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Background: Mortality data at the population level are often aggregated in age classes, for example 5-year age groups with an open-ended interval for the elderly aged 85+. Capturing detailed age-specific mortality patterns and mortality time trends from such coarsely grouped data can be problematic at older ages, especially where open-ended intervals are used.Methods: We illustrate the penalized composite link model (PCLM) for ungrouping to model cancer mortality surfaces. Smooth age-specific distributions from data grouped in age classes of adjacent calendar years were estimated by constructing a two-dimensional regression, based on B-splines, and maximizing a penalized likelihood. We show the applicability of the proposed model, analysing age-at-death distributions from cancers of all sites in Denmark from 1980 to 2014. Data were retrieved from the Danish Cancer Society and the Human Mortality Database.Results: The main trends captured by PCLM are: (i) a decrease in cancer mortality rates after the 1990s for ages 50-75; (ii) a decrease in cancer mortality in later cohorts for young ages, especially, and very advanced ages. Comparing the raw data by single year of age, with the PCLM-ungrouped distributions, we clearly illustrate that the model fits the data with a high level of accuracy.Conclusions: The PCLM produces detailed smooth mortality surfaces from death counts observed in coarse age groups with modest assumptions, that is Poisson distributed counts and smoothness of the estimated distribution. Hence, the method has great potential for use within epidemiological research when information is to be gained from aggregated data, because it avoids strict assumptions about the actual distributional shape.

We studied Heg lnc RNA and Cdk mRNA in mononuclear cells in untreated and treated patient with Graves disease and in normal subjects Heg was inversely correlated with TRAb in untreated patients and inversely correlated with CD mRNA in treated patients and in normal subjects These and other findings suggest that endogenous Heg may reduce expression of CD mRNA and thereby reducing inflammation and autoantibody levels The concentration of Cdk mRNA decreased during Thiamazole treatment Concentrations of TRAb decreased correspondingly Conclusions These and other findings indicate that Heg lnc RNA and Cdk have an effect on autoantibody levels achieved without affecting the risk of developing autoimmune disease Our results also support the hypothesis that inhibition of Cdk or CK by new drugs may inhibit the production of autoantibodies and autoimmunity in the organism

To investigate how fluid shifts, blood pressure and systemic vascular resistance adapt to long duration (3-6 months) spaceflight.

We have previously shown that a long noncoding RNA transcript Heg is negatively correlated with TSH receptor autoantibodies (TRAb) in patients with untreated Graves' disease and with CD14 mRNA in treated patients and controls. Thus patients with high concentrations of Heg RNA have low levels of TRAb or CD14 mRNA, respectively. Here we show that an additional factor, gene expression of Cdk1 in mononuclear cells, is positively related to concentrations of TRAb in patients with untreated Graves' disease. Cdk1 mRNA is very important for regulation of cell cycle activity. It is well known that TRAb decrease significantly during treatment with antithyroid drugs. This decrease during treatment cannot be explained by Heg RNA, which remains unchanged. Cdk1 mRNA decreased significantly during treatment to values below values obtained in normal subjects. Thus both Heg RNA and Cdk1 mRNA may influence the level of TSH receptor autoantibodies but by different mechanisms.

Approximately 10% of the pheochromocytomas and 20% of the paragangliomas are malignant with poor survival. As the biological behaviour of these tumours cannot be predicted with certainty from pathology the diagnosis of malignancy is difficult. Genetic testing is gaining impact as mutations in the tumour suppressor gene Von Hippel-Lindau and the mitochondrial succinate dehydrogenase enzyme complex subunit B (SDHB) are associated with malignancy. Excess release of catecholamines is characteristic for pheochromocytomas. High levels of chromogranin A, that is co-stored and co-secreted with catecholamines, may indicate tumour mass and malignancy and can be used to monitor response and relapse. The secretory and non-secretory tumours can be visualised with functional (specific and non-specific) imaging as SPECT and PET using ¹²³I-MIBG, somatostatin analogues, ¹⁸F-DOPA, and ¹⁸F-FDG. These modalities are recommended in patients with extra-adrenal and suspected metastatic/malignant disease, in case of distorted post-operative anatomy, and when suspected recurrence. The sensitivities of ¹²³I-MIBG scintigraphy or ¹⁸F-DOPA PET are relatively low in SDHB mutated tumours, but high using ¹⁸F-FDG. Specific PET imaging with somatostatin analogues generally has high sensitivity in malignant disease. There are no curative therapeutic options for malignant, metastatic pheochromocytomas/paragangliomas, wherefore consolidation of quality of life is essential. Adjuvant radionuclide treatment with beta-emitting isotopes coupled to MIBG or somatostatin analogues have shown response in approximately 30%. Chemotherapy is restricted to patients not accessible for surgery and resistant to radionuclide therapy. Novel targeted therapies, which mainly through a cytostatic effect interfere with specific targeted molecules needed for carcinogenesis and tumour growth show encouraging results.

Blood glucose, serum insulin, growth hormone and free fatty acids (FFA) have been measured in eight young healthy subjects after oral glucose loads of 25, 50, 100 and 200 g. While the blood glucose areas only quadrupled, the insulin areas rose by a factor of 16 lhrough the eightfold increase in oral glucose load. In the early part of the tests blood glucose was the same after high and low doses, while serum insulin was much higher after large doses. The significance of the 1/G ratio in oral glucose tolerance tests is discussed in the light of the results. The serum growth hormone suppres- sion phase increased with increasing glucose loads in male as well as in female subjects. In female subjects, however, this regular pattern was obscured by inter- mittent peaks. The serum FFA suppression phase also in- creased its glucose loads increased. Serum FFA patterns were identical in male and female subjects.

