Bretylium depresses the slope of regression lines relating frequency of sympathetic nerve stimulation to magnitude of contractions of the cat nictitating membrane. In contrast, guanethidine and reserpine preferentially abolish responses to low rates of nerve stimulation and cause a roughly parallel shift of the regression lines. The hypersensitivity of the nictitating membranes of cats to intravenous adrenaline or noradrenaline is far greater after a series of small daily doses of bretylium or guanethidine than after single large doses. The maximal sensitivity produced was similar to that after postganglionic sympathetic nerve section and exceeded that produced by ganglion blockade. The development of hypersensitivity to catechol amines is accompanied by some return of responses of the nictitating membranes to sympathetic nerve stimulation despite continued daily administration of bretylium or guanethidine. In cats given bretylium daily, responses to low rates of nerve stimulation become greater than in controls unless the dose of bretylium given subcutaneously is 50 mg/kg or more. When marked hypersensitivity to catechol amines has been produced by giving bretylium or guanethidine daily for 7 or 14 days, the sympathomimetic effects of these compounds are greater. Responses to intravenous dimethylphenylpiperazinium are also increased and the results suggest that even large daily doses of adrenergic neurone blocking agents do not appreciably impair the functioning of the adrenal medulla. The pressor effects of intravenous adrenaline, noradrenaline and dimethylphenylpiperazinium iodide increase less than the corresponding nictitating membrane responses. These results are discussed in relation to tolerance to adrenergic neurone blockade, and differences between the effects of bretylium and guanethidine found in man. Bretylium and guanethidine depress the slopes of the dose-response curves for the pressor and nictitating membrane contracting effects of tyramine. When single doses or a short series of daily doses were given, guanethidine caused more depression of the slopes than did bretylium, but nevertheless large depressions of slope were found after giving bretylium daily for several weeks. The magnitude of the responses can be greater or less than in controls depending on the dose of the sympathomimetic amine, the dose of the adrenergic neurone blocking agent and the duration of its administration. The results suggest that injection of tyramine produces a progressively smaller release of adrenaline or noradrenaline during the daily administration of bretylium (or guanethidine) but that in some test situations this is more than compensated for by the development of hypersensitivity to the catechol amine released. Some corresponding changes in responses to amphetamine and ephedrine are also described.

To elucidate the mechanism of alcohol-induced atrial fibrillation (AF) we studied the heart rate variability and parameters of the adrenergic system during alcohol intake, hangover, and exercise in 6 men (mean age 43 years) prone to alcohol-induced AF, together with 6 age-matched controls. The ambulatory (15 hour) electrocardiogram was recorded and blood samples were taken for lymphocytic beta adrenoceptor, plasma catecholamine, and cyclic adenosine monophosphate (cAMP) measurements before and after alcohol intake (blood alcohol 1.5 per thousand), during hangover, and after a standardized bicycle exercise test. The beta-adrenoceptor density in lymphocytes was unchanged in the control group after alcohol intake or during hangover. Each of the AF patients had an increase in beta-adrenoceptor density after ethanol drinking (mean increase 29%, p <0.05). The hangover or exercise beta-receptor values did not differ from those in corresponding controls. Plasma adrenaline concentration tended to decrease and noradrenaline to increase after drinking and during hangover in both groups. Plasma cAMP levels were lower in patients after drinking than in controls (p <0.05). The exercise values of the adrenergic parameters were very similar in AF patients whether or not preceded by alcohol. Analysis of ambulatory electrocardiography showed a very low rate of ectopic beats in both AF patients and controls. Analysis of heart rate variability revealed a tendency toward an increase in sympathetic/parasympathetic component ratio (low-frequency/high-frequency ratio) in AF patients, but not in controls, after ethanol drinking. In conclusion, no signs of arrhythmogenic cardiac disease were detected in patients with AF to explain the tendency toward AF. Increases in beta-adrenoceptor density and low-frequency/high-frequency ratio during ethanol intoxication in patients with AF suggest an exaggerated sympathetic reaction.

Twelve non-specifically trained volunteers (aged 26.5 years, SD 3.6) performed exhausting incremental graded exercise (ST) and 1-min anaerobic cycle ergometer exercise (AnT) at 2-h intervals for the purpose of investigating beta-endorphin (beta-E) behaviour dependent on exercise intensity and anaerobic metabolism. In order to determine [beta-E], adrenocorticotropic hormone [ACTH], cortisol [C], adrenaline [A] and noradrenaline [NA] concentrations, venous blood samples were collected prior and subsequent to exercise until the 20th min of the recovery period, as well as in ST before and after exceeding the individual anaerobic threshold (THan,i). Before, during and after ST, lactate concentration, heart rate and perceived degree of exertion were also determined; after AnT maximum lactate concentration was measured. Both types of exercise led to significant increases in [beta-E], [ACTH], [A] and [NA], with levels of [beta-E] and [ACTH] approximately twice as high after ST as after AnT. The [C] increased significantly only after ST. During ST significant changes in [beta-E] and [ACTH] were measured only after exceeding THan,i. At all measuring times before and after ST and AnT both hormones correlated positively. In AnT the increases of [beta-E] and [A] demonstrated a correlation (r = 0.65; P less than 0.05). Both in AnT and ST there was a relationship between the maximum concentrations of beta-E and lactate (r = 0.63 and 0.71; each P less than 0.05). We therefore conclude that physical exercise with increasing or mostly anaerobic components leads to an increase in [beta-E], the extent correlating with the degree of lactate concentration.(ABSTRACT TRUNCATED AT 250 WORDS)

