-37. In contrast to enterohemorrhagic Escherichia coli (EHEC), we have found no role for the two-component systems QseBC and QseEF in the adrenergic regulation of any of the identified genes. Furthermore, hormone-regulated gene expression could not be blocked by the QseC inhibitor LED209, suggesting that sensing of hormones is mediated through alternative signaling pathways in S. Typhimurium. This study has identified a role for host-derived neuroendocrine stress hormones in downregulating S. Typhimurium virulence gene expression to the benefit of the host, thus providing further insights into the field of host-pathogen communication.

OBJECTIVE

Stress has been implicated in the development of cancers. Adrenaline levels are increased in response to stress. The effects of adrenaline on colon cancer are largely unknown. The aims of the study are to determine the effects of adrenaline in human colon adenocarcinoma HT-29 cells and the possible underlying mechanisms involved.

METHODS

The effect of adrenaline on HT-29 cell proliferation was determined by [(3)H] thymidine incorporation assay. Expression of cyclooxygenase-2 (COX-2) and vascular endothelial growth factor (VEGF) were detected by Western blot. Matrix metalloproteinase-9 (MMP-9) activity and prostaglandin E(2) (PGE(2)) release were determined by zymography and enzyme immunoassay, respectively.

RESULTS

Adrenaline stimulated HT-29 cell proliferation. This was accompanied by the enhanced expression of COX-2 and VEGF in HT-29 cells. Adrenaline also upregulated MMP-9 activity and PGE(2) release. Adrenaline stimulated HT-29 cell proliferation which was reversed by COX-2 inhibitor sc-236. COX-2 inhibitor also reverted the action of adrenaline on VEGF expression and MMP-9 activity. Further study was performed to determine the involvement of β-adrenoceptors. The stimulatory action of adrenaline on colon cancer growth was blocked by atenolol and ICI 118,551, a β(1)- and β(2)-selective antagonist, respectively. This signified the role of β-adrenoceptors in this process. In addition, both antagonists also abrogated the stimulating actions of adrenaline on COX-2, VEGF expression, MMP-9 activity and PGE(2) release in HT-29 cells.

CONCLUSIONS

These results suggest that adrenaline stimulates cell proliferation of HT-29 cells via both β(1)- and β(2)-adrenoceptors by a COX-2 dependent pathway.

OBJECTIVE

This study was designed to assess the prevalence and nature of autonomic dysfunction (AD) in 34 patients with systemic sclerosis (SSc).

METHODS

Patients were questioned for current symptoms possibly related to AD. Five noninvasive cardiovascular autonomic function tests and sequential plasma catecholamine estimations at rest, during standing, and during sustained handgrip were performed. Seven patients with manometrically documented esophageal involvement and high resting plasma adrenaline levels were treated with clonidine (75 to 375 micrograms/d). One month later, resting plasma catecholamine estimations and esophageal motility studies were repeated.

RESULTS

Autonomic testing revealed AD in each patient, while symptoms were experienced by 33 of them. Findings on two of the three heart rate tests and both blood pressure tests were significantly impaired as compared with those in 25 matched control subjects. Mean resting plasma adrenaline levels were 18 times higher than in 10 matched controls (p less than 0.001). Plasma catecholamine (adrenaline, noradrenaline, and dopamine) concentrations and mean arterial blood pressures fluctuated inappropriately during standing and sustained handgrip in 28 (82%) of the patients. The presence of headaches correlated significantly with sympathetic overactivity and instability (p less than 0.05). Resting plasma adrenaline concentrations correlated inversely with disease duration (p less than 0.05). Significant suppression of sympathetic overactivity and increases in resting lower esophageal sphincter pressures were observed in the seven patients treated with clonidine.

CONCLUSIONS

AD is extremely common in SSc. It is characterized by parasympathetic impairment and marked sympathetic overactivity, particularly in early disease. The potential role of AD in the pathogenesis of SSc deserves further study.