A study of blood flow in the anterior tibial muscle was performed in a series of 75 young and middle-aged diabetics. Only three of the patients had symptoms and signs of peripheral vascular insufficiency in the legs. Peak muscular flow after maximal work during ischaemia was reduced in the diabetic patients and decreased with increasing duration of diabetes. Medial calcification of the arteries was common, and it was possible to demonstrate that the decrease in maximal blood flow with increasing duration of diabetes was associated with the presence of arterial calcification. The latency of peak flow was reduced in the diabetics, as has been previously observed by other authors.

Urinary excretion of prostaglandin E2 (PGE2) and F2 alpha (PGF2 alpha), plasma concentrations of renin (PRC), aldosterone (PAC), noradrenaline (PNA) and adrenaline (PA) were determined in the third trimester of pregnancy, 5 days and 3 months after delivery in preeclampsia and normotensive pregnant and non-pregnant control subjects. PGE2 was higher in pregnant control subjects than in non-pregnant subjects, but reduced to non-pregnant level in preeclampsia. PGF2 alpha was the same in preeclampsia and normotensive pregnancy but higher than in the non-pregnant group. PRC and PAC were increased during pregnancy, but considerably lesser in preeclampsia than during normotensive pregnancy. PNA and PA were the same in all three groups. All parameters were normal 3 months after delivery. There were no correlations between any of the hormones and blood pressure in any of the groups. PGE2 was positively correlated to PRC. The lack of renal PGE2 in preeclampsia might be responsible for the decrease in renal blood flow and sodium excretion, and the changes in PRC and PAC are supposed to be secondary to changes in PGE2. It is hypothesised that preeclampsia is a state of prostaglandin deficiency.

The sympathetic nervous system is of major importance for the regulation of several physiological functions. Drugs which inhibit the actions of catecholamines and adrenergic drugs are used in the treatment of many clinical disorders. The potential role of catecholamines in a number of human diseases has, however, until recent years been studied to a limited extent only due to lack of methods for quantitation of sympathetic nervous activity. After the development of enzymatic isotope-derivative assays, reliable measurements of noradrenaline and adrenaline in plasma became available. Studies in man have shown that plasma noradrenaline is an index of sympathetic nervous activity. The present survey deals with sympathetic nervous activity and plasma adrenaline in a number of clinical disorders viz. arterial hypertension, duodenal ulcer, thyrotoxicosis, diabetes mellitus and ketotic hypoglycemia.

Objective To investigate endogenous cerebrospinal fluid catecholamines in Parkinson's disease. Material and methods Basal concentrations of free norepinephrine (NE), dopamine (DA), epinephrine (E), 3,4-dihydroxyphenylacetic acid (DOPAC) and 3,4-dihydroxyphenylalanine (DOPA) in cerebrospinal fluid (csf) and plasma were measured using reverse-phase HPLC with electrochemical detection in 16 patients with Parkinson's disease and 21 control patients with low back pain. Results Parkinsonian patients had significantly decreased values of csf NE and DOPAC, the strong relationship between plasma and csf NE was disrupted and neither was there any age related increase of plasma NE. In l-DOPA treated patients plasma DA and DOPA concentrations were raised and csf DOPAC values were inversely related to severity of disease (Hoehn and Yahr score). Csf E concentrations were also reduced in parkinsonian patients whereas csf DA concentrations were unchanged. Csf DOPA concentrations were insignificantly decreased in parkinsonian patients. Conclusions These results point towards a diffuse neuronal dysfunction in Parkinson's disease and indicate that lumbar csf NE and csf DOPAC are of central nervous origin.

Udgivelsesdato: maj 2006 Patients with untreated heart failure (HF) exhibit a blunted hemodynamic and neuroendocrine response to a high sodium intake, leading to excessive sodium and water retention. However, it is not known whether this is the case for patients with compensated HF receiving angiotensin-converting enzyme inhibitors and beta-adrenoreceptor blockers. Therefore, we determined the hemodynamic and neuroendocrine responses to 1 wk of a low-sodium diet (70 mmol/day) and 1 wk of a high-sodium diet (250 mmol/day) in 12 HF patients and 12 age-matched controls in a randomized, balanced fashion. During steady-state conditions, hemodynamic and neuroendocrine examinations were performed at rest and during bicycle exercise. In seated HF patients, high sodium intake increased body weight (1.6 +/- 0.4%), plasma volume (9 +/- 2%), cardiac index (14 +/- 6%), and stroke volume index (21 +/- 5%), whereas mean arterial pressure was unchanged. Therefore, the total peripheral resistance decreased by 10 +/- 4%. Similar hemodynamic changes were observed during an incremental bicycle exercise test. Plasma concentrations of angiotensin II and norepinephrine were suppressed, whereas plasma pro-B-type natriuretic peptide remained unchanged. In conclusion, high sodium intake was tolerated without any excessive sodium and water retention in medically treated patients with compensated HF. The observation that high sodium intake improves cardiac performance, induces peripheral vasodilatation, and suppresses the release of vasoconstrictor hormones does not support the advice for HF patients to restrict dietary sodium.

