Showing papers by "University of Copenhagen published in 2000"

Exercise and the Immune System: Regulation, Integration, and Adaptation

Abstract: Stress-induced immunological reactions to exercise have stimulated much research into stress immunology and neuroimmunology. It is suggested that exercise can be employed as a model of temporary immunosuppression that occurs after severe physical stress. The exercise-stress model can be easily manipulated experimentally and allows for the study of interactions between the nervous, the endocrine, and the immune systems. This review focuses on mechanisms underlying exercise-induced immune changes such as neuroendocrinological factors including catecholamines, growth hormone, cortisol, β-endorphin, and sex steroids. The contribution of a metabolic link between skeletal muscles and the lymphoid system is also reviewed. The mechanisms of exercise-associated muscle damage and the initiation of the inflammatory cytokine cascade are discussed. Given that exercise modulates the immune system in healthy individuals, considerations of the clinical ramifications of exercise in the prevention of diseases for which the...

Chronic pain as an outcome of surgery. A review of predictive factors.

Abstract: ONE potential adverse outcome from surgery is chronic pain. Analysis of predictive and pathologic factors is important to develop rational strategies to prevent this problem. Additionally, the natural history of patients with and without persistent pain after surgery provides an opportunity to improve the understanding of the physiology and psychology of chronic pain. Ideally, studies of chronic postoperative pain should include (1) sufficient preoperative data (assessment of pain, physiologic and psychologic risk factors for chronic pain); (2) detailed descriptions of the operative approaches used (location and length of incisions, handling of nerves and muscles); (3) the intensity and character of acute postoperative pain and its management; and (4) follow-up at intervals to 1 yr or more. In addition, there would be information about postoperative interventions that may influence pain, such as radiation therapy or chemotherapy. At long-term follow-up visits, patient function, physical signs, and symptoms would be evaluated using a standardized algorithm, including quantitative and descriptive pain assessments. We found no studies that contain all of these data. For this review, we specifically sought population data that reflect the incidence of chronic postoperative pain or predictors (medical, physiologic, and psychologic) of chronic pain. We selected five groups of surgeries (limb amputations, breast surgery, gallbladder surgery, lung surgery, and inguinal hernia surgery). These surgeries were selected because the incidence of pain is known to be high, thus improving the probability of detecting predictive factors. They also represent a range of major surgical procedures.

Effects of Controlled-Release Metoprolol on Total Mortality, Hospitalizations, and Well-being in Patients With Heart Failure: The Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF)

Abstract: For editorial comment see p 1335. Context Results from recent studies on the effects of b1-blockade in patients with heart failure demonstrated a 34% reduction in total mortality. However, the effect of b1-blockade on the frequency of hospitalizations, symptoms, and quality of life in patients with heart failure has not been fully explored. Objective To examine the effects of the b1-blocker controlled-release/extendedrelease metoprolol succinate (metoprolol CR/XL) on mortality, hospitalization, symptoms, and quality of life in patients with heart failure.

Uncovering Molecular Mechanisms Involved in Activation of G Protein-Coupled Receptors

Abstract: G protein-coupled, seven-transmembrane segment receptors (GPCRs or 7TM receptors), with more than 1000 different members, comprise the largest superfamily of proteins in the body. Since the cloning of the first receptors more than a decade ago, extensive experimental work has uncovered multiple aspects of their function and challenged many traditional paradigms. However, it is only recently that we are beginning to gain insight into some of the most fundamental questions in the molecular function of this class of receptors. How can, for example, so many chemically diverse hormones, neurotransmitters, and other signaling molecules activate receptors believed to share a similar overall tertiary structure? What is the nature of the physical changes linking agonist binding to receptor activation and subsequent transduction of the signal to the associated G protein on the cytoplasmic side of the membrane and to other putative signaling pathways? The goal of the present review is to specifically address these questions as well as to depict the current awareness about GPCR structure-function relationships in general. (Endocrine Reviews 21: 90 ‐113, 2000)