Patients with essential thrombocythemia (ET) and polycythemia vera (PV), complicated by microvascular ischemic or thrombotic events, have shortened platelet survival, increased beta-thromboglobulin, platelet factor 4, and thrombomodulin levels, and increased urinary thromboxane B2 excretion. These are all reversible by inhibition of platelet cyclooxygenase 1 with aspirin, and are therefore indicative of platelet activation and platelet-mediated thrombotic processes. The thrombotic tendency persists as long as platelet counts are above the upper limit of normal (400 x 10 (9)/L). Despite strong evidence of in vivo platelet activation, the ex vivo platelet function tests are impaired. Platelet dysfunction in ET and PV typically is characterized by a missing second-wave adrenaline aggregation, an increased adenosine diphosphate aggregation threshold, and reduced secretion products, but a normal arachidonic acid or collagen-induced aggregation. The proposed concept is that platelets in thrombocythemia (ET and PV) are hypersensitive. Due to the existing high shear stress in the microvasculature (end-arterial circulation), platelets spontaneously activate, secrete their products, form aggregates mediated by von Willebrand factor (vWF) that transiently plug the microcirculation, deaggregate, and then recirculate as exhausted defective platelets with secondary storage pool disease on ex vivo analysis. At increasing platelet counts from below to above 1000 x 10 (9)/L, the thrombotic condition changes into an overt spontaneous bleeding tendency as a result of a functional vWF deficiency that is caused by proteolysis of large vWF multimers. This is consistent with acquired type 2 von Willebrand syndrome (AvWS). AvWS is reversible by reduction of the platelet count to normal. The acquired JAK2 V617F gain of function mutation is the cause of trilinear myeloproliferative disease with the sequential occurrence of ET and PV. Heterozygous JAK2 V617F mutation with slightly increased kinase activity is enough for the induction of spontaneous megakaryopoiesis and erythropoiesis, and an increase of hypersensitive platelets is the cause of aspirin-sensitive, platelet-mediated microvascular ischemic and thrombotic complications in ET and early PV mimicking ET. Homozygous JAK2 mutation with pronounced increase of kinase activity is associated with pronounced trilinear megakaryocyte, erythroid, and granulocytic myeloproliferation, with the most frequent clinical picture of classical PV complicated by major thrombosis, in addition to the platelet-mediated microvascular thrombotic syndrome of thrombocythemia.

Grass pollen immunotherapy is effective, although efficacy must be balanced against side-effects. In a double-blind, placebo-controlled trial of 40 adult patients with summer hay fever, immunotherapy with a depot grass pollen extract (Phleum pratense, Alutard SQ) reduced symptoms and medication requirements with an acceptable minimal level of side-effects (31). The original placebo group, as well as the actively treated group, have now received active immunotherapy in an open fashion for a further 3 years. An important question was whether continued injection treatment was accompanied by maintained clinical improvement. By analysis of diary symptoms, rescue medication, and visual analogue scores during the pollen season, we show that efficacy was maintained throughout the 3-4-year study period. Clinical improvement was accompanied by a sustained and marked decrease in immediate conjunctival allergen sensitivity and a further significant decrease in the size of the allergen-induced late cutaneous response. In contrast, an initial decrease in the allergen-induced immediate cutaneous response was not maintained at 3-4 years. Of the patients, 37/40 completed the first year, 33/40 the second year, and 32/40 the third year of treatment. Patients dropped out for reasons other than the outcome of immunotherapy. During a total of 2598 injections, five immediate systemic reactions were observed, all during the induction (not maintenance) phase, and all occurred within 10 min of injection and responded promptly to adrenaline. Grass pollen immunotherapy is effective and safe, provided it is performed on carefully selected patients by trained physicians with immediate access to resuscitative measures.

OBJECTIVE

To assess the prevalence of diabetes in patients with pheochromocytoma and the probability of pheochromocytoma occurring in hypertensive patients with or without diabetes.

METHODS

A tertiary, referral hypertension department.