Udgivelsesdato: april 2006 The present study attempts to assess the efficacy combination therapy for heart failure. Genuine dose-response studies on combination therapy are not available and published studies involved adding one drug on top of 'usual treatment'. Sixteen different dosage combinations of trandolapril and bumetanide was tested in a double blind, double placebo-controlled, randomized, multiple cross-over study in a 16 times six balanced incomplete Latin square design. Patients reported optimal quality of life on the sub maximal dose bumetanide. Bumetanide decreased left ventricular function and increased heart rate and plasma noradrenaline in a dose dependent manner. Doses of bumetanide of more than 0.5 mg, given twice daily significantly decreased the quality of life and increased diuresis. Weight loss was maximal on 0.5 mg bumetanide twice daily. Trandolapril significantly reduced systolic blood pressure with the maximal effect at 0.5 mg daily. Both drugs significantly increased renin concentration with a significant potentiating interaction. It was not possible to detect beneficial effects of combination therapies. The optimal dosage of Bumetanide appeared to be 0.5 mg twice daily based on its effect on quality of life and weight loss. Estimated by the reduction in systolic blood pressure the optimal dosage of Trandolapril appeared to be 0.5 mg once daily. CONCLUSIONS: It appears that patients should be given less than the usually recommended dosages. Patients may be treated with a low dose loop diuretic, if signs of water retention are present or if symptomatic relief is desired.

Systolic left ventricular function was examined by radionuclide ventriculography in 12 habitual smokers with known or suspected ischaemic heart disease, aged 33-69 years, before, during, and after smoking of two cigarettes in a row and was repeated on a non-smoking control day. Plasma concentrations of adrenaline, noradrenaline, renin, and angiotensin II were determined on the smoking day, before and immediately after smoking. During smoking, there were significant increases in heart rate (+27%), rate-pressure product (+23%), and cardiac output (+14%) in the face of a significant increase in left ventricular end-systolic volume (+5%) and significant decreases in ejection fraction (-6%) and stroke volume (-8%). Blood pressure was virtually unchanged, and total peripheral resistance remained constant. Plasma adrenaline increased by 100%, renin decreased by 21%, and noradrenaline and angiotensin II did not change. The humoral changes were not correlated to changes in any of the haemodynamic variables. Areas of myocardial hypokinesis emerged or widened during smoking in 11 of 12 patients. Thus, in patients with known or suspected ischaemic heart disease, smoking was associated with an acute decrease in systolic ventricular function and development of widespread hypokinesis despite adrenaline stimulation.

Angiotensin II is synthesized locally in various tissues; however, the role of interstitial angiotensin II in the regulation of regional metabolism and tissue perfusion is not clear. We characterized the effect of interstially applied angiotensin II in skeletal muscle and subcutaneous adipose tissue of young, normal-weight, healthy subjects by using the microdialysis technique. Furthermore, we tested the hypothesis that the effect of interstitial angiotensin II is modulated by nitric oxide. Tissues were perfused with 0.01, 0.1, and 1 μmol/L angiotensin II in the presence of the l - or d -isomer of N G -nitro-arginine-methyl ester (L- or D-NAME), the effective and noneffective isomer, respectively, for blocking nitric oxide synthase. Dialysate ethanol, glycerol, glucose, lactate, and pyruvate concentrations were measured to assess changes in blood flow (ethanol dilution technique), lipolysis, and glycolysis, respectively. Baseline blood flow and dialysate concentrations of the metabolites were similar with L- and D-NAME in both tissues. Blood flow and dialysate glucose and lactate did not change significantly in both tissues during perfusion with angiotensin II. Dialysate glycerol dose-dependently increased in adipose tissue ( P P P P

The hypothesis was tested that suppression of generation of ANG II is one of the mechanisms of the water immersion (WI)-induced natriuresis in humans. In one protocol, eight healthy young males were subjected to 3 h of 1) WI (WI + placebo), 2) WI combined with ANG II infusion of 0.5 ng · kg−1· min−1(WI + ANG II-low), and 3) a seated time control (Con). In another almost identical protocol, 7–10 healthy young males were investigated to delineate the tubular site(s) of action of ANG II by the lithium clearance method (CLi) and were on an additional fourth study day subjected to infusion of ANG II at a rate of 1.5 ng · kg−1· min−1(WI + ANG II-high). During WI + placebo, plasma concentration of ANG II decreased from 16 ± 2 to 8 ± 1 pg/ml ( P < 0.05) and renal sodium excretion increased from 104 ± 15 to 294 ± 27 μmol/min ( P < 0.05). During WI + ANG II-low, plasma ANG II was not suppressed by WI, and the natriuresis was blunted by 52 ± 13% ( P < 0.05). During WI + ANG II-low and WI + ANG II-high, an increase in CLiwas prevented that was otherwise observed during WI, and fractional distal reabsorption of sodium was facilitated. In conclusion, maintaining plasma concentration of ANG II unchanged at the level of control attenuates the natriuresis of WI considerably in humans. Therefore, suppression of generation of ANG II is an important mechanism of the natriuresis of WI in humans. Furthermore, infusion of ANG II during WI prevents an otherwise induced increase in CLiand facilitates the fractional distal reabsorption of sodium, probably via an effect on aldosterone release.

