Ventricular arrhythmias, a leading cause of sudden cardiac death, can be triggered by cardiomyocyte early afterdepolarizations (EADs). EADs can result from an abnormal late activation of L-type Ca2+ channels (LTCCs). Current LTCC blockers (class IV antiarrhythmics), while effective at suppressing EADs, block both early and late components of I-Ca,I-L, compromising inotropy. However, computational studies have recently demonstrated that selective reduction of late I-Ca,I-L (Ca2+ influx during late phases of the action potential) is sufficient to potently suppress EADs, suggesting that effective antiarrhythmic action can be achieved without blocking the early peak I-Ca,I-L, which is essential for proper excitation-contraction coupling. We tested this new strategy using a purine analogue, roscovitine, which reduces late I-Ca,I-L with minimal effect on peak current. Scaling our investigation from a human Ca(V)1.2 channel clone to rabbit ventricular myocytes and rat and rabbit perfused hearts, we demonstrate that (1) roscovitine selectively reduces I-Ca,I-L noninactivating component in a human Ca(V)1.2 channel clone and in ventricular myocytes native current, (2) the pharmacological reduction of late I-Ca,I-L suppresses EADs and EATs (early after Ca2+ transients) induced by oxidative stress and hypokalemia in isolated myocytes, largely preserving cell shortening and normal Ca2+ transient, and (3) late I-Ca,I-L reduction prevents/suppresses ventricular tachycardia/fibrillation in ex vivo rabbit and rat hearts subjected to hypokalemia and/or oxidative stress. These results support the value of an antiarrhythmic strategy based on the selective reduction of late I-Ca,I-L to suppress EAD-mediated arrhythmias. Antiarrhythmic therapies based on this idea would modify the gating properties of Ca(V)1.2 channels rather than blocking their pore, largely preserving contractility.

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KCNE beta-subunits assemble with and modulate the properties of voltage-gated K+ channels. In the heart, KCNE1 associates with the alpha-subunit KCNQ1 to generate the slowly activating, voltage-dependent potassium current (IKs) in the heart that controls the repolarization phase of cardiac action potentials. By contrast, in epithelial cells from the colon, stomach, and kidney, KCNE3 coassembles with KCNQ1 to form K+ channels that are voltage-independent K+ channels in the physiological voltage range and important for controlling water and salt secretion and absorption. How KCNE1 and KCNE3 subunits modify KCNQ1 channel gating so differently is largely unknown. Here, we use voltage clamp fluorometry to determine how KCNE1 and KCNE3 affect the voltage sensor and the gate of KCNQ1. By separating S4 movement and gate opening by mutations or phosphatidylinositol 4,5-bisphosphate depletion, we show that KCNE1 affects both the S4 movement and the gate, whereas KCNE3 affects the S4 movement and only affects the gate in KCNQ1 if an intact S4-to-gate coupling is present. Further, we show that a triple mutation in the middle of the transmembrane (TM) segment of KCNE3 introduces KCNE1-like effects on the second S4 movement and the gate. In addition, we show that differences in two residues at the external end of the KCNE TM segments underlie differences in the effects of the different KCNEs on the first S4 movement and the voltage sensor-to-gate coupling.

Heart rate variability (HRV) analysis is used as a marker of autonomic nervous system activity which may be related to mental and/or physical activity. HRV features can be extracted by detecting QRS complexes from an electrocardiogram (ECG) signal. The difficulties in QRS complex detection are due to the artifacts and noises that may appear in the ECG signal when subjects are performing their daily life activities such as exercise, posture changes, climbing stairs, walking, running, etc. This study describes a strong computation method for real-time QRS complex detection. The detection is improved by the prediction of the position of R waves by the estimation of the RR intervals lengths. The estimation is done by computing the intensity of the electromyogram noises that appear in the ECG signals and known here in this paper as ECG Trunk Muscles Signals Amplitude (ECG-TMSA). The heart rate (HR) and ECG-TMSA increases with the movement of the subject. We use this property to estimate the lengths of the RR intervals. The method was tested using famous databases, and also with signals acquired when an experiment with 17 subjects from our laboratory. The obtained results using ECG signals from the MIT-Noise Stress Test Database show a QRS complex detection error rate (ER) of 9.06%, a sensitivity of 95.18% and a positive prediction of 95.23%. This method was also tested against MIT-BIH Arrhythmia Database, the result are 99.68% of sensitivity and 99.89% of positive predictivity, with ER of 0.40%. When applied to the signals obtained from the 17 subjects, the algorithm gave an interesting result of 0.00025% as ER, 99.97% as sensitivity and 99.99% as positive predictivity.

Objective: Endothelial function is important for regulating peripheral blood flow to meet varying metabolic demands and can be measured indirectly during vascular provocations. In this study, we compared the PAT finger response (EndoPAT) after a 5-minutes arterial occlusion to that from forearm skin comprehensive microcirculation analysis (EPOS). Methods: Measurements in 16 subjects with varying cardiovascular risk factors were carried out concurrently with both methods during arterial occlusion, while forearm skin was also evaluated during local heating. Results: Peak values for EPOS skin Perf(conv) and speed-resolved total perfusion after the release of the occlusion were significantly correlated to the EndoPAT RHI (rho =.68, P = .007 and rho =.60, P = .025, respectively), mainly due to high-speed blood flow. During local heating, EPOS skin oxygen saturation, SO2, was significantly correlated to RHI (rho = .62, P =.043). This indicates that SO2 may have diagnostic value regarding endothelial function. Conclusions: We have demonstrated for the first time a significant relationship between forearm skin microcirculatory perfusion and oxygen saturation and finger PAT. Both local heating and reactive hyperemia are useful skin provocations. Further studies are needed to understand the precise regulation mechanisms of blood flow and oxygenation during these tests.

Objective: Shear forces play a key role in the maintenance of vessel wall integrity. Current understanding regarding shear-dependent gene expression is mainly based on in vitro or in vivo observations with experimentally deranged shear, hence reflecting acute molecular events in relation to flow. Our objective was to determine wall shear stress (WSS) in the rat aorta and study flow-dependent vessel wall biology under physiological conditions.

Methods and Results: Animal-specific aortic WSS magnitude and vector direction were estimated using computational fluid dynamic simulation based on aortic geometry and flow information acquired by MRI. Two distinct flow pattern regions were identified in the normal rat aorta; the distal part of the inner curvature being exposed to low WSS and a non-uniform vector direction, and a region along the outer curvature being subjected to markedly higher levels of WSS and a uniform vector direction. Microarray analysis revealed a strong differential expression between the flow regions, particularly associated with transcriptional regulation. In particular, several genes related to Ca²⁺-signalling, inflammation, proliferation and oxidative stress were among the most highly differentially expressed.

Conclusions: Microarray analysis validated the CFD-defined WSS regions in the rat aorta, and several novel flow-dependent genes were identified. The importance of these genes in relation to atherosusceptibility needs further investigation.

A network of thin (C and A delta) afferents relays various signals related to the physiological condition of the body, including sensations of gentle touch, pain, and temperature changes. Such afferents project to the insular cortex, where a somatotopic organization of responses to noxious and cooling stimuli was recently observed. To explore the possibility of a corresponding body-map topography in relation to gentle touch mediated through C tactile (CT) fibers, we applied soft brush stimuli to the right forearm and thigh of a patient (GL) lacking A beta afferents, and six healthy subjects during functional magnetic resonance imaging (fMRI). For improved fMRI analysis, we used a highly sensitive multivariate voxel clustering approach. A somatotopic organization of the left (contralateral) posterior insular cortex was consistently demonstrated in all subjects, including GL, with forearm projecting anterior to thigh stimulation. Also, despite denying any sense of touch in daily life, GL correctly localized 97% of the stimuli to the forearm or thigh in a forced-choice paradigm. The consistency in activation patterns across GL and the healthy subjects suggests that the identified organization reflects the central projection of CT fibers. Moreover, substantial similarities of the presently observed insular activation with that described for noxious and cooling stimuli solidify the hypothesized sensory-affective role of the CT system in the maintenance of physical well-being as part of a thin-afferent homeostatic network.

Bud Craig, an outstanding neuroscientist, died on 15 July 2023 at age 71. Bud made unique contributions to the fields of pain and interoception, challenging major dogmas and offering powerful explanations for various phenomena including central pain and the subjective awareness of feelings, with great implications for our understanding of consciousness.