METHODS

We compared age, body mass index and the frequency of diabetes in 191 patients with pheochromocytoma and a random sample of 880 patients with essential hypertension. Diabetes was defined as current antihyperglycemic treatment or two fasting blood glucose concentrations>>or= 7 mmol/l. For patients with pheochromocytoma, we also recorded plasma catecholamine concentrations, the urinary excretion of metanephrines, and tumor characteristics.

RESULTS

Diabetes was present in 68 (35.6%) patients with pheochromocytoma and 192 (21.8%) patients with essential hypertension (P < 0.001). Pheochromocytoma patients with or without diabetes did not differ in body mass index, plasma noradrenaline concentration, metanephrine excretion or tumor characteristics. Age, duration of hypertension and plasma adrenaline concentration were significantly and independently associated with diabetes in patients with pheochromocytoma. They were younger, more likely to be female and had a lower body mass index than those with essential hypertension (P < 0.01). After adjustment for these three variables, the odds ratio for pheochromocytoma in hypertensive patients with diabetes was 5.5 (95% confidence interval, 3.5-8.7). For patients younger than the age of 51 years with a body mass index < 25 kg/m2, the odds ratio was 18.9 (95% confidence interval, 5.9-58.8).

CONCLUSIONS

Diabetes is present in one in three patients with pheochromocytoma. In young patients with hypertension and normal body weight, the presence of diabetes is a clinical clue to the diagnosis of pheochromocytoma.

Plasma noradrenaline (NA), adrenaline (A), and corticosterone (CS) responses to social and nonsocial stressors were studied in male members of a strain of wild-type rats, widely differing in their level of aggression. The aggressiveness was preliminarily established by measuring the latency time to attack (ALT) a male intruder in a standard resident-intruder test. Animals were then provided with a jugular vein cannula for blood sampling during stress exposure. Implanted rats were randomly assigned to 3 experimental treatments: social stress (defeat experience, SD), nonsocial stress (presentation of a shock-prod, SP) and control (animals undisturbed in their home cages, CTR). A significant correlation was found between ALT and the amount of time spent in burying the probe in SP rats: the more aggressive the animal, the higher the rate of burying behavior. SD induced a much stronger effect on plasma NA, A, and CS concentrations than SP. A significant negative correlation was found between ALT scores and values of the area under the response time curve for NA and A, in both SD and SP situations: the more aggressive the animal, the higher the catecholaminergic reactivity to the stressors. On the contrary, no evidence of a correlation between aggressiveness and plasma corticosterone responses was found, neither in SD nor in SP rats. These findings in an unselected strain of wild-type rats confirmed that an aggressive/active coping strategy is associated with a high sympathetic-adrenomedullary activation and support the concept of individual differentiation in coping styles as a coherent set of behavioral and neuroendocrine characteristics.

This year is the 50th anniversary of the introduction into clinical use of the first modern inhaler for the management of asthma--the pressurised metered-dose inhaler (pMDI). The pMDI was initially used for the administration of the non-selective beta-agonists adrenaline and isoprenaline. However, the epidemic of asthma deaths which occurred in the 1960s led to these drugs being superseded by the selective short-acting beta-agonist salbutamol, and the first inhaled corticosteroid (ICS) beclomethasone. At the same time, sodium cromoglycate was introduced, to be administered via the first dry-powder inhaler--the Spinhaler--but owing to its relatively weak anti-inflammatory action its use is now very limited. Over the last 10 years, the long-acting beta-agonists (LABAs) have become an important add-on therapy for the management of asthma, and they are now often used with ICS in a single ICS/LABA combination inhaler.

Thiol and glutathione (GSH) efflux across the sinusoidal plasma membrane in isolated perfused rat liver was stimulated by addition of hormones such as vasopressin, phenylephrine and adrenaline, whereas glucagon or dibutyryl cyclic AMP were without effect. Phenylephrine and adrenaline effects were sensitive to prazosin and phentolamine, respectively. The increase in thiol efflux was largely accounted for by an increase in GSH efflux. Thiol efflux and the hormone effects were abolished in GSH-depleted liver. Biliary GSH efflux was diminished upon hormone addition. The newly discovered hormone-dependence of GSH release across the sinusoidal plasma membrane may explain the known loss of GSH during conditions of experimental shock (traumatic or endotoxin) and stress and peripheral inflammation.