OBJECTIVES: To characterize the lipolytic response in the subcutaneous abdominal adipose tissue in older women to endurance exercise. DESIGN: Cross-sectional exercise study. SETTING: Exercise laboratory, Copenhagen, Denmark. PARTICIPANTS: Seven healthy, older women (mean age ± standard error = 75 ± 2 years); weight: 67.8 ± 4.9 kg; body fat: 40 ± 3%; maximal oxygen uptake (VO 2 max): 1.43 ± 0.07 L.min -1 ). MEASUREMENTS: Body composition (dual energy x-ray absorptiometry (DEXA)), maximal oxygen uptake (VO 2 max, maximal cycling test), lipolytic response to exercise (arterial and adipose tissue venous catheterization at rest and during 60 minutes of continuous cycling at a load corresponding to 60% of VO 2 max), adipose tissue blood flow (ATBF) ( 133 Xenon ( 133 Xe) washout), oxygen consumption and respiratory exchange ratio during exercise (indirect calorimetry), whole blood glycerol, plasma nonesterified fatty acids (NEFA), lactate, glucose, epinephrine, norepinephrine, insulin, serum growth hormone, and hematocrit. RESULTS: Glycerol and NEFA mobilization rates increased by 250% and 180%, respectively, from rest to exercise. This was achieved primarily by an increase in veno-arterial differences, because ATBF did not increase significantly. NEFA:glycerol mobilization ratio was about two at rest and remained at that level during exercise, indicating significant local reesterification in both conditions. After an initial decrease, arterial plasma NEFA concentration increased significantly, by 26%, indicating that NEFA delivery exceeded muscle uptake. CONCLUSIONS: Older women are capable of prompt and substantial increase in subcutaneous abdominal adipose tissue glycerol and NEFA mobilization rates in response to moderate acute endurance exercise. The lipolytic response matches skeletal muscle NEFA uptake, and decreased ability to mobilize fat during exercise is therefore not likely to cause increased fat mass with advancing age.

The hypothesis was tested that acute water immersion to the neck (WI) compared with 6° head-down tilt (HDT) induces a more pronounced distension of the heart and lower plasma levels of vasoconstrictor hormones. Ten healthy males underwent 30 min of HDT, WI, and a seated control (randomized). During WI, left atrial diameter and stroke volume increased to the same extent as during HDT. Cardiac output increased by 1 l/min more during WI than during HDT. ( P < 0.05). Plasma atrial natriuretic peptide increased during WI ( P < 0.05) but not during HDT, whereas plasma norepinephrine, vasopressin, and renin activity were suppressed similarly. Mean arterial pressure decreased by 9 mmHg ( P < 0.05) during HDT and was unchanged during WI, and heart rate decreased more during HDT ( P < 0.05). Arterial pulse pressure increased considerably more during HDT than during WI. In conclusion, the hypothesis was not confirmed because the cardiac atria were similarly distended by acute HDT and WI and the release of vasoconstrictor hormones were suppressed to the same extent.

During prolonged, static carotid baroreceptor stimulation by neck suction (NS) in seated humans, heart rate (HR) decreases acutely and thereafter gradually increases. This increase has been explained by carotid baroreceptor adaptation and/or buffering by aortic reflexes. During a posture change from seated to supine (Sup) with similar carotid stimulation, however, the decrease in HR is sustained. To investigate whether this discrepancy is caused by changes in central blood volume, we compared ( n = 10 subjects) the effects of 10 min of seated NS (adjusted to simulate carotid stimulation of a posture change), a posture change from seated to Sup, and the same posture change with left atrial (LA) diameter maintained unchanged by lower body negative pressure (Sup + LBNP). During Sup, the prompt decreases in HR and mean arterial pressure (MAP) were sustained. HR decreased similarly within 30 s of NS (65 ± 2 to 59 ± 2 beats/min) and Sup + LBNP (65 ± 2 to 58 ± 2 beats/min) and thereafter gradually increased to values of seated. MAP decreased similarly within 5 min during Sup + LBNP and NS (by 7 ± 1 to 9 ± 1 mmHg) and thereafter tended to increase toward values of seated subjects. Arterial pulse pressure was increased the most by Sup, less so by Sup + LBNP, and was unchanged by NS. LA diameter was only increased by Sup. In conclusion, static carotid baroreceptor stimulation per se causes the acute (

In the present study, the effect of endurance training alone and endurance training combined with recombinant human growth hormone (rhGH) administration on subcutaneous abdominal adipose tissue lipolysis was investigated. Sixteen healthy women [age 75 ± 2 yr (mean ± SE)] underwent a 12-wk endurance training program on a cycle ergometer. rhGH was administered in a randomized, double-blinded, placebo-controlled design in addition to the training program. Subcutaneous abdominal adipose tissue lipolysis was estimated by means of microdialysis combined with measurements of subcutaneous abdominal adipose tissue blood flow (ATBF; 133Xe washout). Whole body fat oxidation was estimated simultaneously by indirect calorimetry. Before and after completion of the training program, measurements were performed both at rest and during 60 min of continuous cycling at a workload corresponding to 60% of pretraining peak oxygen uptake. Endurance training alone did not affect subcutaneous abdominal adipose tissue lipolysis either at rest or during exercise, as reflected by identical levels of interstitial adipose tissue glycerol, subcutaneous abdominal ATBF, and plasma nonesterified fatty acids before and after completion of the training program. Similarly, no effect on subcutaneous abdominal adipose tissue lipolysis was observed when combining endurance training with rhGH administration. However, in both the placebo and the GH groups, fat oxidation was significantly increased during exercise performed at the same absolute workload after completion of the training program. We conclude that the changed lipid metabolism during exercise observed after endurance training alone or after endurance training combined with rhGH administration is not due to alterations in subcutaneous abdominal adipose tissue metabolism in elderly women.