Anthropometric and physiological predispositions for elite soccer

Abstract: This review is focused on anthropometric and physiological characteristics of soccer players with a view to establishing their roles within talent detection, identification and development programmes. Top-class soccer playershave to adapt to the physical demandsof the game, which are multifactorial. Players may not need to have an extraordinary capacity within any of the areas of physical performance but must possess a reasonably high level within all areas. This explains why there are marked individual differences in anthropometric and physiological characteristics among top players. Various measurements have been used to evaluate specific aspects of the physical performance of both youth and adult soccer players.The positional role of a player is related to his or her physiological capacity. Thus, midfield players and full-backs have the highest maximal oxygen intakes (> 60 ml·kg -1 ·min -1 ) and perform best in intermittent exercise tests. On the other hand, midfield players tend to have the lowest mus...

All-cause mortality associated with physical activity during leisure time, work, sports, and cycling to work

Abstract: BACKGROUND: Physical activity is associated with low mortality in men, but little is known about the association in women, different age groups, and everyday activity. OBJECTIVE: To evaluate the relationship between levels of physical activity during work, leisure time, cycling to work, and sports participation and all-cause mortality. DESIGN: Prospective study to assess different types of physical activity associated with risk of mortality during follow-up after the subsequent examination. Mean follow-up from examination was 14.5 years. SETTING: Copenhagen University Hospital, Copenhagen, Denmark. PARTICIPANTS: Participants were 13,375 women and 17,265 men, 20 to 93 years of age, who were randomly selected. Physical activity was assessed by self-report, and health status, including blood pressure, total cholesterol level, triglyceride levels, body mass index, smoking, and educational level, was evaluated. MAIN OUTCOME MEASURE: All-cause mortality. RESULTS: A total of 2,881 women and 5,668 men died. Compared with the sedentary, age- and sex-adjusted mortality rates in leisure time physical activity groups 2 to 4 were 0.68 (95% confidence interval, 0.64-0.71), 0.61 (95% confidence interval, 0.57-0.66), and 0.53 (95% confidence interval, 0.41-0.68), respectively, with no difference between sexes and age groups. Within the moderately and highly active persons, sports participants experienced only half the mortality of nonparticipants. Bicycling to work decreased risk of mortality in approximately 40% after multivariate adjustment, including leisure time physical activity. CONCLUSIONS: Leisure time physical activity was inversely associated with all-cause mortality in both men and women in all age groups. Benefit was found from moderate leisure time physical activity, with further benefit from sports activity and bicycling as transportation.

Tracing European founder lineages in the Near Eastern mtDNA pool.

Abstract: Founder analysis is a method for analysis of nonrecombining DNA sequence data, with the aim of identification and dating of migrations into new territory. The method picks out founder sequence types in potential source populations and dates lineage clusters deriving from them in the settlement zone of interest. Here, using mtDNA, we apply the approach to the colonization of Europe, to estimate the proportion of modern lineages whose ancestors arrived during each major phase of settlement. To estimate the Palaeolithic and Neolithic contributions to European mtDNA diversity more accurately than was previously achievable, we have now extended the Near Eastern, European, and northern-Caucasus databases to 1,234, 2,804, and 208 samples, respectively. Both back-migration into the source population and recurrent mutation in the source and derived populations represent major obstacles to this approach. We have developed phylogenetic criteria to take account of both these factors, and we suggest a way to account for multiple dispersals of common sequence types. We conclude that (i) there has been substantial back-migration into the Near East, (ii) the majority of extant mtDNA lineages entered Europe in several waves during the Upper Palaeolithic, (iii) there was a founder effect or bottleneck associated with the Last Glacial Maximum, 20,000 years ago, from which derives the largest fraction of surviving lineages, and (iv) the immigrant Neolithic component is likely to comprise less than one-quarter of the mtDNA pool of modern Europeans.