Tyrosine 3-monooxygenase (tyrosine hydroxylase) is a non-heme iron, tetrahydropterin-dependent enzyme which catalyzes the rate-limiting step in the biosynthesis of catecholamines. The highly purified bovine adrenal enzyme contains an unusual blue-green chromophore with lambda max at around 700 nm (epsilon = 1.3 (mM subunit enzyme)-1 cm-1). On excitation at 605.2 nm, resonance-enhanced Raman vibrations are observed at 454, 494, 527, 604, 635, 835, 1130, 1271, 1320, 1426, and 1476 cm-1. The excitation profiles of the modes of 1276 and 1476 cm-1 (from 488 to 620 nm) follow the contour of the 700 nm absorption band. The vibrations observed strongly indicate the presence of a bidentate catecholamine-Fe(III) complex in the enzyme as isolated which gives rise to the characteristic charge-transfer transitions. This is further supported by the release of 0.11 +/- 0.04 mol of noradrenaline and 0.25 +/- 0.06 mol of adrenaline per mol of enzyme subunit on denaturation of the enzyme. The energies of the catecholate to Fe(III) charge-transfer transitions indicate a mixture of histidines and carboxylate(s) coordinated to the iron center in tyrosine hydroxylase. At neutral pH, the enzymatic activity was inhibited more than 50% by 10 microM dopamine, noradrenaline, and adrenaline. The high affinity of the catecholamines to the nonphosphorylated form of tyrosine hydroxylase may have significance in vivo since catecholamines are potent feedback inhibitors of the enzyme.

1. The responses of the smooth muscle of the capsule and blood vessels of the isolated, perfused human spleen to sympathetic nerve stimulation, adrenaline, noradrenaline, angiotensin, oxytocin, vasopressin, isoprenaline and acetylcholine have been investigated and compared with those of dog spleen.2. Stimulation of the postganglionic sympathetic nerves to the human spleen at frequencies of 3-10 Hz evoked graded vasoconstriction but very small changes in spleen volume.3. The injection of adrenaline and noradrenaline in doses of 0.25-25 mug to the human spleen produced graded increases in splenic vascular resistance with very small decreases in spleen volume.4. Administration of the alpha-adrenoceptor blocking drug phenoxybenzamine completely abolished or considerably reduced the vascular responses of the human spleen to sympathetic nerve stimulation or the injection of noradrenaline.5. The vascular action of adrenaline was often reversed to elicit a vasodilatation after phenoxybenzamine suggesting the presence of beta-adrenoceptors in the vascular bed. This was confirmed by the administration of isoprenaline which induced a marked reduction in vascular resistance of the human spleen.6. The polypeptides angiotensin and vasopressin induced a marked vasoconstriction in the human spleen without changes in the spleen volume. These effects were uninfluenced by the administration of phenoxybenzamine.7. The polypeptide oxytocin caused a slight vasodilatation in the human spleen, an effect almost exactly mimicked by the preservative chlorobutanol.8. Preliminary experiments suggest that noradrenaline is the transmitter released by the postganglionic nerves to the human spleen.9. These results provide direct evidence that the normal human spleen, unlike that of the dog, does not have a reservoir function. It is suggested that contractions of the enlarged human spleen may occur in various pathological conditions.

Afferent fibers ending in nerve end neuromas in rats generate a substantial ectopic discharge and are sensitive to light pressure and to circulating adrenaline. Treatment of the nerve with colchicine or vinblastine at the time of the nerve section resulted in a dose-dependent reduction in the extent of this discharge. Such treatment also reduced neuroma discharge that had already gotten underway.

Sympatho-adrenal and hemodynamic responses to mental stress induced by Stroop's color word test (CWT) were examined in 12 healthy volunteers. CWT increased heart rate and blood pressures by 28 beats/min and 29/14 mmHg, on the average. The pressor response was caused by an increase in cardiac output (from 6.3 +/- 0.3 to 10.9 +/- 0.6 l/min, p less than 0.001), since systemic vascular resistance was reduced by approximately 30% during CWT. Calf vascular resistance (mainly muscle) was also reduced. At rest there was a net production of NA and a net removal of adrenaline (ADR) in the forearm tissues. About 45% of the NA in antecubital venous plasma appeared to be derived from the forearm tissues. During CWT arterial NA increased (from 1.53 +/- 0.20 to 2.13 +/- 0.15 nM, p less than 0.001), but antecubital venous NA levels remained unchanged. There was removal of ADR (about 19%) and a calculated production of NA by the lungs at rest, both of which disappeared during stress. CWT caused a "defence reaction"-like hemodynamic response with cardiac activation, but unchanged or reduced peripheral sympathetic nerve activity. This explains the lack of increase in antecubital venous NA, which is markedly influenced by sympathetic activity in the forearm tissues. Arterial plasma catecholamine measurements provide better information concerning sympatho-adrenal activity in the body as a whole than do peripheral venous measurements. Regional sympathetic activity is preferably studied by NA outflow determinations from the target organs.