We hypothesized that the more-pronounced hypotensive and bradycardic effects of an antiorthostatic posture change from seated to supine than water immersion are caused by hydrostatic carotid baroreceptor stimulation. Ten seated healthy males underwent five interventions of 15-min each of 1) posture change to supine, 2) seated water immersion to the Xiphoid process (WI), 3) seated neck suction (NS), 4) WI with simultaneous neck suction (−22 mmHg) adjusted to simulate the carotid hydrostatic pressure increase during supine (WI + NS), and 5) seated control. Left atrial diameter increased similarly during supine, WI + NS, and WI and was unchanged during control and NS. Mean arterial pressure (MAP) decreased the most during supine (7 ± 1 mmHg, P < 0.05) and less during WI + NS (4 ± 1 mmHg) and NS (3 ± 1 mmHg). The decrease in heart rate (HR) by 13 ± 1 beats/min ( P < 0.05) and the increase in arterial pulse pressure (PP) by 17 ± 4 mmHg ( P< 0.05) during supine was more pronounced ( P < 0.05) than during WI + NS (10 ± 2 beats/min and 7 ± 2 mmHg, respectively) and WI (8 ± 2 beats/min and 6 ± 1 mmHg, respectively, P < 0.05). Plasma vasopressin decreased only during supine and WI, and plasma norepinephrine, in addition, decreased during WI + NS ( P < 0.05). In conclusion, WI + NS is not sufficient to decrease MAP and HR to a similar extent as a 15-min seated to supine posture change. We suggest that not only static carotid baroreceptor stimulation but also the increase in PP combined with low-pressure receptor stimulation is a possible mechanism for the more-pronounced decrease in MAP and HR during the posture change.

Nitric oxide (NO) may be an important modulator of sympathetic tone. We used im and sc microdialysis in humans to characterize the interaction of NO synthase inhibition and adrenoreceptor stimulation on tissue perfusion, metabolism, and norepinephrine release. Microdialysis probes were perfused with l- or d-nitro-l-arginine-methyl-ester (100 μmol/L) followed by incremental doses of isoproterenol, epinephrine, or nitroprusside. Blood flow was estimated based on the ethanol dilution technique. In muscle, the increase in blood flow with isoproterenol was abolished by l-NAME. The ethanol ratio was 0.03 ± 0.011 with d-NAME and 0.075 ± 0.014 with l-NAME during isoproterenol treatment (1μ mol/L). The effect was less pronounced in adipose tissue. The vasodilatory effect of nitroprusside was similar with d- and l-NAME. l-NAME augmented isoproterenol- and epinephrine-induced glycerol release. Dialysate glycerol during 1 μmol/L isoproterenol was 47 ± 6.7 μmol/L with d-NAME and 72 ± 15 μmol/L with l-NAME. In skeletal...

After administration of 0.2 mg adrenaline subcutaneously to 8 healthy individuals, natural killer (NK) cell activity of peripheral mononuclear cells increased within 15–30 min (p < 0.005) and returned to baseline values within two hours. The activity was correlated to plasma adrenaline concentration (r = 0.52, p < 0.001). No changes in NK cell activity were observed in 3 control subjects receiving an injection of 0.2 ml saline.

Measuring peak flow in the anterior tibial muscle with radioactive xenon in normal and diabetic persons, it was shown that the same results were obtained during ischaemia both after one minute of work and after maximal work. There was no difference when the peak flow was measured after the injection of 0.05 and 0.2 ml of the solution of radioactive xenon. The coefficient of variation in repeated experiments was 18% for the peak flow and 30% for the latency time. In a group of non-diabetics (age range between 20 and 49 years) the resting flow was 1.6 ml per 100 g per min ± 0.8. The peak flow after maximal work during ischaemia was 71 ml per 100 g per min ± 18. The mean latency time was 0.47 min ± 0.18.

This study measured the pressor and plasma catecholamine response to local hypothermia during adaptation to hypobaric hypoxia. Eight healthy men were studied at rest and after 10 and 45 min of local cooling of one hand and forearm as well as after 30 min of rewarming at sea level and again 24 h and 5 days after rapid, passive transport to high altitude (4,559 m). Acute mountain sickness scores ranged from 5 to 16 (maximal attainable score: 20) on the first day but were reduced to 0–8 by the fifth day. Systolic blood pressure, heart rate, and plasma epinephrine increased on day 1 at altitude compared with sea level but declined again on day 5, whereas diastolic and mean blood pressures continued to rise in parallel with plasma norepinephrine. With local cooling, an increased vasoactive response was seen on the fifth day at altitude. Very high pressures were obtained, and the pressure elevation was prolonged. Heart rate increased twice as much on day 5 compared with the other two occasions. Thoracic fluid index increased with cooling on day 5, suggesting an increase in pulmonary vascular resistance. In conclusion, prolonged hypoxia seems to elicit an augmented pressor response to local cooling in the systemic and most likely also the pulmonary circulation.

We tested the hypothesis that sympathoadrenal activity in humans is low during spaceflight and that this effect can be simulated by head-down bed rest (HDBR). Platelet norepinephrine and epinephrine were measured as indexes of long-term changes in sympathoadrenal activity. Ten normal healthy subjects were studied before and during HDBR of 2-wk duration, as well as during an ambulatory study period of a similar length. Platelet norepinephrine concentrations (half-life = 2 days) were studied in five cosmonauts, 2 wk before launch, within 12 h after landing after 11–12 days of flight, and at least 2 wk after return to Earth. Because of the long half-life of platelet norepinephrine, data obtained early after landing would still reflect the microgravity state. Platelet norepinephrine decreased markedly during HDBR ( P < 0.001), whereas there were no significant changes when subjects were ambulatory. Platelet epinephrine did not change during HDBR. During microgravity, platelet norepinephrine and epinephrine increased in four of the five cosmonauts. Platelet norepinephrine concentrations expressed in percentage of preflight and pre-HDBR values, respectively, were significantly different during microgravity compared with HDBR [153 ± 28% (mean ± SE) vs. 60 ± 6%, P < 0.004]. Corresponding values for platelet epinephrine were also significant (293 ± 85 vs. 90 ± 12%, P < 0.01). The mechanism of the platelet norepinephrine and epinephrine response during spaceflight flight is most likely related to the concomitant decrease in plasma volume. HDBR cannot be applied to simulate changes in sympathoadrenal activity during microgravity.