Rab7: a key to lysosome biogenesis.

Abstract: The molecular machinery behind lysosome biogenesis and the maintenance of the perinuclear aggregate of late endocytic structures is not well understood. A likely candidate for being part of this machinery is the small GTPase Rab7, but it is unclear whether this protein is associated with lysosomes or plays any role in the regulation of the perinuclear lysosome compartment. Previously, Rab7 has mainly been implicated in transport from early to late endosomes. We have now used a new approach to analyze the role of Rab7: transient expression of Enhanced Green Fluorescent Protein (EGFP)-tagged Rab7 wt and mutant proteins in HeLa cells. EGFP-Rab7 wt was associated with late endocytic structures, mainly lysosomes, which aggregated and fused in the perinuclear region. The size of the individual lysosomes as well as the degree of perinuclear aggregation increased with the expression levels of EGFP-Rab7 wt and, more dramatically, the active EGFP-Rab7Q67L mutant. In contrast, upon expression of the dominant-negative mutants EGFP-Rab7T22N and EGFP-Rab7N125I, which localized mainly to the cytosol, the perinuclear lysosome aggregate disappeared and lysosomes, identified by colocalization of cathepsin D and lysosome-associated membrane protein-1, became dispersed throughout the cytoplasm, they were inaccessible to endocytosed molecules such as low-density lipoprotein, and their acidity was strongly reduced, as determined by decreased accumulation of the acidotropic probe LysoTracker Red. In contrast, early endosomes associated with Rab5 and the transferrin receptor, late endosomes enriched in the cation-independent mannose 6-phosphate receptor, and the trans-Golgi network, identified by its enrichment in TGN-38, were unchanged. These data demonstrate for the first time that Rab7, controlling aggregation and fusion of late endocytic structures/lysosomes, is essential for maintenance of the perinuclear lysosome compartment.

Production of interleukin‐6 in contracting human skeletal muscles can account for the exercise‐induced increase in plasma interleukin‐6

Abstract: 1. Plasma interleukin (IL)-6 concentration is increased with exercise and it has been demonstrated that contracting muscles can produce IL-The question addressed in the present study was whether the IL-6 production by contracting skeletal muscle is of such a magnitude that it can account for the IL-6 accumulating in the blood. 2. This was studied in six healthy males, who performed one-legged dynamic knee extensor exercise for 5 h at 25 W, which represented 40% of peak power output (Wmax). Arterial-femoral venous (a-fv) differences over the exercising and the resting leg were obtained before and every hour during the exercise. Leg blood flow was measured in parallel by the ultrasound Doppler technique. IL-6 was measured by enzyme-linked immunosorbent assay (ELISA). 3. Arterial plasma concentrations for IL-6 increased 19-fold compared to rest. The a-fv difference for IL-6 over the exercising leg followed the same pattern as did the net IL-6 release. Over the resting leg, there was no significant a-fv difference or net IL-6 release. The work was produced by 2.5 kg of active muscle, which means that during the last 2 h of exercise, the median IL-6 production was 6.8 ng min-1 (kg active muscle)-1 (range, 3.96-9.69 ng min-1 kg-1). 4. The net IL-6 release from the muscle over the last 2 h of exercise was 17-fold higher than the elevation in arterial IL-6 concentration and at 5 h of exercise the net release during 1 min was half of the IL-6 content in the plasma. This indicates a very high turnover of IL-6 during muscular exercise. We suggest that IL-6 produced by skeletal contracting muscle contributes to the maintenance of glucose homeostasis during prolonged exercise.

Aid effectiveness disputed

Abstract: There is a widespread perception among academic researchers and aid practitioners alike that empirical cross-country analysis fails to find any significant link between aid flows and growth, and that aid is successful only when associated with good policies in the recipient countries. These positions do not stand up to careful scrutiny of existing studies. In this paper, we offer a re-examination of the literature on the aid-savings, aid-investment, and aid growth relationships, and a comparative appraisal of more recent research contributions. Using an analytic framework for evaluating the empirical work, a coherent and positive picture of the aid-growth link emerges. Aid works, even in countries hampered by an unfavorable policy environment.