The following NEKY have been studied: 1-kynurenine (KYN), 3-hydroxyKYN (3HKYN), kynurenic (KYNA), anthranilic (ANT), 3-hydroxyANT (3HANT), quinolinic (QUIN), picolinic (PICA), xanthurenic (XAN), nicotinic (NIC) acids, 3-indole-pyruvate (IPA), nicotinamide (NAM). NEKY antagonize the central effects of precursors of serotonin (tryptophan and 5-HTP), and tryptamine as well. Seizures induced by central administration of KYN and QUIN are prevented by centrally injected dopamine and diminished by noradrenaline and adrenaline. KYN, 3HANT, PIC and NIC potentiate oxotremorine hypothermia mediated by acetylcholine. Central administration of GABA, glycine or taurine, as well as proline and melatonin, prevented seizures induced by QUIN and KYN. Behavioral inhibitory effects of these amino acids are diminished by pretreament with KYN, 3HKYN and QUIN. Elevation of concentrations of corticosteroids is resulted in rise of level of NEKY due to hormonal induction of liver tryptophan pyrrolase and brain 2,3 dioxigenase. NEKY, in their turn, activate both enzymes. Thus, a "vicious circle" is formed and it supports an elevated level of NEKY for a long time, hours and days. Long-lasting increased concentrations of NEKY in tissues can lead to significant after-effects and numerous pathogenic consequences. One can not exclude that a rise of the level of some NEKY, e.g. KYNA, IPA, PIC and XAN, may play an "adaptogenic" role in stress antagonizing some pathologic effects of KYN and QUIN, e.g. anxiogenic, neurotoxic and proconvulsive. It has been demonstrated that the excitatory NEKY, KYN, 3HKYN, QUIN, possess an anxiogenic activity in the standard animal models of anxiety. NEKY with opposite neuroactivities, namely KYNA, IPA, PICA and XAN, have a pharmacological profile of anxiolytics and antagonize both anxiogenic NEKY and standard anxiogens, like caffeine, pentylenetetrazole and yohimbine. Major emphasis is made on KYN as a putative endogenous anxiogen. Studies on the interaction of NEKY with other endogenous metabolites involved in anxiety (beta-phenylethylamine, cholecystokynine, melatonin) are in progress.

Dietary preferences influence basal human metabolism and gut microbiome activity that in turn may have long-term health consequences. The present study reports the metabolic responses of free living subjects to a daily consumption of 40 g of dark chocolate for up to 14 days. A clinical trial was performed on a population of 30 human subjects, who were classified in low and high anxiety traits using validated psychological questionnaires. Biological fluids (urine and blood plasma) were collected during 3 test days at the beginning, midtime and at the end of a 2 week study. NMR and MS-based metabonomics were employed to study global changes in metabolism due to the chocolate consumption. Human subjects with higher anxiety trait showed a distinct metabolic profile indicative of a different energy homeostasis (lactate, citrate, succinate, trans-aconitate, urea, proline), hormonal metabolism (adrenaline, DOPA, 3-methoxy-tyrosine) and gut microbial activity (methylamines, p-cresol sulfate, hippurate). Dark chocolate reduced the urinary excretion of the stress hormone cortisol and catecholamines and partially normalized stress-related differences in energy metabolism (glycine, citrate, trans-aconitate, proline, beta-alanine) and gut microbial activities (hippurate and p-cresol sulfate). The study provides strong evidence that a daily consumption of 40 g of dark chocolate during a period of 2 weeks is sufficient to modify the metabolism of free living and healthy human subjects, as per variation of both host and gut microbial metabolism.

Five years have passed since the Japanese Pediatric Guideline for Food Allergy (JPGFA) was first revised in 2011 from its original version. As many scientific papers related to food allergy have been published during the last 5 years, the second major revision of the JPGFA was carried out in 2016. In this guideline, food allergies are generally classified into four clinical types: (1) neonatal and infantile gastrointestinal allergy, (2) infantile atopic dermatitis associated with food allergy, (3) immediate-type of food allergy (urticaria, anaphylaxis, etc.), and (4) special forms of immediate-type of food allergy such as food-dependent exercise-induced anaphylaxis and oral allergy syndrome (OAS). Much of this guideline covers the immediate-type of food allergy that is seen during childhood to adolescence. Infantile atopic dermatitis associated with food allergy type is especially important as the onset of most food allergies occurs during infancy. We have discussed the neonatal and infantile gastrointestinal allergy and special forms of immediate type food allergy types separately. Diagnostic procedures are highlighted, such as probability curves and component-resolved diagnosis, including the recent advancement utilizing antigen-specific IgE. The oral food challenge using a stepwise approach is recommended to avoid complete elimination of causative foods. Although oral immunotherapy (OIT) has not been approved as a routine treatment by nationwide insurance, we included a chapter for OIT, focusing on efficacy and problems. Prevention of food allergy is currently the focus of interest, and many changes were made based on recent evidence. Finally, the contraindication between adrenaline and antipsychotic drugs in Japan was discussed among related medical societies, and we reached an agreement that the use of adrenaline can be allowed based on the physician's discretion. In conclusion, this guideline encourages physicians to follow the principle to let patients consume causative foods in any way and as early as possible.

