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Our aim was to compare three research-grade accelerometers for their accuracy in step detection and energy expenditure (EE) estimation in a laboratory setting, at different speeds, especially in overweight/obese participants. Forty-eight overweight/obese subjects participated. Participants performed an exercise routine on a treadmill with six different speeds (1.5, 3, 4.5, 6, 7.5, and 9 km/h) for 4 min each. The exercise was recorded on video and subjects wore three accelerometers during the exercise: Sartorio Xelometer (SX, hip), activPAL (AP, thigh), and ActiGraph GT3X (AG, hip), and energy expenditure (EE) was estimated using indirect calorimetry for comparisons. For step detection, speed-wise mean absolute percentage errors for the SX ranged between 9.73–2.26, 6.39–0.95 for the AP, and 88.69–2.63 for the AG. The activPALs step detection was the most accurate. For EE estimation, the ranges were 21.41–15.15 for the SX, 57.38–12.36 for the AP, and 59.45–28.92 for the AG. All EE estimation errors were due to underestimation. All three devices were accurate in detecting steps when speed exceeded 4 km/h and inaccurate in EE estimation regardless of speed. Our results will guide users to recognize the differences, weaknesses, and strengths of the accelerometer devices and their algorithms.

Summary Multiple endocrine neoplasia type 1 NM_001370259.2(MEN1):c.466G>C(p.Gly156Arg) is characterized by tumors of various endocrine organs. We report on a rare, growth hormone-releasing hormone (GHRH)-releasing pancreatic tumor in a MEN1 patient with a long-term follow-up after surgery. A 22-year-old male with MEN1 syndrome, primary hyperparathyroidism and an acromegalic habitus was observed to have a pancreatic tumor on abdominal CT scanning, growth hormone (GH) and insulin-like growth factor 1 (IGF1) were elevated and plasma GHRH was exceptionally high. GHRH and GH were measured before the treatment and were followed during the study. During octreotide treatment, IGF1 normalized and the GH curve was near normal. After surgical treatment of primary hyperparathyroidism, a pancreatic tail tumor was enucleated. The tumor cells were positive for GHRH antibody staining. After the operation, acromegaly was cured as judged by laboratory tests. No reactivation of acromegaly has been seen during a 20-year follow-up. In conclusion, an ectopic GHRH-producing, pancreatic endocrine neoplasia may represent a rare manifestation of MEN1 syndrome. Learning points Clinical suspicion is in a key position in detecting acromegaly. Remember genetic disorders with young individuals having primary hyperparathyroidism. Consider multiple endocrine neoplasia type 1 syndrome when a person has several endocrine neoplasia. Acromegaly may be of ectopic origin with patients showing no abnormalities in radiological imaging of the pituitary gland.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) degrades low-density lipoprotein cholesterol (LDL-C) receptors, and thus regulates the LDL-C levels in the circulation. Type 2 diabetics often have elevated LDL-C levels. However, the functions of PCSK9 in patients with alterations of glu-cose metabolism and statin therapy are still unclear. Method: we investigated a large cohort of 608 subjects, born in 1945 in Oulu, Finland (Oulu Cohort 1945). We studied the effects of PSCK9 lev-els with different glucose tolerances (normal glucose tolerance (NGT), prediabetes (PreDM) or type 2 diabetes (T2D)) with and without statin medication, and analyzed clinical data, NMR metabolomics and PCSK9 plasma levels. Results: PCSK9 plasma levels did not significantly differ between the three groups. Statin therapy significantly increased the PCSK9 levels in NGT, PreDM and T2D groups compared with subjects with no statins. In the NGT group, negative associations between PCSK9 and LDL-C, intermediate-density lipoprotein cholesterol (IDL-C), very low-density lipoprotein cholesterol (VLDL-C), total cholesterol and LDL and IDL triglycerides were observed under statin medication. In contrast, in the PreDM and T2D groups, these associa-tions were lost. Conclusions: our data suggest that in subjects with abnormal glucose metabolism and statin therapy, the significant PCSK9-mediated effects on the lipid metabolites are lost com-pared to NGT subjects, but statins reduced the LDL-C and VLDL-C levels.

Milk is an evolutionary benefit for humans. For infants, it offers optimal nutrients for normal growth, neural development, and protection from harmful microbes. Humans are the only mammals who drink milk throughout their life. Lipids in colostrum originate mostly from milk fat globule membrane (MFGM) droplets extruded from the mammary gland. The MFGM gained much interest as a potential nutraceutical, due to their high phospholipid (PL), ganglioside (GD), and protein contents. In this review, we focused on health effects of MFGM ingredients and dairy food across the life span, especially on neurodevelopment, cardiometabolic health, and frailty in older adults. The MFGM supplements to infants and children reduced gastrointestinal and respiratory tract infections and improved neurodevelopment due to the higher content of protein, PL, and GD in MFGM. The MFGM formulas containing PL and GD improved brain myelination and fastened nerve conduction speed, resulting in improved behavioral developments. Administration of MFGM-rich ingredients improved insulin sensitivity and decreased inflammatory markers, LDL-cholesterol, and triglycerides by lowering intestinal absorption of cholesterol and increasing its fecal excretion. The MFGM supplements, together with exercise, improved ambulatory activities, leg muscle mass, and muscle fiber velocity in older adults. There are great variations in the composition of lipids and proteins in MFGM products, which make comparisons of the different studies impossible. In addition, investigations of the individual MFGM components are required to evaluate their specific effects and molecular mechanisms. Although we are currently only beginning to understand the possible health effects of MFGM products, the current MFGM supplementation trials as presented in this review have shown significant clinical health benefits across the human life span, which are worth further investigation.