Aim The I-Ks channel is important for termination of the cardiac action potential. Hundreds of loss-of-function mutations in the I-Ks channel reduce the K+ current and, thereby, delay the repolarization of the action potential, causing Long QT Syndrome. Long QT predisposes individuals to Torsades de Pointes which can lead to ventricular fibrillation and sudden death. Polyunsaturated fatty acids (PUFAs) are potential therapeutics for Long QT Syndrome, as they affect I-Ks channels. However, it is unclear which properties of PUFAs are essential for their effects on I-Ks channels. Methods To understand how PUFAs influence I-Ks channel activity, we measured effects on I-Ks current by two-electrode voltage clamp while changing different properties of the hydrocarbon tail. Results There was no, or weak, correlation between the tail length or number of double bonds in the tail and the effects on or apparent binding affinity for I-Ks channels. However, we found a strong correlation between the positions of the double bonds relative to the head group and effects on I-Ks channels. Conclusion Polyunsaturated fatty acids with double bonds closer to the head group had higher apparent affinity for I-Ks channels and increased I-Ks current more; shifting the bonds further away from the head group reduced apparent binding affinity for and effects on the I-Ks current. Interestingly, we found that omega-6 and omega-9 PUFAs, with the first double bond closer to the head group, left-shifted the voltage dependence of activation the most. These results allow for informed design of new therapeutics targeting I-Ks channels in Long QT Syndrome.

Repolarization and termination of the ventricular cardiac action potential is highly dependent on the activation of the slow delayed-rectifier potassium I-Ks channel. Disruption of the I-Ks current leads to the most common form of congenital long QT syndrome (LQTS), a disease that predisposes patients to ventricular arrhythmias and sudden cardiac death. We previously demonstrated that polyunsaturated fatty acid (PUFA) analogues increase outward K+ current in wild type and LQTS-causing mutant I-Ks channels. Our group has also demonstrated the necessity of a negatively charged PUFA head group for potent activation of the I-Ks channel through electrostatic interactions with the voltage-sensing and pore domains. Here, we test whether the efficacy of the PUFAs can be tuned by the presence of different functional groups in the PUFA head, thereby altering the electrostatic interactions of the PUFA head group with the voltage sensor or the pore. We show that PUFA analogues with taurine and cysteic head groups produced the most potent activation of I-Ks channels, largely by shifting the voltage dependence of activation. In comparison, the effect on voltage dependence of PUFA analogues with glycine and aspartate head groups was half that of the taurine and cysteic head groups, whereas the effect on maximal conductance was similar. Increasing the number of potentially negatively charged moieties did not enhance the effects of the PUFA on the I-Ks channel. Our results show that one can tune the efficacy of PUFAs on I-Ks channels by altering the pK(a) of the PUFA head group. Different PUFAs with different efficacy on I-Ks channels could be developed into more personalized treatments for LQTS patients with a varying degree of I-Ks channel dysfunction.

Hypertrophic cardiomyopathy is a heart disease that is characterized by an enlarged heart muscle. Mutations to sarcomere proteins in the muscle fibers give rise to the disease, and this review aims to compile the mechanisms by which the mutations cause the disease phenotype. β-myosin heavy chain mutants affect the thick filament structure and contraction velocity of the muscle. Mutations to the myosin-binding protein C produces truncated proteins with decreased expression in the cells. Troponin T mutants cause myofibrillar disarray, alters affinity to α-tropomyosin, and are linked to a higher risk of sudden death. Troponin I is an unpredictable mutant that needs to be further researched but is thought to cause regulatory problems. Mutations to α-tropomyosin and the regulatory myosin light chain both affect the Ca2+-affinity of the proteins and leads to contractile problems. Hypercontractility as a result of the mutations seems to be the primary cause of the disease. Hypertrophic cardiomyopathy is linked to sudden death, and factors such as a family history of sudden death, multiple simultaneous mutations, unexplained syncope, non-sustained ventricular tachycardia, abnormal blood pressure response and extreme hypertrophy (>30 mm) heightens the risk of a sudden death. An increased knowledge about the disease will aid in the mission to better the treatments for the affected, but further investigation of pathological pathways needs to be performed.

Many animal species do not breathe in a continuous, rhythmic fashion, but rather display a variety of breathing patterns characterized by prolonged periods between breaths (inter-breath intervals), during which the heart continues to beat. Examples of intermittent breathing abound across the animal kingdom, from crustaceans to cetaceans. With respect to human physiology, intermittent breathing-also termed 'periodic' or 'episodic' breathing-is associated with a variety of pathologies. Cardiovascular phenomena associated with intermittent breathing in diving species have been termed 'diving bradycardia', 'submersion bradycardia', 'immersion bradycardia', 'ventilation tachycardia', 'respiratory sinus arrhythmia' and so forth. An examination across the literature of terminology applied to these physiological phenomena indicates, unfortunately, no attempt at standardization. This might be viewed as an esoteric semantic problem except for the fact that many of the terms variously used by different authors carry with them implicit or explicit suggestions of underlying physiological mechanisms and even human-associated pathologies. In this article, we review several phenomena associated with diving and intermittent breathing, indicate the semantic issues arising from the use of each term, and make recommendations for best practice when applying specific terms to particular cardiorespiratory patterns. Ultimately, we emphasize that the biology-not the semantics-is what is important, but also stress that confusion surrounding underlying mechanisms can be avoided by more careful attention to terms describing physiological changes during intermittent breathing and diving. What is the topic of this review? This review examines the rather confusing semantics that has been used to describe patterns in the field of cardiorespiratory physiology as it applies to intermittent breathing, particularly in diving species. What advances does it highlight? This review highlights the various cardiorespiratory phenomena associated with intermittent breathing and diving. It highlights the semantic issues associated with describing each and offers a rationale for standardizing terms based on underlying mechanisms to reduce confusion and advance the study of cardiorespiratory phenomena in both medical and comparative physiological investigations.

Background: Caused by a lesion or disease of the somatosensory system, neuropathic pain is notoriously difficult to treat with conventional analgesics. It has been suggested that inflammatory cytokines play a role in the development and maintenance of neuropathic pain. But human studies of these substances are relatively few and partly contradictory. Objectives: To simultaneously investigate the plasma levels of chemokine interleukin 8 (IL-8) and the cytokines IL-6, IL-1, and Granulocyte macrophage colony-stimulating factor (GM-CSF) in patients with peripheral neuropathic pain (most of whom due to failed back surgery syndrome) (n = 14) compared to controls (n = 17). Results: IL-6 was significantly higher in patients than in controls (0.92 ± 0.12 pg/ml vs. 0.57 ± 0.08 pg/ml, p = 0.012). IL-1, IL-8, and GM-CSF levels did not differ between the two groups. A multivariate analysis showed a tendency for patients also to have higher GM-CSF plasma levels than controls. Conclusions: This study found an increased level of IL-6 in plasma in patients with neuropathic pain, but not for the other pro-inflammatory substances investigated. There are several possible confounders not registered or controlled for in this and other studies of neuropathic pain. Implications: Larger studies that take several possible confounders into consideration are needed to further investigate the levels of plasma cytokines in different pain conditions. © 2015 Scandinavian Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

Background: The possibility of non-invasively assessing load-independent parameters characterizing cardiac function is of high clinical value. Typically, these parameters are assessed during resting conditions. However, for diagnostic purposes, the parameter behavior across a physiologically relevant range of heart rate and loads is more relevant than the isolated measurements performed at rest. This study sought to evaluate changes in non-invasive estimations of load-independent parameters of left-ventricular contraction and relaxation patterns at rest and during dobutamine stress. Methods: We applied a previously developed approach that combines non-invasive measurements with a physiologically-based, reduced-order model of the cardiovascular system to provide subject-specific estimates of parameters characterizing left ventricular function. In this model, the contractile state of the heart at each time point along the cardiac cycle is modeled using a time-varying elastance curve. Non-invasive data, including four-dimensional magnetic resonance imaging (4D Flow MRI) measurements, were acquired in nine subjects without a known heart disease at rest and during dobutamine stress. For each of the study subjects, we constructed two personalized models corresponding to the resting and the stress state. Results: Applying the modeling framework, we identified significant increases in the left ventricular contraction rate constant [from 1.5 +/- 0.3 to 2 +/- 0.5 (p = 0.038)] and relaxation constant [from 37.2 +/- 6.9 to 46.1 +/- 12 (p = 0.028)]. In addition, we found a significant decrease in the elastance diastolic time constant from 0.4 +/- 0.04 s to 0.3 +/- 0.03 s = 0.008). Conclusions: The integrated image-modeling approach allows the assessment of cardiovascular function given as model-based parameters. The agreement between the estimated parameter values and previously reported effects of dobutamine demonstrates the potential of the approach to assess advanced metrics of pathophysiology that are otherwise difficult to obtain non-invasively in clinical practice.