The hypothesis was tested that hemodilution is one of the determinants of the water immersion (WI)-induced natriuresis. Eight males were subjected to 3 h of 1) WI to the midchest (Chest), 2) WI to the neck combined with thigh cuff-induced (80 mmHg) venous stasis (Neck + stasis), and 3) a seated time control ( n = 6). Central venous pressure and left atrial diameter increased to the same extent during Chest and Neck + stasis ( P < 0.05), whereas renal sodium excretion only increased during Chest from 77 ± 7 to 225 ± 13 μmol/min ( P < 0.05). During Chest, plasma colloid osmotic pressure (COP) decreased from 27.7 ± 0.7 to 25.1 ± 0.7 mmHg ( P< 0.05), and plasma volume (PV) increased from 3,263 ± 129 to 3,581 ± 159 ml ( P < 0.05), whereas these variables remained unchanged during Neck + stasis. Plasma norepinephrine concentration decreased similarly during Chest and Neck + stasis by 45 ± 7 and 34 ± 4%, respectively ( P < 0.05), whereas plasma renin activity decreased only during Chest ( P < 0.05). In conclusion, during WI in humans 1) hemodilution (decrease in COP and increase in PV) is a pivotal stimulus for the natriuresis and 2) central blood volume expansion without hemodilution does not augment renal sodium output.

1. The hypothesis was tested that in hydrated humans the release of arginine vasopressin and angiotensin II is suppressed by water immersion (WI) and that this is a mechanism of the immersion-induced diuresis and natriuresis. Seven male subjects on controlled sodium (65-75 mmol per 24 h for 4 days) and water intake were studied. 2. Plasma vasopressin was promptly suppressed by WI, declining from 0. 76 +/- 0.13 to 0.23 +/- 0.08 pg ml-1 (P < 0.05), with a concomitant increase in renal water output (CH2O) from -0.4 +/- 0.2 to 4.4 +/- 0.7 ml min-1 (P < 0.05). Subsequently, CH2O returned to the level of control, whereas plasma vasopressin remained suppressed. Plasma osmolality gradually increased from 285 +/- 1 to 289 +/- 1 mosmol kg-1 (P < 0.05). WI caused a 9-fold increase in renal sodium excretion. Plasma angiotensin II decreased from 27.1 +/- 5.3 to 4.3 +/- 0.7 pg ml-1 (P < 0.05), and the intraindividual correlation coefficients between sodium excretion rates and angiotensin II concentrations varied between 0.73 and 0.96 (P < 0.002). 3. The data demonstrate that plasma vasopressin and angiotensin II concentrations decrease during WI in hydrated humans, concomitantly with initial increases in CH2O and sodium excretion. Therefore, vasopressin could constitute a mediator of CH2O and angiotensin II of the natriuresis of WI. The subsequent return of CH2O to the level of control is, however, also caused by other factors.

Body weight and obesity show familial resemblance that could be the result of familial correlation of fat oxidation, low levels of which have been implicated in the etiology of weight gain and obesity. We studied the familial correlation of both 24-h respiratory quotient (RQ), an index of the ratio of fat to carbohydrate oxidation, and the possible influence of dietary macronutrient composition expressed by the food quotient (FQ), i.e. the theoretical RQ produced by the diet. We measured the habitual FQ of the 7 days diet by weighed food records, followed by measurement of 24-h RQ in respiration chambers in 71 healthy Caucasian siblings from 31 families. After adjustment for age, gender, and 24-h energy balance, 24-h RQ correlated in families as indicated by an intraclass correlation coefficient (r(i)) of 0.31 (P = 0.03). FQ, adjusted for age and gender, was also a familial trait for the two days immediately preceding diet (r(i) = 0.32, P < 0.01). The familial effect on 24-h RQ, adjusted for age, gender, and 24-h energy balance, remained after adjustment for the FQ of the two days preceding diet (r(i) = 0.27, P < 0.05) and was reduced but not abolished after further adjustment for fasting plasma insulin plus free fatty acids (r(i) = 0.24, P < 0.09). By a correlation analysis aimed at separating familial and individual nonfamilial factors influencing both 24-h RQ and FQ, we found a great but insignificant familial (etaF = 0.49, P < 0.18) and a somewhat lower, but significant individual nonfamilial correlation (etaNF = 0.35, P < 0.03). We conclude that substrate oxidation rates measured by RQ exhibit familial correlation after proper adjustment for confounders such as energy balance, gender, and age, and that this effect could not be fully explained by preceding diet composition, fasting plasma insulin, and free fatty acids. Further RQ and the habitual dietary composition shared familial and nonfamilial factors.