OBJECTIVE

To assess the variability of synovial histology, immunohistology, and cytokine mRNA expression at different sites within the knee joints of subjects with rheumatoid arthritis receiving slow acting antirheumatic drugs. The effects of intraarticular bupivacaine and adrenaline, and a comparison of synovial fluid cell and synovial membrane cytokine expression, were also investigated.

METHODS

Arthroscopically directed synovial biopsies were taken at 3 or 4 predetermined sites from the knee joints of 11 patients. Histology for synovial lining layer, sublining cellularity and vascularity, and immunohistology for T cells, T cell subsets, and macrophages were assessed. Messenger RNA expression of interleukins 1beta, 2, 4, 6, 8, 10, granulocyte-monocyte colony stimulating factor, tumor necrosis factor-alpha, and interferon-gamma was detected using the reverse transcription/polymerase chain reaction technique.

RESULTS

Synovial histology, immunohistology, and cytokine mRNA expression did not vary significantly. CD8 cell immunohistology was variable. Intraarticular bupivacaine and adrenaline did not change synovial characteristics. Synovial fluid cell and membrane cytokine expression did not match in 35% of comparisons.

CONCLUSIONS

Biopsies from the suprapatellar pouch, medial gutter, and cartilage-pannus junction will provide a representative sample of synovial membrane pathology in patients with rheumatoid arthritis.

The metabolism of phosphatidate in rat parotid acinar cells was investigated, particularly with regard to the actions of agonists known to act by mobilizing Ca2+. When cells were incubated in medium containing 10 microM-[32P]Pi, phosphatidate was rapidly labelled, approaching an apparent steady-state with a half-time of approx. 20 min. Methacholine provoked a more than doubling of phosphatidate radioactivity, which was reversed by the muscarinic antagonist atropine. These results suggest that phosphatidate labels to near steady-state rapidly and that in cells prelabelled for 60 min the increase in radioactivity induced by agonists probably reflects net synthesis rather than an increase in specific radioactivity. Phosphatidate synthesis in response to methacholine was rapid and occurred, within the resolution of a few seconds, with no measurable latency. Adrenaline and substance P also stimulated phosphatidate synthesis but both agonists were less efficacious than methacholine. A Ca2+ ionophore, ionomycin, did not provoke phosphatidate synthesis. By using a protocol that eliminates the receptor-regulated Ca2+ pool, it was demonstrated that methacholine-induced phosphatidate formation does not come about as a consequence of Ca2+ influx nor of Ca2+ release. These results indicate that the phosphatidate synthesis response has characteristics compatible with its previously suggested role as a primary mediator of membrane Ca2+-gating.

Exposure to tobacco products is responsible for the majority of all human cancers. Nicotinic acetylcholine receptors (nAChRs) were identified as early as 1989 as important regulators of cancer cells. In analogy to its function in the brain, the homomeric α7nAChR has "accelerator function" on the most common human cancers by stimulating the synthesis and release of excitatory neurotransmitters (serotonin in small cell lung cancer, noradrenaline/adrenaline in most other cancers) that drive cell proliferation, migration, angiogenesis, neurogenesis and metastasis while inhibiting apoptosis. These effects are not only caused by α7nAChRs expressed in cancer cells but also by α7nAChRs in ganglia and nerves of the sympathetic part of the autonomic nervous system that release noradrenaline/adrenaline into the tumor environment. In the nervous system, α7nAChR protein undergoes paradoxical upregulation without concomitant desensitization upon chronic exposure to nicotine. The same phenomenon has been reported for α7nAChR expressed in cancer cells of the lungs and pancreas where chronic nicotine or nicotine-derived nitrosamines upregulated the receptor protein, resulting in hyperactivity of its effectors. Strategies that target the α7nAChR for cancer intervention are highly promising but should aim to reduce signaling downstream of the receptor rather than blocking the receptor because of its numerous vital functions in the mammalian organism.

The adrenal medulla is composed principally of groups of adrenergic and noradrenergic chromaffin cells, with minor populations of small intensely fluorescent cells and ganglionic neurones. Different molecular stimuli evoke distinct secretory events in the gland, involving the release of either adrenaline or noradrenaline together with various neuroactive peptides. The nature of the secretory response can be controlled at a central level or regulated locally within the gland. Specific innervation patterns to the different types of chromaffin cell have been implicated in central regulatory mechanisms, while several explanations for regulating secretion locally have been proposed. The differential distribution of various types of receptors between cell phenotypes, such as muscarinic or nicotinic acetylcholine receptors, histamine receptors, angiotensin receptors and different classes of opiate receptors between the two principal chromaffin cell populations could be involved in local control. In addition exocytosis parameters could be modulated differently in adrenergic and noradrenergic cells by phenotype-specific mechanisms, possibly involving molecules like Growth Associated Protein-43, Synaptosomal Associated Protein-25 isoforms or the p11 annexin subunit. The distribution of the various types of calcium channels is also known to vary between chromaffin cell subtypes. This short review examines possible ways in which specific innervation patterns in the adrenal gland could be programmed and discusses exocytosis mechanisms that could differ between chromaffin cell phenotypes. Data reviewed here suggest that the adrenal medulla should no longer be viewed as a homogeneous entity but as consisting of an ensemble of individual cell subpopulations each with a distinct secretory response that could in part reflect its local history.