Regular physical activity (PA) improves cognitive functions, prevents brain atrophy, and delays the onset of cognitive decline, dementia, and Alzheimer’s disease. Presently, there are no specific recommendations for PA producing positive effects on brain health and little is known on its mediators. PA affects production and release of several peptides secreted from peripheral and central tissues, targeting receptors located in the central nervous system (CNS). This review will provide a summary of the current knowledge on the association between PA and cognition with a focus on the role of (neuro)peptides. For the review we define peptides as molecules with less than 100 amino acids and exclude myokines. Tachykinins, somatostatin, and opioid peptides were excluded from this review since they were not affected by PA. There is evidence suggesting that PA increases peripheral insulin growth factor 1 (IGF-1) levels and elevated serum IGF-1 levels are associated with improved cognitive performance. It is therefore likely that IGF-1 plays a role in PA induced improvement of cognition. Other neuropeptides such as neuropeptide Y (NPY), ghrelin, galanin, and vasoactive intestinal peptide (VIP) could mediate the beneficial effects of PA on cognition, but the current literature regarding these (neuro)peptides is limited.

This article studies how an individual’s physical wellbeing contributes to one’s online user experience. The study subjects were elderly people at high risk for type 2 diabetes. The results suggest that the web usage experience of these pre-diabetic individuals is related to their physical health status and level of physical activity. Those with a better physical health status were more likely to feel ease of orientation in their web usage, and those with more frequent regular physical activity were more likely to perceive pleasure in navigating the web. In practice, variation in physical health and activity levels between individuals could, and should. be addressed in designing systems and services. In more general, studying user experience on par with biochemical measurements provides an exciting combination of research methods and paves the way for new design practices.

Introduction: Physical activity (PA) has been associated with telomere shortening. The association of PA intensity or volume with telomere length (TL) is nonetheless unclear. The aim of our study was to investigate the associations of exercise intensity and volume with TL in elderly adults from Northern Finland (65° latitude North). Methods: Seven hundred elderly subjects born in 1945 in the Oulu region were investigated. PA was measured during a 2-week period with a wrist-worn accelerometer. In addition, a questionnaire was used to assess sedentary time and to achieve a longitudinal PA history and intensity. Relative telomere lengths (RTL) were determined from frozen whole blood samples using a qPCR-based method. Results: Relative telomere lengths were significantly longer in women than men and negatively correlated with age in both genders (men r = -0.210, p = 0.000, women r = -0.174, and p = 0.000). During the 2-week study period, women took more steps than men (p = 0.001), but the association between steps and RTL was only seen in men (p = 0.05). Total steps taken (r = 0.202 and p = 0.04) and sedentary time (r = -0.247 and p = 0.007) significantly correlated with RTLs in 70-year old subjects. Moderate PA was associated with RTL in subjects with the highest quartile of moderate PA compared to the three lower quartiles (p-values: 0.023 between 4th and 1st, 0.04 between 4th and 2nd, and 0.027 between 4th and 3rd) in the 70-year old subjects. Conclusion: Women had longer RTL and a higher step count compared to men. However, exercise volume and RTL correlated positively only in men. Surprisingly, age correlated negatively with RTL already within an age difference of 2 years. This suggests that telomere attrition rate may accelerate in older age. Moderate physical activity at the time of study was associated with RTL.

Este artículo se encuentra disponible en la página web de la revista en la siguiente URL: https://www.nature.com/articles/s41598-018-25755-4 Este artículo fue presentado en parte en el 77th Scientific Sessions of the American Diabetes Association, June 9-13, 2017, San Diego, California, USA. Carotid-femoral pulse wave velocity ((cf)PWV) is a measure of arterial stiffness, predicting cardiovascular disease. We hypothesized that the amount of physical activity (PA) is correlated with reduced arterial stiffness in Type 2 diabetic (T2D) subjects. 570 subjects from the 1945 Oulu birth cohort were included in the analysis. (cf)PWV was determined by a non-invasive applanation tonometry. Oral glucose tolerance test was performed and LDL and HDL cholesterol analyzed. PA was registered daily with a wrist-worn acceleration meter for two weeks. (cf)PWV values in subjects with impaired glucose metabolism (IGM) and T2D were higher than in normal glycemic subjects (P < 0.001). PA, fasting and 2 h glucose and HbA1c correlated significantly with (cf)PWV, but HDL or LDL cholesterol did not. The 2 h glucose, heart rate and alcohol consumption in T2D subjects had independent effects on (cf)PWV in multiple regression analysis. T2D and IGM were significantly associated to (cf)PWV. Interestingly, lipids did not have an additional effect on (cf)PWV. Subjects walking more than 10 000 steps/day had 0.2 m/s lower (cf)PWV than those walking less than 6000 steps/day. Presence of T2D, elevated heart rate and alcohol consumption in males were associated with increased aortic stiffening in elderly subjects.

Our objectives were to determine if there are quantitative associations between amounts and intensities of physical activities (PA) on NMR biomarkers and changes in skeletal muscle gene expressions in subjects with high risk for type 2 diabetes (T2D) performing a 3-month PA intervention. We found that PA was associated with beneficial biomarker changes in a factor containing several VLDL and HDL subclasses and lipids in principal component analysis (P =

Mice are used extensively in physiological research. Automated home‐cage systems have been developed to study single‐housed animals. Increased stress by different housing conditions might affect greatly the results when investigating metabolic responses. Urinary corticosteroid concentration is considered as a stress marker. The aim of the study was to compare the effects of different housing conditions and an automated home‐cage system with indirect calorimetry located in an environmental chamber on corticosterone levels in mice. Male mice were housed in different conditions and in automated home‐cage system to evaluate the effects of housing and measuring conditions on urine corticosterone levels. Corticosterone levels in single‐housed mice in the laboratory animal center were consistently lower compared with the group‐housed mice. Single‐housed mice in a separate, small animal unit showed a rise in their corticosterone levels a day after they were separated to their individual cages, which decreased during the following 2 days. The corticosterone levels of group‐housed mice in the same unit were increased during the first 7 days and then decreased. On day 7, the corticosterone concentrations of group‐housed mice were significantly higher compared with that of single‐housed mice, including the metabolic measurement protocol. In conclusion, single housing caused less stress when compared with group‐housed mice. In addition, the urine corticosterone levels were decreased in single‐housed mice before the metabolic measurement started. Thus, stress does not affect the results when utilizing the automated system for measuring metabolic parameters like food and water intake and calorimetry.