Research suggests that the discriminative and affective aspects of touch are processed differently in the brain. Primary somatosensory cortex is strongly implicated in touch discrimination, whereas insular and prefronal regions have been associated with pleasantness aspects of touch. However, the role of secondary somatosensory cortex (S2) is less clear. In the current study we used inhibitory repetitive transcranial magnetic stimulation (rTMS) to temporarily deactivate S2 and probe its role in touch perception. Nineteen healthy adults received two sessions of 1-Hz rTMS on separate days, one targeting right S2 and the other targeting the vertex (control). Before and after rTMS, subjects rated the intensity and pleasantness of slow and fast gentle brushing of the hand and performed a 2-point tactile discrimination task, followed by fMRI during additional brushing. rTMS to S2 (but not vertex) decreased intensity ratings of fast brushing, without altering touch pleasantness or spatial discrimination. MRI showed a reduced response to brushing in S2 (but not in S1 or insula) after S2 rTMS. Together, our results show that reducing touch evoked activity in S2 decreases perceived touch intensity, suggesting a causal role of S2 in touch intensity perception. Published by Elsevier Ireland Ltd.

Neuroscientific research on pleasant touch has focused on the C-tactile pathway for gentle stroking and has successfully explained how these sensory fibers transmit information about affective social touch to the brain and induce sensations of pleasantness. The C-tactile social/affective touch hypothesis even proposes that C-tactile fibers form a privileged pathway underlying social touch. However, deep pressure is a type of touch commonly considered pleasant and calming, occurring in hugs, cuddling, and massage. In this paper we introduce a paradigm for studying pleasant deep pressure and propose that it constitutes another important form of social touch. We describe development of the oscillating compression sleeve (OCS) as one approach to administering deep pressure and demonstrate that this touch is perceived as pleasant and calming. Further, we show that deep pressure can be imaged with functional magnetic resonance imaging (MRI) using the air-pressure driven OCS and that deep pressure activates brain regions highly similar to those that respond to C-tactile stroking, as well as regions not activated by stroking. We propose that deep pressure constitutes another social touch pathway of evolutionary importance signaling the close proximity of conspecifics. This article is part of a Special Issue entitled: The Neurobiology of Social and Affective Touch. (c) 2020 The Authors. Published by Elsevier Ltd on behalf of IBRO. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/ licenses/by-nc-nd/4.0/). research on pleasant touch has focused on the C-tactile pathway for gentle stroking and has successfully explained how these sensory fibers transmit information about affective social touch to the brain and induce sensations of pleasantness. The C-tactile social/affective touch hypothesis even proposes that C-tactile fibers form a privileged pathway underlying social touch. However, deep pressure is a type of touch commonly considered pleasant and calming, occurring in hugs, cuddling, and massage. In this paper we introduce a paradigm for studying pleasant deep pressure and propose that it constitutes another important form of social touch. We describe development of the oscillating compression sleeve (OCS) as one approach to administering deep pressure and demonstrate that this touch is perceived as pleasant and calming. Further, we show that deep pressure can be imaged with functional magnetic resonance imaging (MRI) using the air-pressuredriven OCS and that deep pressure activates brain regions highly similar to those that respond to C-tactile stroking, as well as regions not activated by stroking. We propose that deep pressure constitutes another social touch pathway of evolutionary importance signaling the close proximity of conspecifics. This article is part of a Special Issue entitled: The Neurobiology of Social and Affective Touch. (c) 2020 The Authors. Published by Elsevier Ltd on behalf of IBRO. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/ licenses/by-nc-nd/4.0/).

Background: Electrical cardioversion in patients with atrial fibrillation is followed by a transiently impaired atrial mechanical function, termed atrial stunning. During atrial stunning, a retained risk of left atrial thrombus formation exists, which may be attributed to abnormal left atrial blood flow patterns. 4D Flow cardiovascular magnetic resonance (CMR) enables blood flow assessment from the entire three-dimensional atrial volume throughout the cardiac cycle. We sought to investigate left atrial 4D blood flow patterns and hemostasis during left atrial stunning and after left atrial mechanical function was restored. Methods: 4D Flow and morphological CMR data as well as blood samples were collected in fourteen patients at two time-points: 2-3 h (Time-1) and 4 weeks (Time-2) following cardioversion. The volume of blood stasis and duration of blood stasis were calculated. In addition, hemostasis markers were analyzed. Results: From Time-1 to Time-2: Heart rate decreased (61 +/- 7 vs. 56 +/- 8 bpm, p = 0.01); Maximum change in left atrial volume increased (8 +/- 4 vs. 22 +/- 15%, p = 0.009); The duration of stasis (68 +/- 11 vs. 57 +/- 8%, p = 0.002) and the volume of stasis (14 +/- 9 vs. 9 +/- 7%, p = 0.04) decreased; Thrombin-antithrombin complex (TAT) decreased (5.2 +/- 3.3 vs. 3.3 +/- 2.2it.g/L, p = 0.008). A significant correlation was found between TAT and the volume of stasis (r(2) = 0.69, p amp;lt; 0.001) at Time-1 and between TAT and the duration of stasis (r(2) = 0.34, p = 0.04) at Time-2. Conclusion: In this longitudinal study, left atrial multidimensional blood flow was altered and blood stasis was elevated during left atrial stunning compared to the restored left atrial mechanical function. The coagulability of blood was also elevated during atrial stunning. The association between blood stasis and hypercoagulability proposes that assessment of left atrial 4D flow can add to the pathophysiological understanding of thrombus formation during atrial fibrillation related atrial stunning.

Arterial pathology is the major contributor to cardiovascular diseases and mortality. The mechanical properties of arteries are independent factors for cardiovascular disease and mortality, where genetics influence the structure of the arterial wall, which may result in change in arterial stiffness. The aims of this thesis were to study the mechanical properties of the popliteal artery (PA) in healthy subjects and the influence of angiotensin-converting enzyme (ACE) polymorphism and Fibrillin-1 (FBN1) polymorphism on large arteries. Further, the impact of FBN1 polymorphism on cardiovascular morbidity and mortality was investigated.

The PA is, after the abdominal aorta, the most common site of aneurysmal development. The PA was studied in healthy subject with ultrasound and the diameter increased and the distensibility decreased with age, with men having lower distensibility than women. This seems not to be the behavior of a true muscular artery but rather of a central elastic artery such as the aorta, and might have implications for the susceptibility to aneurysm formation, as well as the association of dilating disease between the PA and the aorta. The wall stress in the PA was low and unaffected by age, probably caused by a compensatory remodeling response with an increase in wall thickness. This indicates that other mechanisms than wall stress contribute to the process of pathological dilatation in the PA.

The ACE D allele may be associated with abdominal aortic aneurysm. Elderly men with the ACE D allele were associated with increased abdominal aortic stiffness compared to men carrying the I/I genotype. This suggests that the ACE D allele impairs arterial wall integrity, and in combination with local hemodynamic and other genetic factors it may have a roll in aneurysm formation.

The FBN1 2/3 genotype has been associated with increased systolic blood pressure. The FBN1 2/3 genotype in middle-aged men was associated with increased abdominal aortic stiffness and blood pressure which indicates an increased risk for developing cardiovascular disease. The increased presence of plaque in the carotid artery of middle-aged men with the FBN1 2/3 genotype indicates a pathological arterial wall remodeling with a more pronounced atherosclerotic burden, but did however not affect the risk of cardiovascular events and/or death in this population. This relationship needs to be studied further.

Objective: Fibrillin-1 is an important constituent of the vascular wall and earlier studies have indicated an effect of the Fibrillin-1 (FBN1) 2/3 genotype on blood pressure as well as aortic stiffness in men. The aim was to determine if the FBN1 2/3 genotype was associated with presence of carotid plaque and incident cardiovascular morbidity and mortality in middle-aged subjects.

Material and Method: The FBN1 genotype was characterized in 5765 subjects (2424 men, 3341 women; aged 45-69 years) recruited from the Malmö Diet and Cancer Study Cardiovascular Cohort, Sweden. Plaque occurrence and intima media thickness (IMT) of the carotid artery were assessed by ultrasound. Incidence of first cardiovascular events (myocardial infarction and stroke) and cause-specific mortality was monitored during a mean of 13.2 years follow-up.

Results: The most common FBN1 genotypes were 2/2, 2/3 and 2/4 which accounted for 92.2% (n=5317) of the subjects. There were no differences between the three genotypes regarding age, blood pressure, glucose, lipids, smoking habits, CCA diameter and IMT in men and women. Presence of plaque in the carotid artery was higher in men with genotype 2/3 as compared to the 2/2 and 2/4 genotypes, (55% vs. 46% and 50%, p=0.007). No similar difference was observed in women. No significant relationship was observed between FBN1 genotypes and incidence of CVD or all-cause mortality.

Conclusions: The increased prevalence of plaque in the carotid artery of middle-aged men with FBN1 2/3 genotype indicates a pathological arterial wall remodeling with a more pronounced atherosclerotic burden. 