During strenuous exercise, extracellular K(+) ([K(+)](o)) is increased, which potentially can reduce muscle excitability and force production. In addition, exercise leads to accumulation of lactate and H(+) and increased levels of circulating catecholamines. Individually, reduced pH and increased catecholamines have been shown to counteract the depressing effect of elevated K(+). This study examines (i) whether the effects of addition of lactic acid and adrenaline on the excitability of isolated muscles are caused by separate mechanisms and are additive and (ii) whether the effect of adding lactic acid or increasing CO(2) is related to a reduction of intra- or extracellular pH. Rat soleus muscles were incubated at a [K(+)](o) of 15 mM, which reduced tetanic force by 85%. Subsequent addition of 20 mM lactic acid or 10(-5) M adrenaline led to a small recovery of force, but when added together induced an almost complete force recovery. Compound action potentials showed that the force recovery was associated with recovery of muscle excitability. The improved excitability after addition of adrenaline was associated with increased Na(+)-K(+) pump activity resulting in hyperpolarization and an increase in the chemical Na(+) gradient. In contrast, addition of lactic acid had no effect on the membrane potential or the Na(+)-K(+) pump activity, but most likely increased excitability via a reduction in intracellular pH. It is concluded that the protective effects of acidosis and adrenaline on muscle excitability and force took place via different mechanisms and were additive. The results suggest that circulating catecholamines and development of acidosis during exercise may improve the tolerance of muscles to elevated [K(+)](o).

This study investigated the effects on ovine fetal basal cardiovascular and endocrine functions of fetal intravenous dexamethasone treatment, resulting in circulating concentrations that were one-fifth of the values measured clinically in human infants following maternal antenatal glucocorticoid therapy. Between 117-120 days gestation (dGA; term: ca 145 dGA), 26 Welsh Mountain sheep fetuses were surgically prepared under general anaesthesia with vascular catheters and a Transonic flow probe positioned around a femoral artery. At 125 +/- 1 dGA, fetuses were infused with dexamethasone (2.06 +/- 0.13 microg kg(-1) h(-1) i.v.; n = 13) or saline (n = 13) for 48 h. Daily fetal arterial blood samples were taken and cardiovascular data were recorded continuously (data acquisition system). Pressor, vasoconstrictor and chronotropic responses to exogenously administered doses of phenylephrine, angiotensin II and arginine vasopressin (AVP) were determined at 124 +/- 1 (pre-infusion), 126 +/- 1 (during infusion) and 128 +/- 1 (post-infusion) dGA. Fetal cardiac baroreflex curves were constructed using peak pressor and heart rate responses to phenylephrine. Dexamethasone treatment elevated fetal mean arterial blood pressure by 8.1 +/- 1.0 mmHg (P < 0.05), increased femoral vascular resistance by 0.65 +/- 0.12 mmHg (ml min(-1))(-1) (P < 0.05), depressed plasma noradrenaline concentrations and produced a shift in set-point, but not sensitivity, of the cardiac baroreflex (P < 0.05). Elevations in fetal arterial blood pressure, but not femoral vascular resistance and the shift in baroreflex set-point, persisted at 48 h following dexamethasone treatment. By 48 h following dexamethasone infusion, basal plasma noradrenaline concentration was restored, whilst plasma adrenaline and neuropeptide Y (NPY) concentrations were enhanced, compared with controls (P < 0.05). Fetal dexamethasone treatment did not alter the fetal pressor or femoral vasoconstrictor responses to adrenergic, vasopressinergic or angiotensinergic agonists. These data show that fetal treatment with low concentrations of dexamethasone modifies fetal basal cardiovascular and endocrine functions. Depending on the variable measured, these changes may reverse, persist or become enhanced by 48 h following the cessation of treatment.