Objective: To explore through an interdisciplinary approach the potential to tailor health information on the basis of human information behaviour (HIB) on par with the results of basic physiological measurements of individuals’ health. Methods: The data were collected at the baseline of a physical activity and diabetes prevention intervention with 72 prediabetic participants, conducted in Oulu, Finland, by the University of Oulu and Oulu Deaconess Institute in 2010. Body mass index (BMI), fitness classifications and glucose values were obtained from all prediabetic participants. The interest in, the search for and the use of information on nutrition, physical activity and diabetes were examined through a self-report questionnaire with a response rate of 95.8%. The data were analysed with the SPSS statistics 18 software. Results and conclusions: The study shows that information behaviour of prediabetic individuals differs according to their BMI and fitness level. Poor physical fitness classifications and high BMI values were associated with an increased desire to receive tailored information on nutrition and physical activity frequently. These results add knowledge on the types and preferred frequencies of tailored information. Because of the small sample size, the results should be validated further.

Mechanisms regulating stretch response in the left ventricle are investigated in detail but not well understood in atrial myocardium. Hypertrophic growth of atrial myocardium contributes to the pathogenesis of atrial fibrillation. In this study, we sought to elucidate mechanisms of stretch-induced activation of key signaling pathways and hypertrophy-associated genes in rat atria. Stretching of isolated atria induced a rapid increase in phosphorylation of p38 MAPK and ERK and induced a p38 MAPK-dependent increase in DNA binding activity of transcription factors Elk-1 and GATA-4. Inhibition of the ERK pathway had no effect on the cardiac transcription factors studied. Stretch-induced increase in atrial contractile function was substantially enhanced by inhibition of p38 MAPK. p38 MAPK also regulated stretch-induced increase in c-fos, β-myosin heavy chain, B-type natriuretic peptide mRNA levels, and atrial natriuretic peptide secretion in isolated atria. Various autocrine/paracrine factors are known to mediate the stretch response in the left ventricle. Stretching of isolated atria resulted in a robust increase in endothelin-1 (ET-1) mRNA levels, while apelin and adrenomedullin signaling cascades were downregulated. Administration of mixed ETA/Breceptor antagonist bosentan attenuated the stretch-induced activation of GATA-4 in isolated atria, whereas ANG II receptor type-1 antagonist CV-11974 had no effect. Moreover, analysis of RNA from intact atrial and ventricular myocardium revealed significantly higher mRNA levels of ETAreceptor and ET converting enzyme-1 in atrial compared with ventricular myocardium. In conclusion, our findings identify the local ET-1 system and p38 MAPK as key regulators of load-induced hypertrophic response in isolated rat atria.

Background: NT-proXNP, a new natriuretic peptide analyte, incorporates information about the concentrations of both N-terminal pro-atrial and pro-brain natriuretic peptides (NT-proANP, NT-proBNP). We aimed to investigate whether NT-proXNP is a reliable indicator of the cardiac index (CI) and the hemodynamic state in neonates and infants undergoing an open heart surgery. Methods: We enrolled 26 children under the age of 1 year into this prospective study. All patients underwent an elective cardiac operation with cardiopulmonary bypass (CPB) to achieve complete biventricular repair. Peri-operative hemodynamic parameters were assessed by transpulmonary thermodilution and natriuretic peptide levels were recorded. Results: The NT-proXNP level correlated significantly with the simultaneously measured NT-proANP level (r = 0.60, P < 0.001), but more strongly with the NT-proBNP level (r = 0.89, P < 0.001) and the arithmetic sum of both (r = 0.88, P < 0.001). NT-proXNP had a strong correlation with CI (r = ― 0.85, P < 0.001), the stroke volume index (r = ― 0.80, P < 0.001) and the global ejection fraction (r = ― 0.67, P < 0.009) throughout the post-operative period. Conventionally measured parameters such as heart rate, mean arterial pressure and pulse-pressure product exhibited weaker correlations with CI than NT-proXNP. Among laboratory values, creatinine levels correlated significantly with CI (r = ― 0.77, P

Introduction The associations between melatonin and thyroid hormones and changes in mood and cognitive performance caused by exposure to cold and darkness were examined in 12 circumpolar residents during winter and summer. Methods Each participant was exposed to three different experimental conditions in random order: 1) 22 degrees C and bright light; 2) 10 degrees C and bright light; and 3) 10 degrees C and dim light. The duration of each exposure was 24 h. Results Increased serum melatonin and thyrotropin were associated with decreased rectal temperature (r = -0.446 - -0.580) and increased mean skin temperature (r = 0.204-0.519). Higher serum melatonin was associated with increased vigor (r = 0.330) and decreased accuracy on simple cognitive tasks (r = -0.332 - -0.430). Increased serum free triiodothyronine (fT3) was associated with decreased negative mood scores (r = -0.365 - -0.483), decreased response time (RT) on the simple reaction time (SRT) task (r = -0.606), and decreased accuracy on the addition/subtraction task (r = -0.372). Higher serum free thyroxine was associated with decreased fatigue and anger (r = -0.409 - -0.522). Increased serum thyrotropin was associated with decreased accuracy and RT on the SRT task and decreased RT on the grammatical reasoning task (r = -0.315 - -0.415). Conclusions Associations between serum melatonin and thyroid hormones with mood were consistent with the psychological changes associated with the polar triiodothyronine syndrome. Also, serum melatonin and thyrotropin were associated with impaired and fT3 with improved cognitive performance, supporting the decrements in cognitive performance associated with the polar triiodothyronine syndrome.