Introduction: The popliteal artery (PA) is, after aorta, the most common site for aneurysm formation. Why the PA is more susceptible than other peripheral muscular arteries is unknown. We hypothesised that the wall composition, which in turn affects wall properties, as well as the circumferential wall stress imposed on the arterial wall, might differ compared to other muscular arteries. The aim was to study the circumferential wall stress of the PA in healthy subjects with the adjacent muscular common femoral artery (CFA) as a comparison.

Material and Methods: Ninety-four healthy subjects were included in this study (45 males, range 10-78 years and 49 females, range 10-83 years). The lumen diameter (LD) and intima-media thickness (IMT) in the PA and CFA were investigated with a Philips P700 ultrasound device. Together with blood pressure the circumferential wall stress was defined according to the law of Laplace adjusted for IMT.

Results: The diameter increased with age in both PA and CFA (P<.001), with males having larger diameter than females (P<.001). IMT increased with age in both PA and CFA (P<.001), with higher IMT values in males only in PA (P<0.001). The calculated wall stress was unchanged with age in both arteries, but lower in PA than in CFA in both male and female subjects (P<0.001).

Conclusion: This study shows that the popliteal and common femoral artery wall stress is maintained during ageing, probably due to compensatory remodeling response with an increase in arterial wall thickness. However, the stress imposed on the popliteal artery wall is quite low, indicating that other mechanisms than wall stress contribute to the process of pathological arterial dilatation in the popliteal artery.

Inclusion body myositis is the most common disabling inflammatory myopathy in the elderly. It is more frequent in men and after the age of 50 years. Inflammatory and degenerative features coexist. There is a T-cell mediated autoimmunity driven by in situ clonally expanded cytotoxic CD8-positive T-cells invading non-necrotic muscle fibres expressing MHC-I antigen. The hallmarks of degeneration are the deposition of protein aggregates and the formation of vesicles. The course of the disease is slow and the diagnosis is usually set after several years. The muscle weakness and wasting is assymetric, affecting predominantly distal muscles of the upper extremity and proximal muscles of the legs. The signs and clinical course can be characteristic, but the diagnosis is established by muscle biopsy. less thanbrgreater than less thanbrgreater thanThere is currently no evidence based effective treatment for sIBM. Prednisone, azathioprine, methotrexate, cyclosporine and IFN-beta failed. Oxandrolon did not improve symptoms. Treatment with intravenous immunglobuline (IVIG) induced in some patients a transient improvement of swallowing and of muscle strenght, but the overall study results were negative. less thanbrgreater than less thanbrgreater thanA T-cell depleting monoclonal antibody (alemtuzumab), in a small uncontrolled study slowed down disease progression for a six-month period. Repeated muscle biopsies showed the reduction of T-cells in the muscle and the suppression of some degeneration associated molecules. An effective therapeutic mean should act on both aspects of the pathomechanism, on the inflammatory and the degenerative processes as well.

We have previously shown that changes in the microbiome influence how the healing tendon responds to different treatments. The aim of this study was to investigate if changes in the microbiome influence the response to mechanical loading during tendon healing. 90 Sprague-Dawley rats were used. Specific Opportunist and Pathogen Free (SOPF) rats were co-housed with Specific Pathogen Free (SPF) rats, carrying Staphylococcus aureus and other opportunistic microbes. After 6 weeks of co-housing, the SOPF rats were contaminated which was confirmed by Staphylococcus aureus growth. Clean SOPF rats were used as controls. The rats were randomized to full loading or partial unloading by Botox injections in their calf muscles followed by complete Achilles tendon transection. Eight days later, the healing tendons were tested mechanically. The results were analysed by a 2-way ANOVA with interaction between loading and contamination on peak force as the primary outcome and there was an interaction for both peak force (p = 0.049) and stiffness (p = 0.033). Furthermore, partial unloading had a profound effect on most outcome variables. In conclusion, the response to mechanical loading during tendon healing is influenced by changes in the microbiome. Studies aiming for clinical relevance should therefore consider the microbiome of laboratory animals.

When assessing passive joint range of motion in neurological conditions, concomitant involuntary muscle activity is generally regarded small enough to ignore. This assumption is untested. If false, many clinical and laboratory studies that rely on these assessments may be in error. We determined to what extent small amounts of involuntary muscle activity limit passive range of motion in 30 able-bodied adults. Subjects were seated with the knee flexed 90 degrees and the ankle in neutral, and predicted maximal plantarflexion torque was determined using twitch interpolation. Next, with the knee flexed 90 degrees or fully extended, the soleus muscle was continuously electrically stimulated to generate 1, 2.5, 5, 7.5, and 10% of predicted maximal torque, in random order, while the ankle was passively dorsiflexed to a torque of 9 N.m by a blinded investigator. A trial without stimulation was also performed. Ankle dorsiflexion torque-angle curves were obtained at each percent of predicted maximal torque. On average (mean, 95% confidence interval), each 1% increase in plantarflexion torque decreases ankle range of motion by 2.4 degrees (2.0 to 2.7 degrees; knee flexed 90 degrees) and 2.3 degrees (2.0 to 2.5 degrees; knee fully extended). Thus 5% of involuntary plantarflexion torque, the amount usually considered small enough to ignore, decreases dorsiflexion range of motion by similar to 12 degrees. Our results indicate that even small amounts of involuntary muscle activity will bias measures of passive range and hinder the differential diagnosis and treatment of neural and nonneural mechanisms of contracture. NEW amp; NOTEWORTHY The soleus muscle in able-bodied adults was tetanically stimulated while the ankle was passively dorsiflexed. Each 1% increase in involuntary plantarflexion torque at the ankle decreases the range of passive movement into dorsiflexion by amp;gt;2 degrees. Thus the range of ankle dorsiflexion decreases by similar to 12 degrees when involuntary plantarflexion torque is 5% of maximum, a torque that is usually ignored. Thus very small amounts of involuntary muscle activity substantially limit passive joint range of motion.

Narcolepsy is a chronic sleep disorder, characterised by excessive daytime sleepiness with frequent uncontrollable sleep attacks. In addition to sleeprelated problems, changes in cognition have also been observed in patients with narcolepsy and has been linked to the loss of Orexin-A in a number of studies. Results from previous functional and structural neuroimaging studies would suggest that the loss of Orexin-A has numerous downstream effects in terms of both resting state glucose metabolism and perfusion and reduction in cortical grey matter.

Specifically, studies investigating narcolepsy with positron emission tomography (PET) and single photon emission computed tomography (SPECT) have observed aberrant perfusion and glucose metabolism in the hypothalamus and thalamus, as well as in prefrontal cortex. A very recent PET study in a large cohort of adolescents with type 1 narcolepsy further observed that the hypoand hypermetabolism in many of these cortico-frontal and subcortical brain regions also exhibited significant correlations with performance on a number of neurocognitive tests. These findings parallel those found in structural neuroimaging studies, where a reduction of cortical grey matter in frontotemporal areas has been observed.

The Aim of this thesis was to investigate mechanisms and aetiology behind the symptoms in narcolepsy through the application of different neuroimaging techniques. I present in this thesis evidence supporting that the complaints about subjective memory deficits in narcolepsy are related to a misallocation of resources.

I further describe how this has its seat in defective default mode network activation, possibly involving alterations to GABA and Glutamate signaling. In addition to this, I present our findings of a structural deviation in an area of the brainstem previously not described in the aetiology of narcolepsy.

This finding may have implications for further understanding the aetiology of the disease and the specific neuronal populations involved.

In addition to this, I show evidence from adipose tissue measurements in specific compartments, confirming that weight gain in narcolepsy is characterized by centrally located weight gain and may be specifically related to OX changes, but maybe not brown adipose tissue volume.

The findings presented in this thesis provides new insights to the pathophysiology of narcolepsy beyond the well-known depletion of OX producing neurons in the hypothalamus.

Assessment of the microcirculation is of major importance in understanding the physiology of the vasculature and in assessing te vascular effects of pathological conditions such as diabetes, hypertension and sepsis. Transdermal iontophoresis can be used to non‐invasively introduce vasoactive drugs into the skin. The response to these drugs of the local cutaneous microvasculature can be measured by laser Doppler flowmetry methods. Although these techniques have been used together for over two decades, there are still important methodological issues to be resolved. This work is aimed at optimizing transdermal iontophoresis as a tool for microvascular assessment by focusing on the main methdological issues: non‐specific vasodilatation, drug delivery protocols and analysis of blood flow data.

Non‐specific vasodilatation, an increase blood flow during iontophoresis of non‐vasoactive compounds, is an important problem as it interferes with the response to the administered drug. By investigating this effect in healthy volunteers, we found that the extent of the non‐specific response differs between the positive and negative electrode and that it is dependent on the voltage over the skin andon the ionic strength of the vehicle in which the drug is dissolved. We also found that the extent of the non‐specific response could be reduced by applying local anesthetics and by pre‐treatment with antihistamine drugs. These results suggest that non‐specific effects could be mediated by depolarization or hyperpolarisation of cells, triggering neural and histamine related mechanisms that finally lead to vasodilatation of the local microvasculature.