Aminopeptidase N Is a Receptor for Tumor-homing Peptides and a Target for Inhibiting Angiogenesis

Abstract: Phage that display a surface peptide with the NGR sequence motif home selectively to tumor vasculature in vivo. A drug coupled to an NGR peptide has more potent antitumor effects than the free drug [W. Arap et al., Science (Washington DC), 279: 377-380, 1998]. We show here that the receptor for the NGR peptides in tumor vasculature is aminopeptidase N (APN; also called CD13). NGR phage specifically bound to immunocaptured APN and to cells engineered to express APN on their surface. Antibodies against APN inhibited in vivo tumor homing by the NGR phage. Immunohistochemical staining showed that APN expression is up-regulated in endothelial cells within mouse and human tumors. In another tissue that undergoes angiogenesis, corpus luteum, blood vessels also expressed APN, but APN was not detected in blood vessels of various other normal tissues stained under the same conditions. APN antagonists specifically inhibited angiogenesis in chorioallantoic membranes and in the retina and suppressed tumor growth. Thus, APN is involved in angiogenesis and can serve as a target for delivering drugs into tumors and for inhibiting angiogenesis.

Calcium Ion in Skeletal Muscle: Its Crucial Role for Muscle Function, Plasticity, and Disease

Abstract: Mammalian skeletal muscle shows an enormous variability in its functional features such as rate of force production, resistance to fatigue, and energy metabolism, with a wide spectrum from slow aer...

Massive dissociation of gas hydrate during a Jurassic oceanic anoxic event

Abstract: In the Jurassic period, the Early Toarcian oceanic anoxic event (about 183 million years ago) is associated with exceptionally high rates of organic-carbon burial, high palaeotemperatures and significant mass extinction Heavy carbon-isotope compositions in rocks and fossils of this age have been linked to the global burial of organic carbon, which is isotopically light In contrast, examples of light carbon-isotope values from marine organic matter of Early Toarcian age have been explained principally in terms of localized upwelling of bottom water enriched in 12C versus 13C (refs 1,2,5,6) Here, however, we report carbon-isotope analyses of fossil wood which demonstrate that isotopically light carbon dominated all the upper oceanic, biospheric and atmospheric carbon reservoirs, and that this occurred despite the enhanced burial of organic carbon We propose that--as has been suggested for the Late Palaeocene thermal maximum, some 55 million years ago--the observed patterns were produced by voluminous and extremely rapid release of methane from gas hydrate contained in marine continental-margin sediments

Potent and nontoxic antisense oligonucleotides containing locked nucleic acids

Abstract: Insufficient efficacy and/or specificity of antisense oligonucleotides limit their in vivo usefulness. We demonstrate here that a high-affinity DNA analog, locked nucleic acid (LNA), confers several desired properties to antisense agents. Unlike DNA, LNA/DNA copolymers were not degraded readily in blood serum and cell extracts. However, like DNA, the LNA/DNA copolymers were capable of activating RNase H, an important antisense mechanism of action. In contrast to phosphorothioate-containing oligonucleotides, isosequential LNA analogs did not cause detectable toxic reactions in rat brain. LNA/DNA copolymers exhibited potent antisense activity on assay systems as disparate as a G-protein-coupled receptor in living rat brain and an Escherichia coli reporter gene. LNA-containing oligonucleotides will likely be useful for many antisense applications.