Cold therapy is used to relieve pain and inflammatory symptoms. The present study was designed to determine the influence of long-term regular exposure to acute cold temperature. Two types of exposure were studied: winter swimming in ice-cold water and whole-body cryotherapy. The outcome was investigated on humoral factors that may account for pain alleviation related to the exposures.During the course of 12 weeks, 3 times a week, a group of healthy females (n = 10) was exposed to winter swimming (water 0-2 degrees C) for 20 s and another group (n = 10) to whole-body cryotherapy (air -110 degrees C) for 2 min in a special chamber. Blood specimens were drawn in weeks 1, 2, 4, 8 and 12, on a day when no cold exposure occurred (control specimens) and on a day of cold exposures (cold specimens) before the exposures (0 min), and thereafter at 5 and 35 min.Plasma ACTH and cortisol in weeks 4-12 on time-points 35 min were significantly lower than in week 1, probably due to habituation, suggesting that neither winter swimming nor whole-body cryotherapy stimulated the pituitary-adrenal cortex axis. Plasma epinephrine was unchanged during both experiments, but norepinephrine showed significant 2-fold to 3-fold increases each time for 12 weeks after both cold exposures. Plasma IL-1-beta, IL-6 or TNF alpha did not show any changes after cold exposure.The main finding was the sustained cold-induced stimulation of norepinephrine, which was remarkably similar between exposures. The frequent increase in norepinephrine might have a role in pain alleviation in whole-body cryotherapy and winter swimming.

Summary Background: Natriuretic peptide levels are associated with cardiac output and ventricular function. We hypothesized that concomitant measurement of the peptide fragments and the hemodynamic parameters could elucidate the associations of these parameters after pediatric cardiac surgery. Methods: After approval of the institutional review board and parents’ informed consent, we investigated the clinical data of eight neonates undergoing correction of transposition of the great arteries. We measured the level of N-terminal fragments of prohormones of atrial and brain natriuretic peptides (NT-proANP, NT-proBNP) preoperatively, postoperatively and 12, 24, 48, and 72 h after arrival in the intensive care unit. The hemodynamic status was assessed by transpulmonary thermodilution at the same time points. Creatinine and other laboratory values were analyzed in the first 48 h postoperatively. Results: NT-proBNP levels were inversely correlated with cardiac index (CI, r = −0.47, P = 0.030), stroke volume index (r = −0.65, P = 0.005), and global end-diastolic volume index (GEDI; r = −0.63, P = 0.011). There was strong inverse correlation between the change of NT-proBNP levels and the change of CI between two consecutive measurements during the postoperative period (r = −0.79, P = 0.001). The NT-proBNP level 12 h after surgery was strongly correlated with the creatinine level of the postoperative 24th hour (r = 0.81, P = 0.014). Conclusions: NT-proBNP correlated with the hemodynamic parameters and with the severity of renal dysfunction. Therefore, NT-proBNP is a reliable indicator of the circulatory state and the severity of a low output syndrome after arterial switch operation in neonates.

Introduction: Physical activity is known to enhance the mechanical competence of bone. However, information about the optimal type of exercise is limited. The aim of this study was to evaluate the contribution of jumping exercise to changes in bone geometry. Methods: We carried out a 12-month population-based trial with 120 women (aged 35–40 years), randomly assigned to an exercise group or to a control group. The exercise regimen consisted of supervised, progressive high-impact exercises three times per week and an additional home program. The intensity of impact loading was assessed as the magnitude of acceleration peaks using an accelerometer-based body movement monitor. The activity was analyzed as the daily number of impacts within five acceleration ranges (0.3–1.0g, 1.1–2.4g, 2.5–3.8g, 3.9–5.3g and 5.4–9.2g; g=acceleration of gravity, 9.81 m/s 2 ). Bone geometry was assessed with spiral quantitative computed tomography (QCT) scanner at mid-femur, proximal tibia and distal tibia. Results: Thirty-nine women (65%) in the exercise group and 41 women (68%) in the control group completed the study. QCTand physical activity data were available from 65 subjects. The exercise group showed a significant 0.2% (p=0.033) higher gain in bone circumference compared to the control group at mid-femur. Subgroup analyses revealed geometric changes indicating up to a 2.5% increment in bone strength in favor of the most active exercisers (>66 exercise sessions during the 12 months) compared to the least active exercisers (

The Na(+)/K(+)-ATPase inhibitor ouabain has been shown to trigger hypertrophic growth of cultured cardiomyocytes; however, the significance of endogenous ouabain-like compound (OLC) in the hypertrophic process in vivo is unknown. Here we characterized the involvement of OLC in left ventricular (LV) hypertrophy induced by norepinephrine (NE) and angiotensin II (Ang II) infusions in rats. Administration of NE (300 microg/kg/h) via subcutanously implanted osmotic minipumps for 72 h resulted in a significant increase in left ventricular weight to body weight (LVW/BW) ratio (P0.001) and a substantial up-regulation of atrial natriuretic peptide (ANP) gene expression (13.2-fold, P0.001). NE infusion induced a transient increase in plasma OLC levels at 12 h (P0.05), which returned to control levels by 72 h. Adrenalectomy markedly reduced both basal and NE-induced increase in plasma OLC levels. LVW/BW ratio was not modulated by adrenalectomy; however, ANP gene expression was blunted by 44% (P0.01) and 47% (P0.05) at 12 and 72 h, respectively. In agreement, adrenalectomy reduced up-regulation of ANP without affecting LV mass in rats infused with Ang II (33 microg/kg/h). Administration of exogenous ouabain (1 nM to 100 microM) for 24 h had no effect on ANP gene expression in cultured neonatal rat ventricular myocytes. However, the up-regulation of ANP mRNA levels induced by the alpha-adrenergic agonist phenylephrine (1 microM) was markedly enhanced by ouabain (100 microM) (5.6-fold vs. 9.6-fold, P0.01). These data show that OLC as an adrenal-derived factor may be required for the induction LV ANP gene expression during the hypertrophic process.