An impaired fat oxidation has been implicated to play a role in the etiology of obesity, but it is unclear to what extent impaired fat mobilization from adipose tissue or oxidation of fat is responsible. The present study aimed to examine fat mobilization from adipose tissue and whole body fat oxidation stimulated by exercise in seven formerly obese women (FO) and eight matched controls (C). Lipolysis in the periumbilical subcutaneous adipose tissue, whole body energy expenditure (EE), and substrate oxidation rates were measured before, during, and after a 60-min bicycle exercise bout of moderate intensity. Lipolysis was assessed by glycerol release using microdialysis and blood flow measurement by 133Xe clearance technique. The FO women had lower resting EE than C (3.77 ± 1.01 vs. 4.88 ± 0.74 kJ/min, P < 0.05) but responded similarly to exercise. Adipose tissue glycerol release was twice as high in FO than in C at rest (0.455 ± 0.299 vs. 0.206 ± 0.102 μmol ⋅ 100 g−1 ⋅ min−1, P < 0.05) but increased similarly in FO and C in response to exercise. Despite higher plasma nonesterified fatty acids (NEFA) in FO ( P < 0.001), fat oxidation rates during rest and recovery were lower in FO than in C (1.32 ± 0.84 vs. 3.70 ± 0.57 kJ/min, P < 0.02) and fat oxidation for a given plasma NEFA concentration was lower at rest ( P < 0.001) and during exercise ( P = 0.01) in the formerly obese group. In conclusion, fat mobilization both at rest and during exercise is intact in FO, whereas fat oxidation is subnormal despite higher circulation NEFA levels. The lower resting EE and the failure to use fat as fuel contribute to a positive fat balance and weight gain in FO subjects.

1. Plasma concentrations of 3,4-dihydroxyphenylalanine (DOPA), dopamine sulphate (DA-S), and 3,4-dihydroxyphenylacetic acid (DOPAC) in humans have been claimed to be indexes of sympathetic nervous activity, but the source and significance of plasma DOPA, DOPAC and DA-S have not been completely elucidated. 2. The effects of ordinary meals on plasma concentrations of total dopamine, mainly DA-S, DOPAC and DOPA were studied in seven healthy subjects. Venous blood was collected every hour for 25 h, while subjects were either fasting or received three meals at 9.00 hours, 13.00 hours and 18.00 hours. Catecholamines and metabolites were determined by reverse-phase HPLC with electrochemical detection. Neutral amino acids were measured by ionexchange chromatography with photometric detection. 3. The food contained relatively little DOPA as compared with phenylalanine, tyrosine, isoleucine and tryptophan. The content of DA and DA-S varied considerably, with the greatest amount in the evening meal of open sandwiches. 4. Plasma DOPA decreased significantly after the meals at 13.00 hours and 18.00 hours, whereas concentrations of the other amino acids increased as expected. 5. Plasma DA-S increased significantly after meals and especially after the evening meal. Increments in DA-S above basal values after a meal were closely related to the content of DOPA+DA+DA-S in the meal. Plasma DOPAC increased significantly after the evening meal. 6. The decrease in plasma DOPA observed after a meal was probably due to uptake of DOPA by muscle tissue. Changes in plasma DA-S and DOPAC during this 25-h study reflected to a large extent the content of DOPA, DA and DA-S in the meals.

Previous results from our laboratory demonstrate that changes in haematocrit (Hct) and haemoglobin concentration (Hb) underestimate the relative (%) change in plasma volume (PV) in seated subjects during simulation of weightlessness by water immersion. Therefore, we examined whether changes in Hct and Hb would accurately reflect the changes in PV in seven subjects during simulation of weightlessness by another model, 6 degrees head-down tilted bed rest (HDBR), for 42 days. Since we have previously observed unexpectedly high plasma levels of noradrenaline (NA) in astronauts during space flight, we also took the opportunity to measure this variable. The measurements were compared with those of the supine horizontal position before and after HDBR. During HDBR, PV measured by the Evans blue dye dilution technique decreased by 6.1 +/- 2.8% (P0.05) on day 2 and 9.6 +/- 2.2% (P0.05) on the 42nd day compared with that of the supine, horizontal position. Based on changes in Hct and Hb, PV decreased similarly by 8.3 +/- 2.8 and 10.2 +/- 3.2% (P0.05) respectively. There were no differences comparing the results of the two methods (P0.05). Forearm venous plasma NA was unchanged during the whole course of HDBR compared with that of the pre-HDBR supine position. It is concluded that changes in Hct and Hb reliably reflect the changes in PV comparing prolonged HDBR with the pre- and post-HDBR horizontal, supine position. Thus, changes in Hct and Hb might accurately reflect the change in PV during weightlessness in humans provided that the horizontal supine position is used as the ground-based reference. Furthermore, the results of this study, as well as of previous studies from space, confirm that NA release is unchanged or even increased during weightlessness.

Aims: A substantial part of the genome is transcribed in non-coding RNAs. We review our finding of a long non-coding RNA (designated Heg) in mononuclear cells (MNC) and regulation of TSH receptor autoantibodies (TRAb). Results: The Heg RNA transcript in MNC is negatively correlated with TRAb in patients with early and untreated Graves’ disease. In treated patients and in controls Heg correlated negatively with CD14 mRNA. Transfection studies with fragments of Heg added to MNC (exogenous Heg) decreased CD14 mRNA in MNC and increased gene expression of RIG-I, TLR7 and IFN-γ. Heg is likely to activate TLR7 receptors. CD14 is a co-receptor of TLR7. Decrease in gene expression of CD14 after Heg is a sign of differentiation of MNC to dendritic cells. This may reduce surface expression of CD14, cytokine responses and the responsiveness to TSH receptor antigens. Thus the relationship between TRAb and lnc Heg RNA is most likely explained by receptor crossinterference. Cdk1 mRNA (an index of cell cycle activity) is positively related with TRAb. Cdk1 mRNA and TRAb but not Heg decreased significantly during antithyroid treatment. Cdk1 decreased to values below normal. Conclusion: Thus both Heg RNA and Cdk1 may regulate the level of TRAb but by two different mechanisms.