Global Warming and Terrestrial Ecosystems: A Conceptual Framework for Analysis

Abstract: raise global mean temperature over the next century by 1.0–3.5 °C (Houghton et al. 1995, 1996). Ecologists from around the world have begun experiments to investigate the effects of global warming on terrestrial ecosystems, the aspect of global climate change that attracts the most public attention (Woodwell and McKenzie 1995, Walker and Steffen 1999). The effort to understand response to warming builds on a history of investigations of the effects of elevated CO 2 on plants and ecosystems (Koch and Mooney 1996, Schulze et al. 1999). There are important differences, however, between increases in atmospheric CO 2 and temperature change, both in the temporal and spatial patterns of change and in how they affect ecosystems. The scientists involved in temperature change research have had to face new technical and conceptual challenges in designing and interpreting their experiments (Schulze et al. 1999). In this paper we describe these challenges and present a conceptual framework for interpreting experimental results and predicting effects of warming on ecosystems.

Glycosyltransferase activity of Fringe modulates Notch-Delta interactions.

Abstract: Ligands that are capable of activating Notch family receptors are broadly expressed in animal development, but their activity is tightly regulated to allow formation of tissue boundaries. Members of the fringe gene family have been implicated in limiting Notch activation during boundary formation, but the mechanism of Fringe function has not been determined. Here we present evidence that Fringe acts in the Golgi as a glycosyltransferase enzyme that modifies the epidermal growth factor (EGF) modules of Notch and alters the ability of Notch to bind its ligand Delta. Fringe catalyses the addition of N-acetylglucosamine to fucose, which is consistent with a role in the elongation of O-linked fucose O-glycosylation that is associated with EGF repeats. We suggest that cell-type-specific modification of glycosylation may provide a general mechanism to regulate ligand-receptor interactions in vivo.

Measuring usability: are effectiveness, efficiency, and satisfaction really correlated?

Abstract: Usability comprises the aspects effectiveness, efficiency, and satisfaction. The correlations between these aspects are not well understood for complex tasks. We present data from an experiment where 87 subjects solved 20 information retrieval tasks concerning programming problems. The correlation between efficiency, as indicated by task completion time, and effectiveness, as indicated by quality of solution, was negligible. Generally, the correlations among the usability aspects depend in a complex way on the application domain, the user's experience, and the use context. Going through three years of CHI Proceedings, we find that 11 out of 19 experimental studies involving complex tasks account for only one or two aspects of usability. When these studies make claims concerning overall usability, they rely on risky assumptions about correlations between usability aspects. Unless domain specific studies suggest otherwise, effectiveness, efficiency, and satisfaction should be considered independent aspect of usability and all be included in usability testing.

Classification of geomorphological effects downstream of dams

Abstract: The effects of dams on downstream geomorphology are reviewed and a typology is devised, consisting of nine cases. The classification can be seen as a further development of Lane's balance between water discharge, sediment load, grain size, and river slope. Depending on changes in released water flow and changes in released sediment load, relative to the transport capacity of the flow, it is possible to estimate resulting cross-sectional geomorphology. The longitudinal extent of changes and their variability with time, and the tributary response to altered mainstream cross-section changes, are also discussed.

Phylogeny of some of the major genera of dinoflagellates based on ultrastructure and partial LSU rDNA sequence data, including the erection of three new genera of unarmoured dinoflagellates