To prevent non‐specific effects from occurring during the experiments, our results show that the current strength and the total electric charge during iontophoresis should be limited to 0.02 mA and12 mC, respectively. Furthermore, drug solutions at physiological ionic strengths should be used. Under these conditions, adequate responses to the most commonly used drugs, acetylcholine (ACh) and sodium nitroprusside (SNP), are obtained while no significant non‐specific vasodilatation occurs.

The results of our investigations show that blood responses to ACh and SNP applied by a single iontophoretic pulse can well be escribed by conventional dose‐response models, which enables a more powerful analysis and comparison between drugs or possibly patient groups as compared with conventional aalysis methods. Finally, we have incorporated drug transport and physiological response to the local drug concentration during iontophoresis of vasoactve drugs into a single model. Validation of this model using measured responses to ACh and SNP shows that the commonly used assumption that the local drug concentration during iontophoresis is linearly proportional to the electric charge may not be valid.

Background Hyperalgesia is a heightened pain response to a noxious stimulus and is a hallmark of many common neuropathic and chronic pain conditions. In a double-blind placebo-controlled drug-crossover trial, the effects of concomitant and delayed minocycline treatment on the initiation and resolution of muscle hyperalgesia were tested. Methods An initial cohort (n = 10) received repeated injections (5 mu g: days 0, 2 and 4) of nerve growth factor (NGF) in the flexor carpi ulnaris muscle of the forearm and pressure pain thresholds were collected at day 0 (control), day 7 (peak) and day 14 (recovery). A second cohort (n = 18) underwent an identical procedure, however, half received a placebo between days 0 and 7 before switching to minocycline from days 7 to 14 (P1/M2), while the remaining subjects received minocycline (day 0: 200mg then 100mg b.i.d. for 7 days) before switching to placebo (M1/P2). Results The initial cohort exhibited a diffuse muscular pain hypersensitivity with a decrease in pressure pain thresholds at day 7 before a partial return to normalcy at day 14. The P1/M2 treatment group exhibited an identical peak in hypersensitivity at day 7, however, after switching to minocycline in week 2 showed a significant reduction in muscle hyperalgesia compared with the initial cohort at day 14. The M1/P2 treatment group had significantly less (similar to 43%) hyperalgesia at day 7 compared with the other groups. Conclusions The study indicates that the administration of minocycline can reduce experimentally induced muscle pain regardless of the time of administration. Significance In a double-blind placebo-controlled drug-crossover study, the common antibiotic minocycline was found to reduce the muscle hyperalgesia induced by intramuscular injection of nerve growth factor. The results of the study showed that both concomitant (pre-emptive) and delayed administration of minocycline can ameliorate the onset and facilitate the resolution of experimentally induced muscle hyperalgesia.

Objectives

The authors sought to measure the turbulent kinetic energy (TKE) in the ascending aorta of patients with aortic stenosis and to assess its relationship to irreversible pressure loss.

Background

Irreversible pressure loss caused by energy dissipation in post-stenotic flow is an important determinant of the hemodynamic significance of aortic stenosis. The simplified Bernoulli equation used to estimate pressure gradients often misclassifies the ventricular overload caused by aortic stenosis. The current gold standard for estimation of irreversible pressure loss is catheterization, but this method is rarely used due to its invasiveness. Post-stenotic pressure loss is largely caused by dissipation of turbulent kinetic energy into heat. Recent developments in magnetic resonance flow imaging permit noninvasive estimation of TKE.

Methods

The study was approved by the local ethics review board and all subjects gave written informed consent. Three-dimensional cine magnetic resonance flow imaging was used to measure TKE in 18 subjects (4 normal volunteers, 14 patients with aortic stenosis with and without dilation). For each subject, the peak total TKE in the ascending aorta was compared with a pressure loss index. The pressure loss index was based on a previously validated theory relating pressure loss to measures obtainable by echocardiography.

Results

The total TKE did not appear to be related to global flow patterns visualized based on magnetic resonance–measured velocity fields. The TKE was significantly higher in patients with aortic stenosis than in normal volunteers (p < 0.001). The peak total TKE in the ascending aorta was strongly correlated to index pressure loss (R² = 0.91).

Conclusions

Peak total TKE in the ascending aorta correlated strongly with irreversible pressure loss estimated by a well-established method. Direct measurement of TKE by magnetic resonance flow imaging may, with further validation, be used to estimate irreversible pressure loss in aortic stenosis.

Turbulent flow, characterized by velocity fluctuations, is a contributing factor to the pathogenesis of several cardiovascular diseases. A clinical noninvasive tool for assessing turbulence is lacking, however. It is well known that the occurrence of multiple spin velocities within a voxel during the influence of a magnetic gradient moment causes signal loss in phase-contrast magnetic resonance imaging (PC-MRI). In this paper a mathematical derivation of an expression for computing the standard deviation (SD) of the blood flow velocity distribution within a voxel is presented. The SD is obtained from the magnitude of PC-MRI signals acquired with different first gradient moments. By exploiting the relation between the SD and turbulence intensity (TI), this method allows for quantitative studies of turbulence. For validation, the TI in an in vitro flow phantom was quantified, and the results compared favorably with previously published laser Doppler anemometry (LDA) results. This method has the potential to become an important tool for the noninvasive assessment of turbulence in the arterial tree.

Global and regional blood flow dynamics are of pivotal importance to cardiac function. Fluid mechanical forces can affect hemolysis and platelet aggregation, as well as myocardial remodeling. In recent years, assessment of blood flow patterns based on time-resolved, three-dimensional, three-directional phase-contrast MRI (3D cine PC MRI) has become possible and rapidly gained popularity. Initially, this technique was mainly known for its intuitive and appealing visualizations of the cardiovascular blood flow. Most recently, the technique has begun to go beyond compelling images toward comprehensive and quantitative assessment of blood flow. In this article, cardiac applications of 3D cine PC MRI data are discussed, starting with a review of the acquisition and analysis techniques, and including descriptions of promising applications of cardiac 3D cine PC MRI for the clinical evaluation of myocardial, valvular, and vascular disorders.

Background: During incremental exercise, systolic blood pressure (SBP) increases due to increasing cardiac output. However, the impact of workload on SBP has often been overlooked. Indexing the increase in SBP to the increase in workload could provide a way of accounting for this. Athletes often reach higher maximal SBP (SBP_max) than untrained subjects, which has been attributed to their superior cardiac capacity. How this affects the relation between SBP and workload is not established.

Aim: We sought to characterise the novel metrics SBP/VO₂-slope and SBP/Watt-slope in endurance athletes and to analyse possible correlations between these metrics and maximal oxygen uptake (VO_2max) in a population of endurance athletes and healthy, non-athletic subjects. We also sought to compare the SBP response of athletes to values predicted by newly published reference equations accounting for workload.

Methods: In 24 endurance athletes and 5 healthy non-athletes we assessed the workload-indexed blood pressure response during a graded bicycle ergometer test. SBP_max was defined as the last SBP during exercise, VO_2max as the mean of the two highest consecutive VO₂ measurements at end of exercise.

Results: The mean SBP/VO₂-slope was 31.1 ± 9.7 mmHg/l/min and the mean SBP/Watt-slope was 0.28 ± 0.08 mmHg/Watt. We found no significant correlation between VO_2max and the SBP/VO₂-slope or the SBP/Watt-slope, nor with SBP at 50 W or at 200 W. In males there was a significant correlation between VO_2max and SBP_max. The endurance athletes had less steep SBP/Watt-slopes and higher SBP_max than predicted by reference equations. 

Conclusion: The SBP/VO₂-slope offers a precise way of indexing blood pressure to workload and could provide a valuable tool in future studies investigating the SBP response to exercise. Our results suggest that different reference equations than in the general population might be needed when evaluating the SBP response in athletes.

ObjectivesThe primary objective was to study the reach, effectiveness, adoption, implementation and maintenance of the Nordic Hamstring Exercise (NHE) programme in womens elite teams in Europe in the 2020-21 season. The secondary objective was to compare hamstring injury rates between teams that used the NHE programme regularly in team training and teams that did not.MethodsEleven teams participating in the Womens Elite Club Injury Study during the 2020-21 season provided data about injury rates and the implementation of the NHE programme.ResultsOne team (9%) used the full original NHE programme, and four teams used the programme in the team training during parts of the season (team training group, n=5). Five teams did not use the NHE, or used it only sporadically for individual players, and one team used NHE only for players with a previous or current hamstring injury (no team training group, n=6). The team training group had a lower incidence of hamstring injuries during match-play (1.4 vs 4.0, p=0.028) than the non-team training group while no difference between groups was shown for the hamstring injury incidence in training (0.6 vs 0.7, p=0.502).ConclusionA low adoption of the NHE programme was reported during the 2020-21 season. However, teams that used NHE for the whole team or most players had a lower hamstring injury incidence at match-play than teams that did not use the NHE or used it for individual players only.