Severe hypothermia has been shown to influence the levels of catecholamines and thrombomodulin, an endothelial protein essentially involved in the regulation of haemostasis and inflammation. A link between thrombomodulin and catecholamines during cold exposure has also been previously suggested. The aim of this study was to assess the influence of short-term cold exposure without hypothermia on catecholamines and the circulating and urinary thrombomodulin levels. Seven healthy male subjects were immersed in cold water (+10°C) for 10 minutes followed by a 20-minute immersion in +28°C water. Warm water immersion was performed separately for each subject (+30°C for 30 minutes). Thrombomodulin and catecholamine concentrations were measured from pre- and post-immersion (up to 23 hours) samples. In urine, the thrombomodulin level correlated strongly with adrenaline (ρ = 0.806) and noradrenaline (ρ = 0.760) levels. There were no significant differences in thrombomodulin levels between immersion temperatures. Post-immersion urinary thrombomodulin levels were significantly lower than the pre-immersion level at both immersion temperatures. Median concentrations of plasma noradrenaline and urinary adrenaline were higher after exposure to +10°C than to +30°C. Thus, further evidence of the association between thrombomodulin and catecholamines was gained in a physiologically relevant setting in humans. Additionally, it is evident that a short-term cold exposure was not able to elicit changes in the thrombomodulin levels in a follow-up period of up to 23 hours. These findings provide further understanding of the physiological responses to cold during immersion, and of the potential influence of stress on haemostatic and inflammatory responses.

The aim of this study was to examine whether urinary melatonin, rather than urinary 6-sulfatoxymelatonin (aMT6s), can be used as an indicator of diurnally and seasonally changing melatonin secretion. The subjects (n=15) spent three separate 24-hr periods in a climatic chamber during winter (n=7) and summer (n=8). Blood and urine samples were obtained during each period at 2- to 5-hr intervals. Serum melatonin and urinary melatonin and aMT6s were assayed by radioimmunoassay. The serum melatonin levels increased nearly 10-fold from low daytime to high nocturnal values. The mean nocturnal increase of urinary melatonin was 1.7-fold and that of urinary aMT6s was 4.6-fold. Both urinary melatonin and aMT6s correlated significantly with area under the curve melatonin in serum during the night, during the day and throughout the entire 24-hr observation period in all cases. The ratio between urinary melatonin and aMT6s excretion showed significant diurnal variation, being ninefold higher at 16:00 hr than at 07:00 or at 09:00 hr. The ninefold decrease in the urinary melatonin/aMT6s excretion ratio between the evening and the morning may reflect increased liver metabolism of melatonin during the night. Both urinary melatonin and aMT6s are good indicators of melatonin secretion, but the variation is significantly smaller for the former molecule.

In response to prepubertal gonadectomy certain inbred mouse strains, including DBA/2J, develop sex steroid-producing adrenocortical neoplasms. This phenomenon has been attributed to a lack of gonadal hormones or a compensatory increase in gonadotropins. To assess the relative importance of these mechanisms, we created a new inbred model of adrenocortical neoplasia using female NU/J nude mice. These mice developed adrenocortical neoplasms in response to either gonadectomy or gonadotropin elevation from xenografts of human chorionic gonadotropin (hCG)-secreting Chinese hamster ovary cells. In each instance the adrenal tumors resembled the neoplasms found in gonadectomized DBA/2J mice and were composed of spindle-shaped A cells and lipid-laden B cells. Both cell populations were defined by ectopic expression of GATA-4 and an absence of the adrenocortical markers melanocortin-2-receptor and steroid 21-hydroxylase, but only B cells expressed the gonadal steroidogenic markers inhibin-alpha, LH receptor, P450c17, and P450c19. Expression of sex steroidogenic markers was attenuated in the neoplastic adrenal cortex of hCG-treated vs. gonadectomized mice. Whereas neoplastic adrenals were an obvious source of estradiol in gonadectomized mice, ovaries appeared to be the major source of this hormone in hCG-treated mice. Gonadectomy and hCG treatment elicited comparable increases in serum estradiol, but testosterone levels increased significantly only in hCG-treated mice. We conclude that chronic gonadotropin elevation, caused by either gonadectomy or hCG administration, signals a population of cells in the adrenal subcapsular region of permissive mice to undergo differentiation along a gonadal rather than an adrenal lineage. Thus, NU/J nude mice can be used as a model to study both neoplasia and adrenogonadal lineage specification.

Background: High circulating concentrations of N-terminal fragments of A- and B-type natriuretic peptides (NT-proANP and NT-proBNP) identify patients with impaired cardiac function. ProANP-derived peptides are particularly sensitive to increased preload of the heart and proBNP-derived peptides to increased afterload; therefore, combining the information from the ANP and BNP systems into a single analyte could produce an assay with increased diagnostic and prognostic power. Methods: We prepared a hybrid peptide containing peptide sequences from both NT-proBNP and NT-proANP (referred to as NT-proXNP) by recombinant techniques and used it to develop a RIA combining weighed concentrations of NT-proANP and NT-proBNP into a new virtual analyte, NT-proXNP. We used the novel method to measure the circulating concentrations in healthy persons and in patients with cardiac disorders. We also characterized the assay by HPLC analysis of the immunoreactive molecular forms in human plasma and serum. Results: The results from the novel assay correlated well with independent home-made NT-proANP and NT-proBNP assays (r2 = 0.75–0.85) as well with the arithmetic sum of NT-proANP and NT-proBNP (r2 = 0.92). Patients with valvular heart disease (VHD) and coronary artery disease (CAD) had significantly increased NT-proXNP concentrations. The areas under the curve (AUC) of the NT-proXNP assay in detecting VHD and CAD (0.961 and 0.924, respectively) were significantly larger than the AUC of either NT-proANP (0.947 and 0.872) or NT-proBNP (0.913 and 0.782) assays. HPLC analysis showed that the novel NT-proXNP assay detects two major classes of circulating immunoreactivity corresponding to peptides derived from NT-proANP and NT-proBNP. Conclusions: Our novel immunoassay mimics the physiologic signaling system working in the body by converging the information obtained from the activation of ANP and BNP into a single virtual analyte, NT-proXNP. It appears to have a diagnostic efficiency equal to or slightly better than that of individual NT-proANP or NT-proBNP assays.