The present study assessed the possible familial effect in 71 healthy Caucasian siblings on each of the variables determining the inter-individual variations in energy expenditure (EE) measured under standardized conditions. We found that the 24-h EE measured in respiration chambers of 71 siblings from 32 different families was positively correlated with fat-free mass, which explained 82% of the variation between subjects (P0.00001). An additional 10% of the total variation was explained by differences in spontaneous physical activity (P0.00001), fat mass (P0.00001), plasma concentration of free T3 (P0.003), and norepinephrine (P0.002), whereas plasma values of epinephrine and androgen hormones did not correlate with 24-h EE. After adjustment for gender, there was a familial aggregation of both 24-h and sleeping EE, as indicated by intraclass correlation coefficients (r) of 0.44 (P0.02) and 0.58 (P0.01), respectively. The familial effect on gender-adjusted 24-h EE was explained mainly by a familial resemblance of fat-free mass (ri = 0.48; P0.015) and fat mass (ri = 0.40; P0.03), whereas spontaneous physical activity and plasma concentrations of T2 and norepinephrine did not correlate in families. It is concluded that the familial aggregation of EE in Caucasians is mediated mainly through familial resemblance of body composition; even though plasma concentrations of free T3 and norepinephrine, independent of body composition, explain an additional proportion of the variation in EE, they do not contribute to the familial correlation.

Endogenous norepinephrine (NE) and epinephrine (E) were demonstrated in lymphocytes isolated from peripheral venous blood. In 13 young subjects lymphocyte NE and E averaged 14.3 and 1.9 pg per 10(7) cells, respectively. The ratio NE/E was similar in plasma and in lymphocytes. Highly significant correlations were obtained between lymphocyte NE and E on the one hand and cAMP in lymphocytes on the other both in the basal state and after stimulation with isoproterenol. In a group of elderly subjects lymphocyte NE concentration was significantly reduced in long-term smokers as compared to non-smokers (7 and 35 pg/10(7) cells, respectively), whereas plasma NE was increased in smokers. Addition of exogenous NE or propranolol to blood samples did not change lymphocyte NE concentration in in vitro experiments. Variability in endogenous lymphocyte concentration of E in 9 young subjects, correlated with concomitant changes in number of NK(CD3-CD56+) cells and cAMP. It is concluded that endogenous lymphocyte NE and E concentrations in healthy subjects reflected basal cAMP production in lymphocytes and lymphocyte subset composition.

A number of studies have demonstrated an association between habitual snoring and ischemic heart disease like angina pectoris, myocardial infarction and ischemic changes on the electrocardiography (ECG). Control for the influence of potential confounders has been inadequate. To further elucidate the issue we examined the association between self-assessed snoring and the relation to atherosclerotic manifestations. 804 70-year-old males and females were classified according to snoring habits. Alcohol and tobacco consumption, blood pressure, body mass index, social group, plasma lipids (triglycerides, cholesterol, high density lipoprotein), fasting blood glucose, glucose tolerance test, plasma epinephrine and norepinephrine were determined. Presence of angina pectoris, claudication intermittens, use of nitroglycerine were questioned, a resting ECG and a distal arterial pressure by use of doppler technique in the lower limbs were determined. Distal atherosclerotic manifestations was defined as complaints of claudication intermittens, pulselessness in one or more foot arteries or a foot/arm systolic pressure ratio < 0.90. ECG changes were classified in accordance to standard criteria (Minnesota codes) into positive ECG signs (Q/OS waves, S-T depressions, T-wave inversion or flattering or left bundle branch block) and definitive myocardial infarction. Snoring showed a weak positive correlation to positive ECG signs and definitive myocardial infarction, but after adjustments for the above confounders, no association was found between snoring and atherosclerotic manifestations. We conclude that, in a 70-year-old population, self-reported snoring is not associated with atherosclerotic manifestations.

Recent studies have indicated that the increase in plasma norepinephrine and sympathetic activity with aging in healthy subjects is largely due to long-term cigarette smoking. In patients who have or have had duodenal ulcer the increase in plasma norepinephrine with age was markedly increased. These patients as a group perceive their lives somewhat more stressful than the general population and they tend to die prematurely due to smoking-associated diseases. These patients may select dysfunctional coping strategies like smoking, which may result in organ pathologies and a compensatory increase in plasma norepinephrine. No close correlation has been established between plasma epinephrine and "ill health." High plasma epinephrine levels may have a deleterious effect on the cardiovascular system in elderly subjects during certain conditions. In a population study, we found, however, that low resting plasma epinephrine levels were associated with an unfavorable survival rate. We speculate that an inadequate response to psychosocial stress and the choice of dysfunctional coping strategies may be more harmful and cause more "ill health" than hypersecretion of stress hormones like epinephrine and cortisol, which has been the traditional view. We suggest that there are different stress states. Stress hormones like epinephrine and cortisol may play a major role during situations like combat, illness, and strenuous exercise. In response to psychosocial stress, dysfunctional coping strategies are, however, largely responsible for harmful effects of stress.

The effect of sham feeding on glucose metabolism was studied in eleven normal subjects. At random, one intravenous glucose tolerance test (25 g glucose/4 min) was preceded by 15 minutes of pure sham feeding (the sight and smell of a meal but not the taste) which continued for the first 15 minutes after the intravenous glucose load. Pancreatic polypeptide increased significantly during sham feeding and decreased significantly in response to the glucose injection. The glucose disappearance rate was significantly improved from 1.56 +/- 0.22 to 2.07 +/- 0.33 min-1 when the glucose tolerance test was preceded by sham feeding (p = 0.02). Incremental areas of plasma insulin, plasma C-peptide, and insulin secretion rates were not significantly influenced by sham feeding. We conclude that sham feeding by the sight and smell of food improves glucose tolerance in normal subjects without alteration in insulin secretion.