Objective To evaluate whether a change of head coach or other head staff before or during a season is correlated to hamstring injury (HI) burden in male elite-level football (soccer) in Europe.Methods The survey was conducted using a questionnaire reporting any staff change within the team. Data about the head staff changes and hamstring injury burdens were collected from 14 teams participating in the Elite Club Injury Study (ECIS) during the 2019/2020, 2020/2021 and 2021/2022 seasons.Results On average, replacing the head coach before or during a season happens in every second season. All changes, except for the change of the head coach during a season, indicate an association with an increase in HI burden (ranging from 10% to 81%). However, only changes in the fitness coach and team doctor roles reached statistical significance. The HI burden seems to be influenced by adding new staff members, such as the head of fitness/performance coach in 36% of the teams and the team doctor in 17%. New head coaches starting the season with their own, for the team new, fitness/performance coach was highly associated with increased HI burden (p&lt;0.001).Conclusions Bringing their own fitness/performance coaches is common for managers entering a new elite male football club. However, this paper has highlighted that this trend seems to lead to a three times increase in HI burden. Similarly, replacing the team doctor was also associated with increased HI burden. Instability among head staff members in male elite-level football teams seems associated with increased HI burden during the season.

Nitric oxide (NO) is an important chemical factor that controls vascular tone in the cardiovascular system. NO is a vasodilatory molecule that plays a role in blood pressure and blood flow regulation as well as vessel formation and tissue cell proliferation. NO influences the flow by which nutrients and other metabolites required for growth are transported to the tissues. The aim of this study was to investigate if NO, through mediation by the NO donors Sodium Nitroprusside (SNP) and S-Nitrosoglutathione (GSNO) affect growth and oxygen consumption of prenatal broiler chicken. The results indicate that, although the treatments did not have clear significant effects on the embryos or the organs examined, a slight delay in development can be observed in the GSNO treatment embryos. The study could not conclude, however, if this was due to effects of NO donors

We are unceasingly exposed to potentially harmful microorganisms. The battle against threatening infectious agents includes activation of both the innate and of the adaptive immune systems. Illness responses are elicited and include inflammation, fever, decreased appetite, lethargy and increased sensitivity to painful stimuli in order to defeat invaders. While many of these signs of disease are controlled by the central nervous system, it has remained an enigma how signals from the peripheral immune system reach the brain through its blood-brain barrier, which precludes macromolecules, including cytokines, from diffusing into the brain parenchyma.

Previous findings indicate the existence of a pathway across the blood-brain barrier, which includes binding of the cytokine interleukin-1 (IL-1) to its receptor in the brain vessels, thereby inducing the production of the prostaglandin E₂ (PGE₂) synthesizing enzymes cyclooxygenase-2 (Cox-2) and microsomal prostaglandin E synthase-1 (mPGES-1), which ultimately synthesize PGE₂. PGE₂ subsequently binds to any of the four prostaglandin E₂ (EP) -receptors. Previous results from our laboratory have suggested that this pathway plays a critical role in the febrile response to infectious stimuli. The present thesis aims at further investigating the molecular events underlying immune-to-brain signalling, with special emphasis on fever, hypothalamic-pituitary-adrenal (HPA) -axis activation and anorexia and their connection to signalling molecules of the cytokine and prostaglandin families, respectively.

In paper I, the molecular processes linking the proinflammatory cytokine interleukin-6 (IL-6) and PGE₂ in the febrile response were investigated. Both IL-6 and PGE₂ have been shown to be critical players in the febrile response, although the molecular connections are not known, i.e. if IL-6 exerts its effects up- or downstream of PGE₂. Mice deficient in IL-6 were unable to respond to bacterial lipopolysaccharide (LPS) with a febrile response, but displayed similar induction of Cox-2 and mPGES-1, and similar concentrations of PGE₂ in the cerebrospinal fluid as wild-type mice. Paradoxically, the IL-6 deficient mice responded with a dose-dependent elevation of body temperature in response to intracerebroventricularly injected PGE₂. Furthermore, IL-6 per se was not pyrogenic when injected peripherally in mice, and did not cause increased levels of PGE₂ in cerebrospinal fluid. IL-6 deficient mice were not refractory to the action of PGE₂ because of excess production of some hypothermia-producing factor, since administration of a Cox-2 inhibitor in LPS-challenged IL-6 deficient mice did not unmask any hypothermic response, and neutralization of tumor necrosis factor α (TNFα), associated with hypothermia, did not produce fever in LPS-challenged IL-6 deficient mice. These data indicate that IL-6 rather than exerting its effects up- or down-stream of PGE₂ affects some process in parallel to PGE₂, perhaps by influencing the diffusion and binding of PGE₂ onto its target neurons.

In papers II and III, we injected the proinflammatory cytokine IL-1β in free-fed wild-type mice, in mice with a deletion of the gene encoding mPGES-1, or in mice deficient in the EP₁, EP₂ and EP₃. Food intake was continuously measured during their active period, revealing that mPGES-1 deficient mice were almost completely resistant to anorexia induced by IL-1β. However, all of the investigated EP receptor deficient mice exhibited a normal profound anorexic response to IL-1β challenge, suggesting that the EP₄ is the critical receptor that mediates IL-1β-induced anorexia. We also investigated the role of mPGES-1 in anorexia induced by lipopolysaccharide (LPS) in mPGES-1 deficient mice. The profound anorexic response after LPS-challenge was similar in mPGES-1 deficient and wild-type mice. To further investigate the anorectic behaviour after LPS injection, we pre-starved the animals for 22 hours before injecting them with LPS. In this paradigm, the anorexia was less profound in mPGES-1 knock-out mice. Our results suggest that while the inflammatory anorexia elicited by peripheral IL-1β seems largely to be dependent on mPGES-1-mediated PGE₂ synthesis, similar to the febrile response, the LPS-induced anorexia is independent of this mechanism in free-fed mice but not in pre-starved animals.

In papers IV and V, the role of prostanoids for the immune-induced HPA-axis response was investigated in mice after genetic deletion or pharmacological inhibition of prostanoid-synthesizing enzymes, including Cox-1, Cox-2, and mPGES-1. The immediate LPS-induced release of ACTH (adrenocorticotropic hormone and corticosteroids was critically dependent on Cox-1 derived prostanoids and occurred independently of Cox-2 and mPGES-1 derived PGE₂. In contrast, the delayed HPA-axis response was critically dependent on immune-induced PGE₂, synthesized by Cox-2 and mPGES-1, and occurred independently of Cox-1 derived enzymes. In addition, in the mPGES-1 deficient mice, the synthesis of CRH hnRNA and mRNA was decreased in the paraventricular nucleus of the hypothalamus after LPS-challenge, indicating that the delayed hormone secretion was mediated by PGE₂-induced gene-transcription of CRH in the hypothalamus. The expression of the c-fos gene and Fos protein, an index of synaptic activation, was maintained in the paraventricular nucleus and its brainstem afferents both after unselective and Cox-2 selective inhibition as well as in Cox-1, Cox-2, and mPGES-1 knock-out mice. This suggests that the immune-induced neuronal activation of autonomic relay nuclei occurs independently of prostanoid synthesis and that it is insufficient for eliciting stress hormone release.

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Background Elite athletes have been the subject of great interest, but athletes at an intermediate level of physical activity have received less attention in respect to the presence of cardiac enlargement and/or hypertrophy. We hypothesized that playing football, often defined as demanding less endurance components than running or cycling, would still induce remodelling similar to sports with a dominating endurance component. Methods 23 male football players, age 25+/- 3.9 yrs. underwent exercise testing, 2D- and 3D- echocardiography and cardiac magnetic resonance (CMR). The results were compared with a control group of engineering students of similar age. The athletes exercised 12 h/week and the control subjects 1 h/week, p &lt; 0.001. Results The football players achieved a significantly higher maximal load at the exercise test (380 W vs 300 W, p &lt; 0.001) as well as higher calculated maximal oxygen consumption, (49.7 vs 37.4 mL x kg(- 1) x min(- 1), p &lt; 0.001) compared to the sedentary group. All left ventricular (LV) volumes assessed by 3DEcho and CMR, as well as CMR left atrial (LA) volume were significantly higher in the athletes (3D-LVEDV 200 vs 154 mL, CMR-LVEDV 229 vs 185 mL, CMR-LA volume 100 vs 89 mL, p &lt; 0.001, p = 0.002 and p = 0.009 respectively). LVEF and RVEF, LV strain by CMR or by echo did not differentiate athletes from sedentary participants. Right ventricular (RV) longitudinal strain, LA and right atrial (RA) strain by CMR all showed similar results in the two groups. Conclusion Moderately trained intermediate level football players showed anatomical but not functional cardiac remodelling compared to sedentary males.