It was the objective of this study to compare the efficacy of oral dexamethasone and inhaled budesonide in children hospitalized with croup, using a three-way, double blind, randomized, placebo-controlled clinical trial design. The trial was carried out in the Emergency Department Observation Ward of a tertiary pediatric hospital. The subjects for the study were 80 children (age range 5 to 158 months) who were hospitalized with croup. Children received either 2 mg of nebulised budesonide, dexamethasone syrup (0.6 mg/kg) or a placebo. Median duration of hospitalization was shorter for children treated with dexamethasone (12 hr) and budesonide (13 hr) compared to placebo (20 hr) (P < 0.03). There was no significant difference in hospitalization time between children treated with dexamethasone and budesonide. Median time to a croup score of < or = 1 was shorter for children treated with dexamethasone (2 hr) or budesonide (3 hr) compared to those who received placebo (8 hr) (P < 0.01). Croup scores for both steroid groups were significantly lower than the placebo group by 1 hr and remained so subsequently. The croup scores did not differ significantly in the 2 steroid treated groups. Six of the 30 children (20%) in the placebo group required adrenaline after the first hour compared to none of the 50 children in the steroid treated groups (P < 0.02). We conclude that oral dexamethasone and inhaled budesonide are both effective in reducing symptoms and duration of hospitalization in children with croup.

OBJECTIVE

Our study sought to compare the efficacy of adrenaline injection in combination with detachable snare versus adrenaline injection alone in the prevention of postpolypectomy bleeding in large colonic polyps.

METHODS

At the time of colonoscopy, patients with at least one colonic polyp>> or =2 cm were randomized to receive treatment either by the injection of a 1:10.000 solution of adrenaline and the position of a detachable snare followed by a conventional snare polypectomy (group A) or injection of adrenaline followed by a conventional snare polypectomy (group B). A total of 159 consecutive patients were randomly assigned to one of the above groups. Out of them, 84 patients (47 men, 37 women, mean age 61 yr) were assigned to group A and 75 (37 men, 38 women, mean age 64 yr) to group B. Early (<24 h) and late (>24 h-30 days) bleeding complications were assessed.

RESULTS

Overall bleeding complications occurred in 10/159 (6.2%) of the patients. There were two cases of bleeding in group A (2.3%), and eight in group B (10.6%) (P= 0.04). The number of early bleeding episodes was significantly reduced in group A patients (1 case) compared to that of group B (7 cases) (P= 0.02). In contrast, there was no significant difference between group A and B as far as late bleeding is concerned.

CONCLUSIONS

Our data suggest that the use of adrenaline injection in combination with detachable snare may significantly decrease the number of early postpolypectomy bleeding episodes in patients with large colonic polyps.

Administration of methoxamine (10 microM, 2 min) to perfused rat hearts increased the rate at which subsequently isolated mitochondria accumulated Ca2+. Methoxamine did not change significantly the development of delta phi with time or the basal rates of Ca2+ flux on inhibition of the uniporter with Ruthenium Red. With 200 microM-Pi, the rates of Ca2+ uptake at constant delta phi were unaffected by the small variations in endogenous [Pi] between mitochondrial preparations, and were also unaffected by changes in internal Ca2+ over the approximate range 8-43 nmol of Ca2+/mg. At low internal Ca2+ (about 8 nmol/mg of protein) the rates of Ca2+ uptake at constant delta phi were unaffected by addition of 200 microM-Pi. Under these conditions, the uniporter activity and the uniporter conductance were increased by 38-40% by methoxamine pretreatment. The endogenous Ca2+ content of mitochondria from control heart was about 1.8 nmol of Ca2+/mg of protein. Perfusion with agonist increased the Ca2+ content as follows: 10 microM-methoxamine (2 min), 48%; 1 microM-isoprenaline (2 min), 100%; 1 microM-adrenaline (2 min), 140%. The implications of the data for the adrenergic control of oxidative metabolism by intramitochondrial Ca2+ is discussed.

1. On treatment of the perfused rabbit heart with adrenaline, the total covalently bound phosphate of troponin I increased from 1.14 mol of phosphate/mol to 1.86 mol of phosphate/mol. 2. Covalently bound phosphate could be identified only in the region of the molecule of cardiac troponin I consisting of residues 1--48. 3. When 32P-labelled orthophosphate was present in the perfusion medium the phosphate at serine-20 became radioactively labelled. This residue was the only significant site of phosphorylation that could be identified. 4. The addition of adrenaline caused a 4--5-fold increase in covalently bound [32P]phosphate. Virtually all of the 32P was located at serine-20. 5. It was concluded from these studies that the extent of phosphorylation of serine-20 of cardiac troponin I increased from 30--40% in the control perfused heart to about 100% in the presence of adrenaline.