The role and value of endoscopic retrograde cholangiopancreatography (ERCP) in the pediatric age group is not well established, because pancreatic and biliary diseases are less common in children. This however is not the case in areas like the Eastern Province of Saudi Arabia where sickle cell disease (SCD) and other hemoglobinopathies are common, with increased frequency of cholelithiasis and choledocholithiasis. The purpose of this study was to evaluate the indications, findings, safety and therapies of ERCP in children. One hundred and twenty five children had diagnostic and/or therapeutic ERCP as part of their management at our hospital. Their medical records were reviewed for: age at diagnosis, sex, Hb electrophoresis, indication for ERCP, findings, therapy and complications. There were 77 males and 48 females. Their age at presentation ranged from 5-18 year (mean 13.25 year). The majority of them had sickle cell disease (77.6%). The indications for ERCP were: obstructive jaundice (67.2%), recurrent biliary colic with or without jaundice (10.4%), acute and chronic pancreatitis (7.2%), postoperative bile leak (2.4%), cholangitis with obstructive jaundice (2.4%), hepatitis of unknown etiology (3.2%), cirrhosis of unknown etiology (4%), thalassemia with jaundice (0.8%), hemobilia (0.8%), acute cholecystitis with jaundice (0.8%), and sickle cell disease with ulcerative colitis and obstructive jaundice (0.8%). In six children, ERCP was done following laparoscopic cholecystectomy. ERCP was carried out under sedation in 91 (72.8%) children and under general anesthesia in 34. It was successful in 121 (96.8%) children while cannulation of the Ampulla failed in four. ERCP was normal in 43 children, but eight of them showed evidence of recent stone passage and in six, there were gallstones. In the remaining children, ERCP revealed: normal CBD with stones (18 patients), dilated CBD with stones (17 patients), dilated CBD without stones (19 patients), dilated biliary tree with stones (10 patients), dilated biliary tree without stones (six patients), bile leak (two patients), dilated biliary tree with stones and choledocho-duodenal fistula (one patient), choledochal cyst (two patients), septate gallbladder (one patient), normal ERCP with multiple pancreatic cysts (one patient) and biliary stricture (one patient). The following procedures were carried out: 35 had endoscopic sphincterotomy and stone extraction, 20 had endoscopic sphincterotomy, four had CBD stenting, one underwent removal of a stent, two had insertion of a nasobiliary tube and one had biliary endoprosethesis. There was no mortality. One had bleeding from the site of sphincterotomy which stopped after adrenaline injection. Four patients (3.2%) developed transient mild pancreatitis which settled conservatively. ERCP in the pediatric age group is safe both as a diagnostic and therapeutic procedure. ERCP can provide valuable information which aid in the diagnosis of biliary and pancreatic diseases in children as well as therapy with the technical feasibility of endoscopic sphincterotomy. This is specially so in the era of laparoscopic cholecystectomy, where ERCP should be the treatment of choice in children with CBD stones who are going or have previously undergone laparoscopic cholecystectomy.

Music therapy (MT) has been used in geriatric nursing hospitals, but there has been no extensive research into whether it actually has beneficial effects on elderly patients with cerebrovascular disease (CVD) and dementia. We investigated the effects of MT on the autonomic nervous system and plasma cytokine and catecholamine levels in elderly patients with CVD and dementia, since these are related to aging and chronic geriatric disease. We also investigated the effects of MT on congestive heart failure (CHF) events.Eighty-seven patients with pre-existing CVD were enrolled in the study. We assigned patients into an MT group (n = 55) and non-MT group (n = 32). The MT group received MT at least once per week for 45 minutes over 10 times. Cardiac autonomic activity was assessed by heart rate variability (HRV). We measured plasma cytokine and catecholamine levels in both the MT group and non-MT group. We compared the incidence of CHF events between these two groups. In the MT group, rMSSD, pNN50, and HF were significantly increased by MT, whereas LF/HF was slightly decreased. In the non-MT group, there were no significant changes in any HRV parameters. Among cytokines, plasma interleukin-6 (IL-6) in the MT group was significantly lower than those in the non-MT group. Plasma adrenaline and noradrenaline levels were significantly lower in the MT group than in the non-MT group. CHF events were less frequent in the MT group than in the non-MT group (P < 0.05). These findings suggest that MT enhanced parasympathetic activities and decreased CHF by reducing plasma cytokine and catecholamine levels.

1. The chronotropic and inotropic responses of the denervated dog heart to intravenous infusions of noradrenaline, adrenaline and isoprenaline were studied.2. The maximum rate of rise of pressure in the left ventricle of the heart, (dP/dt max) measured at a constant heart rate and mean systemic arterial pressure during each series of infusions, was used as an index of inotropic changes (Furnival, Linden & Snow, 1970).3. The order of potency of the catecholamines in producing both chronotropic and inotropic effects was isoprenaline>> adrenaline>> noradrenaline.4. For the same increase in heart rate produced by an infusion of a catecholamine, noradrenaline caused a greater inotropic effect than adrenaline, which in turn caused a greater increase than isoprenaline.5. The chronotropic and inotropic effects of noradrenaline were potentiated by an intravenous injection of cocaine HCl (5 mg/kg), whereas those of isoprenaline were unchanged.6. The relative difference between the responses to noradrenaline and isoprenaline was abolished by an intravenous injection of cocaine HCl.7. It is concluded that the different relative chronotropic and inotropic effects of isoprenaline and noradrenaline are due to the greater uptake of noradrenaline by sympathetic nerve endings in the sinu-atrial node than in the muscle of the left ventricle.