Ventilator-induced or ventilator-associated lung injury (VILI/VALI) is common and there is an increasing demand for a tool that can optimize ventilator settings. Electrical impedance tomography (EIT) can detect changes in impedance caused by pulmonary ventilation and perfusion, but the effect of changes in the position of the body and in the placing of the electrode belt on the impedance signal have not to our knowledge been thoroughly evaluated. We therefore studied ventilation-related and perfusion-related changes in impedance during spontaneous breathing in 10 healthy subjects in five different body positions and with the electrode belt placed at three different thoracic positions using a 32-electrode EIT system. We found differences between regions of interest that could be attributed to changes in the position of the body, and differences in impedance amplitudes when the position of the electrode belt was changed. Ventilation-related changes in impedance could therefore be related to changes in the position of both the body and the electrode belt. Perfusion-related changes in impedance were probably related to the interference of major vessels. While these findings give us some insight into the sources of variation in impedance signals as a result of changes in the positions of both the body and the electrode belt, further studies on the origin of the perfusion-related impedance signal are needed to improve EIT further as a tool for the monitoring of pulmonary ventilation and perfusion.

We examined the role of brown adipose tissue (BAT) for fever and emotional stress-induced hyperthermia. Wild-type and uncoupling protein-1 (UCP-1) knockout mice were injected with lipopolysaccharide intraperitoneally or intravenously, or subjected to cage exchange, and body temperature monitored by telemetry. Both genotypes showed similar febrile responses to immune challenge and both displayed hyperthermia to emotional stress. Neither procedure resulted in the activation of BAT, such as the induction of UCP-1 or peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1 alpha) mRNA, or reduced BAT weight and triglyceride content. In contrast, in mice injected with a beta (3) agonist, UCP-1 and PGC-1 alpha were strongly induced, and BAT weight and triglyceride content reduced. Both lipopolysaccharide and the beta (3) agonist, and emotional stress, induced UCP-3 mRNA in skeletal muscle. A beta (3) antagonist did not attenuate lipopolysaccharide-induced fever, but augmented body temperature decrease and inhibited BAT activation when mice were exposed to cold. An alpha (1)/alpha (2b) antagonist or a 5HT(1A) agonist, which inhibit vasoconstriction, abolished lipopolysaccharide-induced fever, but had no effect on emotional stress-induced hyperthermia. These findings demonstrate that in mice, UCP-1-mediated BAT thermogenesis does not take part in inflammation-induced fever, which is dependent on peripheral vasoconstriction, nor in stress-induced hyperthermia. However, both phenomena may involve UCP-3-mediated muscle thermogenesis.

The dive response, or the master switch of life, is probably the most studied physiological trait in marine mammals and is thought to conserve the available O-2 for the heart and brain. Although generally thought to be an autonomic reflex, several studies indicate that the cardiovascular changes during diving are anticipatory and can be conditioned. The respiratory adaptations, where the aquatic breathing pattern resembles intermittent breathing in land mammals, with expiratory flow exceeding 160 litres s(-1) has been measured in cetaceans, and where exposure to extreme pressures results in alveolar collapse (atelectasis) and recruitment upon ascent. Cardiorespiratory coupling, where breathing results in changes in heart rate, has been proposed to improve gas exchange. Cardiorespiratory coupling has also been reported in marine mammals, and in the bottlenose dolphin, where it alters both heart rate and stroke volume. When accounting for this respiratory dependence on cardiac function, several studies have reported an absence of a diving-related bradycardia except during dives that exceed the duration that is fuelled by aerobic metabolism. This review summarizes what is known about the respiratory physiology in marine mammals, with a special focus on cetaceans. The cardiorespiratory coupling is reviewed, and the selective gas exchange hypothesis is summarized, which provides a testable mechanism for how breath-hold diving vertebrates may actively prevent uptake of N-2 during routine dives, and how stress results in failure of this mechanism, which results in diving-related gas emboli.

The dive response involves three main components - breath holding, reduced heart rate and increased peripheral vasoconstriction - and is ubiquitous during forced dives in air-breathing vertebrates; however, numerous studies in free-diving animals have shown that the heart rate response to diving varies considerably in a manner that suggests cognitive control. Furthermore, studies on free-diving animals and controlled experiments in trained animals both indicate that the dive response can be conditioned, such that the reduction in heart rate begins before submergence and the extent of the reduction is set early in the dive. In addition, numerous species also experience an increase in heart rate and blood flow during ascent at the end of a dive, a phenomenon commonly called 'ascent tachycardia'. Collectively, these data suggest that although the dive response is under autonomic control, many species can vary its magnitude depending on the length and type of the planned dive - an indication of a role for cognition in the overall physiological responses associated with diving. Here, we provide examples of the conditioned cardiac responses - including anticipatory changes in heart rate - in several diving species and propose potential underlying mechanisms. We also discuss how the anticipatory cardiovascular responses not only improve diving capacity, but also prevent diving-related problems, such as decompression sickness or barotrauma, through a mechanism described by the selective gas exchange hypothesis.

Objective: The aim of this study was to evaluate the urea clearance technique for the measurement of drug-induced blood flow changes in human skin, and compare it with two non-invasive techniques: polarization light spectroscopy and laser Doppler perfusion imaging.

Methods: Fifteen microdialysis catheters were placed intracutaneously on the volar aspect of the forearms of healthy human subjects, and were perfused with nitroglycerine, noradrenaline, and again nitroglycerine, to induce local tissue hyperaemia, hypoperfusion, and hyperaemia, respectively.

Results: Urea clearance, but not the other techniques, detected the changes in blood flow during all three periods of altered flow.  The last hyperaemic response was detected by all three methods.

Conclusion: Urea clearance can be used as a relatively simple method to estimate blood flow changes during microdialysis of vasoactive substances, in particular when the tissue is preconditioned in order to enhance the contrast between baseline and the responses to the provocations. Our results support that, in the model described, urea clearance was superior to the optical methods as it detected both the increases and decrease in blood flow, and the returns to baseline between these periods.

This study explored the muscle genome-wide response to long-term unloading (84-day bed rest) in 21 men. We hypothesized that a part of the bed rest-induced gene expression signature would be resilient to a concurrent flywheel resistance exercise (RE) countermeasure. Using DNA microarray technology analyzing 35 345 gene-level probe-sets, we identified 335 annotated probe-sets that were downregulated, and 315 that were upregulated after bed rest (P &lt; .01). Besides a predictable differential expression of genes and pathways related to mitochondria (downregulation; false-discovery rates (FDR) &lt;1E-04), ubiquitin system (upregulation; FDR = 3E-02), and skeletal muscle energy metabolism and structure (downregulation; FDR &lt;= 3E-03), 84-day bed rest also altered circadian rhythm regulation (upregulation; FDR = 3E-02). While most of the bed rest-induced changes were counteracted by RE, 209 transcripts were resilient to the exercise countermeasure. Genes upregulated after bed rest were particularly resistant to training (P &lt; .001 vs downregulated, non-reversed genes). Specifically, "Translation Factors," "Proteasome Degradation," "Cell Cycle," and "Nucleotide Metabolism" pathways were not normalized by RE. This study provides an unbiased high-throughput transcriptomic signature of one of the longest unloading periods in humans to date. Classical disuse-related changes in structural and metabolic genes/pathways were identified, together with a novel upregulation of circadian rhythm transcripts. In the context of previous bed rest campaigns, the latter seemed to be related to the duration of unloading, suggesting the transcriptomic machinery continues to adapt throughout extended disuse periods. Despite that the RE training offset most of the bed rest-induced muscle-phenotypic and transcriptomic alterations, we contend that the human skeletal muscle also displays a residual transcriptomic signature of unloading that is resistant to an established exercise countermeasure.