Abstract: Evidence from partial large-subunit (LSU) rDNA sequencing has been combined with ultrastructure, including details of the flagellar apparatus, in a number of phototrophic dinoflagellates, with the aim of trying to solve some of the most pressing taxonomic problems and to contribute to an improved understanding of the phylogeny within the group. Special attention has been paid to the unarmoured (naked) genera, many of which were described during the 1800s or early 1900s and whose taxonomy is artificial and misleading. This is particularly unsatisfactory because many of the species cause extensive plankton blooms, fish kills and other harmful events. Our studies have indicated that the path of the so-called apical groove (acrobase) is of particular importance for the taxonomy of the unarmoured genera of dinoflagellates. Features presently used to characterize many of the genera, such as the relative size of the epicone and hypocone, are misleading. Our data have resulted in the splitting of the large genus Gymnodinium into four genera. The fish-killing species are confined to two genera, Karenia G. Hansen & Moestrup gen. nov. and Karlodinium J. Larsen gen. nov. The paralytic shellfish poisoning-producing species Gymnodinium catenatum is retained within Gymnodinium, together with a number of harmless species. The fourth genus, Akashiwo G. Hansen & Moestrup gen. nov., presently comprises only the large nontoxic species previously known as Gymnodinium sanguineum. The genus Gyrodinium is redefined. The genus Amphidinium is artificial, but more data are needed before redescription of the genus can be made with any confidence. Within the armoured dinoflagellates, LSU and previously published small-subunit rDNA data show the Gonyaulacales to be a natural group. Peridiniella catenata, sometimes included in the Gonyaulacales based on gross morphology, falls outside this order both genetically and ultrastructurally. Based on the DNA data, the genus Peridinium appears to be artificial. Ultrastructure as well as gene sequences confirm that the genus Heterocapsa is unusual, since it includes both apparently unarmoured species (but with very thin plates) and armoured species.

Pathological outcomes of observational learning

Abstract: This paper explores how Bayes-rational individuals learn sequentially from the discrete actions of others. Unlike earlier informational herding papers, we admit heterogeneous preferences. Not only may type-specific ‘‘herds’’ eventually arise, but a new robust possibility emerges: confounded learning. Beliefs may converge to a limit point where history offers no decisive lessons for anyone, and each type’s actions forever nontrivially split between two actions. To verify that our identified limit outcomes do arise, we exploit the Markov-martingale character of beliefs. Learning dynamics are stochastically stable near a fixed point in many Bayesian learning models like this one.

Ecosystem response of pasture soil communities to fumigation-induced microbial diversity reductions: an examination of the biodiversity-ecosystem function relationship

Abstract: A technique based on progressive fumigation was used to reduce soil microbial biodiversity, and the effects of such reductions upon the stability of key soil processes were measured. Mineral soil samples from a grassland were fumigated with chloroform for up to 24 h and then incubated for 5 months to allow recolonisation by surviving organisms. The diversity of cultivable and non-cultivable bacteria, protozoa and nematodes was progressively reduced by increasing fumigation times, as was the number of trophic groups, phyla within trophic groups, and taxa within phyla. Total microbial biomass was similar within fumigated soils, but lower than for unfumigated soil. There was no direct relationship between biodiversity and function. Some broad-scale functional parameters increased as biodiversity decreased, e.g. thymidine incorporation, growth on added nutrients, and the decomposition rate of plant residues. Other more specific parameters decreased as biodiversity decreased, e.g. nitrification, denitrification and methane oxidation. Thus specific functional parameters may be a more sensitive indicator of environmental change than general parameters. Although fumigation reduced soil microbial biodiversity, there was evidence to suggest that it selected for organisms with particular physiological characteristics. The consequences of this for interpreting biodiversity – function relationships are discussed. The stability of the resulting communities to perturbation was further examined by imposing a transient (brief heating to 40°C) or a persistent (addition of CuSO4) stress. Decomposition of grass residues was determined on three occasions after such perturbations. The soils clearly demonstrated resilience to the transient stress; decomposition rates were initially depressed by the stress and recovered over time. Resilience was reduced in the soils with decreasing biodiversity. Soils were not resilient to the persistent stress, there was no recovery in decomposition rate over time, but the soils with the highest biodiversity were more resistant to the stress than soils with impaired biodiversity. The study of functional stability under applied perturbation is a powerful means of examining the effects of biodiversity.