Rainbow trout,Oncorhynchus mykiss, were exercise-trained for 18 hours per day over 28 days at water velocities up to 60% of their measured Ucrit. Anin situ perfused heart preparation was used to compare maximum cardiac performance between control and trained fish. Trained fish had a larger stroke volume at a given filling pressure, as well as an 18% higher cardiac output and a 25% greater maximum power output. These observations indicate that exercise training in rainbow trout improved maximum cardiac performance. Adrenaline produced positive inotropic and chronotropic effects on the perfused heart, but exercise training did not alter these stimulatory effects. Maximal activities of citrate synthase (CS), B-hydroxyacyl CoA dehydrogenase (HOAD), glutamate dehydrogenase (GDH) and carnitine palmitoyl transferase (CPT) were measured in cardiac and skeletal muscles. CS, HOAD and GDH increased in red and white skeletal muscle as a result of training. Training also increased GDH activity in the endocardium and epicardium, and increased HOAD in the epicardium. While the training regime did not result in a statistically significant increase in Ucrit and produced a decrease in the condition factor of the fish, other training effects were clearly evident. Furthermore, significant correlations were observed between Ucrit and the maximal activities of GDH and HOAD.

The objective of this study was to evaluate retention of ALS knowledge and performance among anaesthesiologists, who, in Italy, respond to in-hospital emergencies as team leaders.

METHODS

47 anaesthesiologists (23 consultants and 24 residents) were invited at one weeks notice to attend a re-evaluation session, 6 months after successful completion of an ERC ALS course. Knowledge retention was assessed by a multiple choice question test, and skills and management by evaluation of performance as team leader in one of the six standardized CAStest scenarios. During the performance, the timeliness of first defibrillation, completion of the three shock sequence, adrenaline (epinephrine) administration and intubation were recorded. Results were compared between consultants and residents.

RESULTS

Compared to the results at the end of the ALS course, the percent of correct answers to the multiple choice question test decreased from 85.89 +/- 5.28% to 79.45 +/- 6.62% (P < 0.001), the number of candidates achieving a pass performance decreased from 47/47 to 30/47 (P < 0.001). Time to first defibrillation was 73.38 +/- 18.72 s, time for completion of the third defibrillation was 113.04 +/- 35.58 s and subsequent ALS interventions were very delayed or forgotten. Comparison between consultants and residents showed that consultants retained knowledge information better, skills decreased comparably in both groups and residents performed tasks faster.

CONCLUSIONS

The significant decay of ALS skills 6 months post-ALS recorded among anaesthesiologists supports the need for periodical reinforcement during intervals before recertification.

In sheep, direct fetal treatment with dexamethasone alters basal cardiovascular function and the cardiovascular response to acute hypoxaemia. However, in human clinical practice, dexamethasone is administered to the mother, not to the fetus. Hence, this study investigated physiological responses to acute hypoxaemia in fetal sheep during and following maternal treatment with dexamethasone in doses and at dose intervals used in human clinical practice. Under anaesthesia, 18 fetal sheep were instrumented with vascular and amniotic catheters, a carotid flow probe and a femoral flow probe at 118 days gestation (term ca 145 days). Following 6 days recovery at 124 days gestation, 10 ewes received dexamethasone (2 x 12 mg daily i.m. injections in saline). The remaining animals were saline-injected as age-matched controls. Two episodes of hypoxaemia (H) were induced in all animals by reducing the maternal F(IO2)for 1 h (H1, 8 h after the second injection; H2, 3 days after the second injection). In fetuses whose mothers received saline, hypoxaemia induced significant increases in fetal arterial blood pressure, carotid blood flow and carotid vascular conductance and femoral vascular resistance, significant falls in femoral blood flow and femoral vascular conductance and transient bradycardia. These cardiovascular responses were accompanied by a fall in arterial pH, increases in blood glucose and blood lactate concentrations and increased plasma concentrations of catecholamines. In fetuses whose mothers were treated with dexamethasone, bradycardia persisted throughout hypoxaemia, the magnitude of the femoral vasoconstriction, the glycaemic, lactacidaemic and acidaemic responses and the plasma concentration of neuropeptide Y (NPY) were all enhanced during H1. However, during H2, all of these physiological responses were similar to saline controls. In dexamethasone fetuses, the increase in plasma adrenaline was attenuated during H1 and the increase in carotid vascular conductance during hypoxaemia failed to reach statistical significance both during H1 and during H2. These data show that maternal treatment with dexamethasone in doses and intervals used in human obstetric practice modified the fetal cardiovascular, metabolic and endocrine defence responses to acute hypoxaemia. Furthermore, dexamethasone-induced alterations to these defences depended on whether the hypoxaemic challenge occurred during or following maternal dexamethasone treatment.