Key points Ribosome biogenesis and MYC transcription are associated with acute resistance exercise (RE) and are distinct from endurance exercise in human skeletal muscle throughout a 24 h time course of recovery. A PCR-based method for relative ribosomal DNA (rDNA) copy number estimation was validated by whole genome sequencing and revealed that rDNA dosage is positively correlated with ribosome biogenesis in response to RE. Acute RE modifies rDNA methylation patterns in enhancer, intergenic spacer and non-canonical MYC-associated regions, but not the promoter. Myonuclear-specific rDNA methylation patterns with acute mechanical overload in mice corroborate and expand on rDNA findings with RE in humans. A genetic predisposition for hypertrophic responsiveness may exist based on rDNA gene dosage. Ribosomes are the macromolecular engines of protein synthesis. Skeletal muscle ribosome biogenesis is stimulated by exercise, although the contribution of ribosomal DNA (rDNA) copy number and methylation to exercise-induced rDNA transcription is unclear. To investigate the genetic and epigenetic regulation of ribosome biogenesis with exercise, a time course of skeletal muscle biopsies was obtained from 30 participants (18 men and 12 women; 31 +/- 8 years, 25 +/- 4 kg m(-2)) at rest and 30 min, 3 h, 8 h and 24 h after acute endurance (n = 10, 45 min cycling, 70% V?O2max) or resistance exercise (n = 10, 4 x 7 x 2 exercises); 10 control participants underwent biopsies without exercise. rDNA transcription and dosage were assessed using quantitative PCR and whole genome sequencing. rDNA promoter methylation was investigated using massARRAY EpiTYPER and global rDNA CpG methylation was assessed using reduced-representation bisulphite sequencing. Ribosome biogenesis and MYC transcription were associated primarily with resistance but not endurance exercise, indicating preferential up-regulation during hypertrophic processes. With resistance exercise, ribosome biogenesis was associated with rDNA gene dosage, as well as epigenetic changes in enhancer and non-canonical MYC-associated areas in rDNA, but not the promoter. A mouse model of in vivo metabolic RNA labelling and genetic myonuclear fluorescence labelling validated the effects of an acute hypertrophic stimulus on ribosome biogenesis and Myc transcription, and also corroborated rDNA enhancer and Myc-associated methylation alterations specifically in myonuclei. The present study provides the first information on skeletal muscle genetic and rDNA gene-wide epigenetic regulation of ribosome biogenesis in response to exercise, revealing novel roles for rDNA dosage and CpG methylation.

This randomized sham-controlled trial investigated anodal transcranial direct current stimulation (tDCS) over the somatosensory cortex contralateral to hand dominance for dose-response (1mA-20 minutes x 5 days) effects on vibrotactile detection thresholds (VDT). VDT was measured before and after tDCS on days 1,3&5 for low (30hz) and high (200hz) frequency vibrations on the dominant and non-dominant hands in 29 healthy adults (mean age = 22.86; 15 males, 14 females). Only the dominant hand 200Hz VDT displayed statistically significant medium effect size improvement for mixed model analysis of variance time x group interaction for active tDCS compared to sham. Post Hoc contrasts were statistically significant for dominant hand 200Hz VDT on day 5 after tDCS compared to day 1 before tDCS , day 1 after tDCS and day 3 before tDCS. There was a linear dose-response improvement with dominant hand 200Hz VDT mean difference decreasing from day 1 before tDCS peaking at -15.5% (SD=34.9%) on day 5 after tDCS. Both groups showed learning effect trends over time for all VDT test conditions but only the non-dominant hand 30Hz VDT was statistically significant (p=0.03) though Post Hoc contrasts were non-significant after Sidak adjustment. No adverse effects for tDCS were reported. In conclusion, anodal tDCS 1mA-20 minutes x 5 days on the dominant sensory cortex can modulate a linear improvement of dominant hand high frequency VDT but not for low frequency or non-dominant hand VDT.

Cryoablation, which induces cellular death without extensive tissue damage, has been extensively used to denervate the myocardium. However, periadventitial external circumferential application of cryotherapy to denervate the renal artery sympathetic nerves has, to our knowledge, never been tested in humans. The main aim of this study was to examine the safety and potential effects of cryotherapy on ambulatory blood pressure levels and other outcomes that are indirectly related to sympathetic tone, including pulse-wave velocity, central pulse pressure, and glucose levels.

Recent studies have correlated kinetic energy (KE) and viscous dissipation rate (VDR) in the left ventricle (LV) with heart health. These studies have relied on 4D-flow imaging or computational fluid dynamics modeling, which are able to measure, or compute, all 3 components (3C) of the blood flow velocity in 3 dimensional (3D) space. This richness of data is difficult to acquire clinically. Alternatively, color Doppler echocardiography (CDE) is more widespread clinically, but only measures a single radial component of velocity and typically only over a planar section. Because of this limitation, prior CDE-based studies have first reconstructed a second component of velocity in the measurement plane prior to evaluating VDR or KE. Herein, we propose 1C-based surrogates of KE and VDR that can be derived directly from the radial component of the flow velocity in the LV. Our results demonstrate that the proposed 1C-based surrogates of KE and VDR are generally as well-correlated with the true KE and VDR values as surrogates that use reconstructed 2C flow data. Moreover, the correlation of these 1C-based surrogates with the true values indicate that CDE (3D in particular) may be useful in evaluating these metrics in practice.

Diabetic nephropathy is one of the most common causes of end stage renal disease and develops in approximately one third of all diabetes patients. Disease progression is characterized by deteriorating glomerular filtration rate and escalating urinary albumin/protein excretion; both are used as clinical markers for disease progression. Recently, it has been proposed that intrarenal hypoxia is a unifying mechanism for chronic kidney disease, including diabetic nephropathy. Several mechanistic pathways have been linked to the development of intrarenal hypoxia and diabetic nephropathy including increased angiotensin II signaling, oxidative stress and hyperglycemia per se. Furthermore, pathological endothelin signaling has recently immerged as a possible contributing factor for chronic kidney disease and diabetic nephropathy. The overall aims of this thesis were therefore to determine the temporal relationship between development of intrarenal hypoxia and kidney disease as well as elucidate the potential link between endothelin signaling, intrarenal hypoxia and kidney disease in experimental insulinopenic diabetes.

It is well established that different mouse strains have different susceptibility for kidney and cardiovascular disease. The first step was therefore to compare four commonly used mouse strains with regards to development of kidney disease after onset of insulinopenic diabetes. From the results of this study, we concluded that the NMRI mouse strain has a disease progression closest to the human disease and this strain was chosen in the subsequent studies in mice.

The next step was to adapt and optimize a suitable method for repetitive measurements of intrarenal oxygen tension during the course of disease development. Electron paramagnetic resonance (EPR) oximetry had previously been used in tumor biology and was now adapted and optimized for measurements of kidney oxygenation in our diabetic mouse model. EPR oximetry in normoglycemic control mice recorded cortical oxygen tension values similar to previous reports using invasive techniques. Surprisingly, intrarenal hypoxia developed already within the first 72h after induction of hyperglycemia and persisted throughout the two-week study period. Importantly, this was well before albuminuria developed.

The final part of this thesis was to investigate the role of endothelin signaling for the intrarenal hypoxia in a diabetic rat model. Endothelin 1 signals via two distinctly different receptor-mediated pathways. In normal physiology, endothelin 1 binding to endothelin receptor type A (ETA) induces vasoconstriction, which can be blocked by the specific ETA antagonist BQ123, whereas endothelin 1 binding to endothelin receptor type B (ETB) induces nitric oxide-dependent vasodilation. ETB receptors can be selectively activated by Sarafotoxin 6c. The results from blocking ETA and activating ETB receptors demonstrated that endothelin 1 signaling via ETA receptors contributes to intrarenal hypoxia in the rat diabetic kidney, and that ETB stimulation significantly reduces the diabetes-induced intrarenal hypoxia. The beneficial effects on kidney oxygen availability in diabetes by ETA blockade or ETB stimulation were mainly linked to hemodynamic improvements rather than direct effects on kidney oxygen consumption or oxidative stress status.

In conclusion, by applying EPR oximetry in a mouse model of insulinopenic diabetes mimicking the human disease, we demonstrated intrarenal hypoxia already within the first couple of days after the onset of hyperglycemia, which is well before detectable signs of kidney disease development. Furthermore, blockade of ETA or activation of ETB receptors significantly reduced intrarenal hypoxia in the diabetic kidney. These results demonstrate involvement of ETA receptor signaling in diabetes-induced intrarenal hypoxia and ETA blockade or ETB activation might provide new therapeutical targets to reduce kidney hypoxia and disease progression in diabetes.

Intrarenal tissue hypoxia has been proposed as a unifying mechanism for the development of chronic kidney disease, including diabetic nephropathy. However, hypoxia has to be present before the onset of kidney disease in order to be the causal mechanism. In order to establish if hypoxia precedes the onset of diabetic nephropathy, we implemented a minimally invasive electron paramagnetic resonance oximetry technique using implanted oxygen sensing probes for repetitive measurements of in vivo kidney tissue oxygen tensions in mice. Kidney cortex oxygen tensions were measured before and up to 15 days after the induction of insulinopenic diabetes in male mice and compared to normoglycemic controls. On day 16, urinary albumin excretions and conscious glomerular filtration rates were determined in order to define the temporal relationship between intrarenal hypoxia and disease development. Diabetic mice developed pronounced intrarenal hypoxia three days after the induction of diabetes, which persisted throughout the study period. On day 16, diabetic mice had glomerular hyperfiltration, but normal urinary albumin excretion. In conclusion, intrarenal tissue hypoxia in diabetes precedes albuminuria thereby being a plausible cause for the onset and progression of diabetic nephropathy.