This study was designed to determine the responses of muscle protein, serum amino acids, and strength performance to bovine colostrum supplementation in physically active men. The rest (R) group (n = 6) and the exercise (E) group (n = 6) carried out twice a 2-week experiment randomly assigned in a double-blind fashion with either placebo (PLA; consuming daily 20 g maltodextrin) or bovine colostrum (COL; consuming daily 20 g colostrum supplement) treatment with one month between. On the test day after the treatment period the measurements were carried out in fasting conditions and E carried out a strength training session (STS). The methods involved the infusion of ring-(2)H(5)-phenylalanine, femoral arterial and venous blood sampling, and biopsies from the vastus lateralis muscle. Serum concentration of essential amino acids during recovery was greater (p0.05) in the COL groups compared with the PLA groups. Both muscle protein synthesis and breakdown increased (p0.05) with COL. There were no differences in phenylalanine net balance or strength performance between the PLA and COL groups. It was concluded that a 2-week supplementation with bovine colostrum in physically active men increases serum concentration of essential amino acids but has no effect either on strength performance or protein net balance in fasting conditions during recovery after STS.

The mechanisms that mediate the various effects of melatonin in mammalian tissues are not always known. Therefore, the aim of this study was to investigate whether MT(1) and MT(2) melatonin receptors are expressed in certain tissues of the rat. The expression of MT(1) and MT(2) melatonin receptor mRNA was determined using a real-time quantitative RT-PCR method. In addition, we examined whether mRNA for either subtype of receptor shows any difference in the expression between midnight and noon, similar to the changes in melatonin concentrations in plasma and tissue samples. MT(1) and MT(2) melatonin receptor mRNAs were found in the rat hypothalamus, retina and small intestine. We also showed a low expression of MT(2) mRNA in the rat liver and heart SA node. In the heart apex and the Harderian gland, no appearance of either of the receptor mRNAs was detectable. A significant difference in the expression of MT(1) mRNA between day and night was found in the hypothalamus. In conclusion, our findings suggest that at least some effects of melatonin are mediated through membrane MT(1) and MT(2) receptors in the hypothalamus, the retina and the small intestine. Down-regulation of receptors might be one reason for the difference in the hypothalamic MT(1) melatonin receptor mRNA expression between midnight and noon. In the liver and the heart SA node, the physiological significance of possible MT(2) receptors remains unclear. According to our negative midnight and noon results in the Harderian gland and heart apex melatonin may exert its effect on these tissues by a non-receptor mechanism.

To determine whether urban circumpolar residents show seasonal acclimatisation to cold, thermoregulatory responses and thermal perception during cold exposure were examined in young men during January-March (n=7) and August-September (n=8). Subjects were exposed for 24 h to 22 and to 10 degrees C. Rectal (T(rect)) and skin temperatures were measured throughout the exposure. Oxygen consumption (VO(2)), finger skin blood flow (Q(f)), shivering and cold (CDT) and warm detection thresholds (WDT) were assessed four times during the exposure. Ratings of thermal sensations, comfort and tolerance were recorded using subjective judgement scales at 1-h intervals. During winter, subjects had a significantly higher mean skin temperature at both 22 and 10 degrees C compared with summer. However, skin temperatures decreased more at 10 degrees C in winter and remained higher only in the trunk. Finger skin temperature was higher at 22 degrees C, but lower at 10 degrees C in the winter suggesting an enhanced cold-induced vasoconstriction. Similarly, Q(f) decreased more in winter. The cold detection threshold of the hand was shifted to a lower level in the cold, and more substantially in the winter, which was related to lower skin temperatures in winter. Thermal sensations showed only slight seasonal variation. The observed seasonal differences in thermal responses suggest increased preservation of heat especially in the peripheral areas in winter. Blunted vasomotor and skin temperature responses, which are typical for habituation to cold, were not observed in winter. Instead, the responses in winter resemble aggravated reactions of non-cold acclimatised subjects.

Whole-body cryotherapy (WBC; -110 degrees C) and winter swimming (WS) in ice-cold water are severe ambient cold exposures, which are voluntarily practiced by humans in minimal clothing. The purpose was to examine thermal sensation and thermal comfort associated with WBC and WS. Twenty women similar in body mass index, age, physical activity, and use of hormonal contraception were pairwise randomized either to the WBC group or the WS group. The duration of each WBC exposure was 2 min, which was repeated three times per week for 3 months (13 weeks). Similar exposure frequency was used for the WS group, but each exposure lasted 20 s in outdoor conditions. Thermal sensation and comfort were asked with standard scales. After WBC, 65% of the thermal sensation votes were 'neutral' or 'slightly cool.' After WS, 81% of the thermal sensation votes were 'warm,' 'neutral,' or 'slightly cool.' Majority of comfort votes immediately after exposures in WBC group (98%) and in the WS group (93%) were 'comfortable' or 'slightly uncomfortable.' Thermal sensation and comfort became habituated in both groups at an early stage of trials, but the changes were less conclusive in WS group due to variable conditions outdoors. In the WBC group, cold sensation was less intense already after the second exposure. In conclusion, repeated exposures to WBC and WS in healthy women were mostly well tolerated and comfortable. The results indicate that during repeated severe whole-body cold stress of short duration, thermal sensation and comfort become habituated during the first exposures.

Background: The N-terminal fragments of A- and B-type natriuretic peptides (NT-proANP and NT-proBNP) are powerful markers of cardiac function. The current assays require refinement with regard to standardization with native calibrators and the ability to detect the actual circulating forms.Methods: The following peptides were prepared with recombinant methods: NT-proANP, NT-proBNP, proBNP1–108, and Tyr0-proBNP77–108. Fifteen peptides of 13–22 amino acids, spanning the sequences of NT-proANP and NT-proBNP, were prepared by solid-phase peptide synthesis. Two immunoassays for NT-proANP and four for NT-proBNP were set up, each with a different epitope specificity. The assays were applied for the measurement of NT-proANP and NT-proBNP in healthy individuals and in patients with acute myocardial infarction. The circulating molecular forms were analyzed by gel-filtration and reversed-phase HPLC.Results: According to the HPLC analyses, circulating NT-proANP consists mainly of the full-length peptide, with some degradation at both ends. In contrast, circulating NT-proBNP is very heterogeneous. Most immunoreactive NT-proBNP is significantly smaller in size than NT-proBNP1–76, with truncation at both termini. The smallest fragments can be detected by assays directed at the central part of NT-proBNP only; assays directed at the ends gave 30–40% lower values. Despite the difference, the various assays correlated reasonably well with each other (r2 = 0.77–0.85). In patients with acute myocardial infarction, NT-proANP and NT-proBNP concentrations were 1.8–2.3 and 4.2–4.5 times higher than in healthy individuals. The development of heart failure further increased the concentrations.Conclusions: Molecular heterogeneity of the circulating forms causes a serious risk of preanalytical errors in assays for NT-proBNP and, to a lesser extent, NT-proANP. The development of a sandwich assay for NT-proBNP would be especially challenging. The most robust and reliable assays use antibodies directed at the central portions of NT-proANP or NT-proBNP.

Objective—To identify variables and evaluate methods for assessing chronic pain in dogs. Design—Prospective study. Animals—41 dogs with canine hip dysplasia (CHD), and 24 apparently healthy dogs with no history of pain. Procedure—2 veterinarians evaluated the dogs' locomotion and signs of pain. Owners of dogs with CHD and control dogs answered a questionnaire regarding their dogs' demeanor, behavior, and locomotion (descriptive scales) and assessed pain and locomotion (visual analog scales). Plasma concentrations of several stress-related hormones were determined, and 13 radiologic variables were assessed in affected hip joints. Results—For many of the questions, answers provided by owners of dogs with CHD differed significantly from those of owners of control dogs. Stress hormone concentrations differed significantly between dogs with CHD and controls, but individual variation was too great for them to be of value in pain assessment. None of the radiologic variables examined correlated well with owner or veterinarian pain scores. Conclusions and Clinical Relevance—Chronic pain could be assessed in dogs with CHD through completion of the study questionnaire by a person familiar with the pet (eg, owner) after receiving appropriate education in its use. Eleven variables were identified as being potentially useful in assessment of chronic pain in dogs. (J Am Vet Med Assoc 2003;222: 1552–1558)

The effects of propofol infusion were compared with propofol/isoflurane anaesthesia in six beagles premedicated with 10 microg/kg intramuscular (i.m.) dexmedetomidine. The suitability of a cold pressor test (CPT) as a stress stimulus in dogs was also studied. Each dog received isoflurane (end tidal 1.0%, induction with propofol) with and without CPT; propofol (200 microg/kg/min, induction with propofol) with and without CPT; premedication alone with and without CPT in a randomized block study in six separate sessions. Heart rate and arterial blood pressures and gases were monitored. Plasma catecholamine, beta-endorphin and cortisol concentrations were measured. Recovery profile was observed. Blood pressures stayed within normal reference range but the dogs were bradycardic (mean heart rate 57 mmHg) when compared with isoflurane (mean < 52 mmHg). Recovery times were longer with propofol than when compared with the other treatments. The mean extubation times were 8 +/- 3.4 and 23 +/- 6.3 min after propofol/isoflurane and propofol anaesthesia, respectively. The endocrine stress response was similar in all treatments except for lower adrenaline level after propofol infusion at the end of the recovery period. Cold pressor test produced variable responses and was not a reliable stress stimulus in the present study. Propofol/isoflurane anaesthesia was considered more useful than propofol infusion because of milder degree of respiratory depression and faster recovery.

Members of the mammalian protein kinase C (PKC) superfamily play key regulatory roles in multiple cellular processes. In the heart, PKC signaling is involved in hypertrophic agonist-induced gene expression and hypertrophic growth. To investigate the specific function of PKC signaling in regulating cardiomyocyte growth, we used antisense oligonucleotides to inhibit PKC alpha, the major isozyme present in the neonatal heart. Transfection of cultured neonatal cardiomyocytes with antisense PKCalpha oligonucleotides resulted in a marked reduction in both PKCalpha mRNA and protein levels. PKCalpha antisense treatment also reduced phenylephrine (PE)-induced PKC activity and perinuclear translocation of PKCalpha. Antisense inhibition of PKCalpha led to reduction of PE-induced increase in skeletal alpha-actin mRNA levels and atrial natriuretic peptide (ANP) secretion but had no significant effects on PE-induced beta-myosin heavy chain, ANP, or B-type natriuretic peptide (BNP) gene expression. On the other hand, antisense PKCalpha treatment attenuated endothelin-1-induced increase in ANP and BNP peptide secretion, whereas endothelin-1-induced gene expression of ANP and BNP remained unchanged. The hypertrophic agonist-induced growth of cardiomyocytes, characterized by increased [(3)H]leucine incorporation, was not affected with antisense PKCalpha treatment. Furthermore, we found that PE-induced increase in extracellular signal-regulated kinase (ERK) activity was partially inhibited by antisense PKCalpha treatment, implicating ERK as a downstream mediator for PKCalpha signaling. These results indicate that PKCalpha isozyme is involved in hypertrophic signaling in cardiomyocytes and provide novel strategies for future studies to identify other cellular targets controlled selectively by PKCalpha or other PKC isozymes.

Melatonin content in the cellular fraction and medium of Tetrahymena pyriformis GL cultures was measured at different time points of light and dark exposures. Tetrahymena produced, stored and secreted immunoreactive melatonin, which in displacement and HPLC studies, behaved like synthetic melatonin. There was not a continuous secretion of melatonin produced by the cells. In contrast to this, storage of melatonin was observed, which was more expressed in dark conditions. Prolonged light exposure suppressed melatonin production and secretion alike, however it did not block it completely.

We investigated whether transcranial bright light (TBL) affects nocturnal melatonin and cortisol secretion in sham-controlled crossover trial. Young healthy adults were exposed in random order to 24 minutes of TBL or sham exposure via ear canals at 01:10 h. Saliva and urine samples were collected hourly between 21 h-03 h and 06 h-09 h. There were no significant differences in melatonin or cortisol concentrations between TBL and sham exposures at any sampling point indicating that TBL via ear canals does not suppress nocturnal melatonin secretion. Thus, non-visual effects of TBL are mediated via a pathway not involving melatonin suppression.

We studied habituation processes by exposing six healthy men to cold air (2 h in a 10°C room) daily for 11 days. During the repeated cold exposures, the general cold sensations and those of hand and foot became habituated so that they were already significantly less intense after the first exposure and remained habituated to the end of the experiment. The decreases in skin temperatures and increases in systolic blood pressure became habituated after four to six exposures, but their habituations occurred only at a few time points during the 120-min cold exposure and vanished by the end of the exposures. Serum thyroid-stimulating hormone, total thyroxine and triiodothyronine, norepinephrine, epinephrine, cortisol, and total proteins were measured before and after the 120-min cold exposure on days 0, 5, and 10. The increase in norepinephrine response became reduced on days 5 and 10 and that of proteins on day 10, suggesting that the sympathetic nervous system became habituated and hemoconcentration became attenuated. Thus repeated cold-air exposures lead to habituations of cold sensation and norepinephrine response and to attenuation of hemoconcentration, which provide certain benefits to those humans who have to stay and work in cold environments.

Ouabain was recently isolated from human plasma, bovine hypothalamus and bovine adrenal in attempts to identify endogenous substances inhibiting the cell membrane sodium pump. A number of radioimmunoassays have been developed in order to study the clinical significance of ouabain. The results have been controversial with regard to the presence and chemical nature of plasma ouabain-like immunoreactivity. We have now measured ouabain in healthy and pregnant individuals using solid-phase extraction of plasma samples followed by a new radioimmunoassay with the extraordinary sensitivity of at least 2 fmol/tube (5 pmol/l). Plasma extracts, a previously isolated human plasma ouabain-like compound and bovine hypothalamic inhibitory factor displaced the tracer in parallel and eluted identically with ouabain in high-performance liquid chromatography. Plasma ouabain immunoreactivity was found to be much lower than reported previously: 12.6+/-1.3 pmol/l in healthy men (mean+/-s.e., n=20) and 9.4+/-0.7 pmol/l in women (n=14). In pregnant women (n=28) plasma ouabain concentration was 16.3+/-4.0 pmol/l during the first trimester, 18.8+/-4.3 pmol/l during the second trimester and 24.3+/-4.0 pmol/l during the third trimester (all P

Erythropoietic response in 10 healthy nonsmoking volunteers exposed to normobaric hypoxia continuously or intermittently 12 h daily for 7 d was evaluated in a randomized cross-over study.An oxygen content of 15.4% corresponding to an altitude of 2500 m was created by adding nitrogen into room air in a flat. Venous blood samples for hemoglobin (Hb), hematocrit (Hct), reticulocytes, serum erythropoietin (S-EPO), red cell 2,3-diphosphoglycerate (2,3-DPG), serum ferritin (S-Ferrit), and serum soluble transferrin receptor (S-TransfR) were drawn at 8:00 a.m.S-EPO was increased from baseline values of 22.9+/-9.6 and 20.5+/-10.1 U x L(-1) to 40.7+/-12.9 (P0.05) and 35+/-14.3 U x L(-1) (P0.05) after the first night in continuous and intermittent hypoxia, respectively, and remained elevated throughout both exposures. Hb and Hct values did not show any significant changes. Red cell 2,3-DPG rose from baseline a value of 5.0+/-0.8 to 5.9+/-0.7 mmol x L(-1) (P0.05) after the first day in continuous hypoxia and from 5.2+/-0.7 mmol x L(-1) to 6.1+/-0.5 mmol x L(-1) on day 3 (P0.05) during intermittent hypoxia. The reticulocyte count rose significantly (P0.05) after 5 d in both experiments. S-transferrin receptor level rose significantly from 2.2+/-0.4 and 2.1+/-0.5 mg x L(-1) to 2.6+/-0.5 mg x L(-1) and 2.3+/-0.6 mg x L(-1) on day 5 (P0.05), to 2.7+/-0.5 mg x L(-1) and 2.5+/-0.6 mg x L(-1) on day 7 (P0.05) under continuous and intermittent hypoxia, respectively.We suggest that intermittent exposure to moderate normobaric hypoxia 12 h daily for 1 wk induces a similar stimulation of erythropoiesis as continuous exposure.

There are three members in the natriuretic peptide hormone family, atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP, brain natriuretic peptide), and C-type natriuretic peptide (CNP), that are involved in the regulation of blood pressure and fluid homeostasis. CNP is found principally in the central nervous system and vascular endothelial cells while ANP and BNP are cardiac hormones. ANP is synthesized mainly in the atria of the normal adult heart, while BNP is produced by both the atria and ventricles. The mechanisms controlling ANP release have been the subject of intense research, and are now fairly well understood. The major determinant of ANP secretion is myocyte stretch. Although much less is known about the factors regulating BNP release from the heart, myocyte stretch has also been reported to stimulate BNP release from both atria and ventricles. However, whether wall stretch acts directly or via factors such as endothelin- , nitric oxide, or angiotensin II liberated in response to distension has not been established. Recent studies show that by stimulating endothelin type A receptors endothelin plays an important physiological role as a mediator of acute-volume load-induced ANP secretion from atrial myocytes in conscious animals. In fact, endogenous paracrine/autocrine factors liberated in response to atrial wall stretch rather than direct stretch appears to be responsible for activation of ANP secretion in response to volume load, as evidenced by almost complete blockade of ANP secretion during combined inhibition of endothelin type A/B and angiotensin II receptors. Furthermore, under certain experimental conditions angiotensin II and nitric oxide may also exert a significant modulatory effect on stretch-activated ANP secretion. The molecular mechanisms by which endothelin-1, angiotensin II, and nitric oxide synergistically regulate stretch-activated ANP release are yet unclear.