Y-Chromosomal Diversity in Europe Is Clinal and Influenced Primarily by Geography, Rather than by Language

Abstract: Clinal patterns of autosomal genetic diversity within Europe have been interpreted in previous studies in terms of a Neolithic demic diffusion model for the spread of agriculture; in contrast, studies using mtDNA have traced many founding lineages to the Paleolithic and have not shown strongly clinal variation. We have used 11 human Y-chromosomal biallelic polymorphisms, defining 10 haplogroups, to analyze a sample of 3,616 Y chromosomes belonging to 47 European and circum-European populations. Patterns of geographic differentiation are highly nonrandom, and, when they are assessed using spatial autocorrelation analysis, they show significant clines for five of six haplogroups analyzed. Clines for two haplogroups, representing 45% of the chromosomes, are continentwide and consistent with the demic diffusion hypothesis. Clines for three other haplogroups each have different foci and are more regionally restricted and are likely to reflect distinct population movements, including one from north of the Black Sea. Principal-components analysis suggests that populations are related primarily on the basis of geography, rather than on the basis of linguistic affinity. This is confirmed in Mantel tests, which show a strong and highly significant partial correlation between genetics and geography but a low, nonsignificant partial correlation between genetics and language. Genetic-barrier analysis also indicates the primacy of geography in the shaping of patterns of variation. These patterns retain a strong signal of expansion from the Near East but also suggest that the demographic history of Europe has been complex and influenced by other major population movements, as well as by linguistic and geographic heterogeneities and the effects of drift.

Transcriptional regulation of gene expression in human skeletal muscle during recovery from exercise

Abstract: Exercise training elicits a number of adaptive changes in skeletal muscle that result in an improved metabolic efficiency. The molecular mechanisms mediating the cellular adaptations to exercise tr...

Global Commodity Chain Analysis and the French Filière Approach: Comparison and Critique

Abstract: This article reviews two approaches to the study of economic restructuring which focus on commodity-specific dynamics of change. The first is the global commodity chain (GCC) approach, which has been developed primarily for the analysis of industrial commodities.The second is the francophone filiere tradition, which has been applied mostly to agricultural commodities originating from former French colonies. The article finds that the GCC approach has a more coherent framework than the filiere approach, although it is still far from constituting a fully fledged 'theory'. The authors provide a number of suggestions for improving some of its key concepts. They also suggest that the GCC approach can be enriched by some of the insights gained in filiere work, especially in terms of improving historical coverage and depth, enlarging the analysis to agricultural commodities, better handling of regulation issues, and including quality convention issues in analysing commodity chain structure and restructuring.

Central sensitization in tension-type headache—possible pathophysiological mechanisms

Abstract: The aim of the present thesis was to investigate the pathophysiology of chronic tension-type headache with special reference to central mechanisms. Increased tenderness to palpation of pericranial myofascial tissues is the most apparent abnormality in patients with tension-type headache. A new piece of equipment, a so-called palpometer, that makes it possible to control the pressure intensity exerted during palpation, was developed. Thereafter, it was demonstrated that the measurement of tenderness could be compared between two observers if the palpation pressure was controlled, and that the Total Tenderness Scoring system was well suited for the scoring of tenderness during manual palpation. Subsequently, it was found that pressure pain detection and tolerance thresholds were significantly decreased in the finger and tended to be decreased in the temporal region in chronic tension-type headache patients compared with controls. In addition, the electrical pain threshold in the cephalic region was significantly decreased in patients. It was concluded that the central pain sensitivity was increased in the patients probably due to sensitization of supraspinal neurones. The stimulus-response function for palpation pressure vs. pain was found to be qualitatively altered in chronic tension-type headache patients compared with controls. The abnormality was related to the degree of tenderness and not to the diagnosis of tension-type headache. In support of this, the stimulus-response function was found to be qualitatively altered also in patients with fibromyalgia. It was concluded that the qualitatively altered nociception was probably due to central sensitization at the level of the spinal dorsal horn/trigeminal nucleus. Thereafter, the prophylactic effect of amitriptyline, a non-selective serotonin (5-HT) reuptake inhibitor, and of citalopram, a highly selective 5-HT reuptake inhibitor, was examined in patients with chronic tension-type headache. Amitriptyline reduced headache significantly more than placebo, while citalopram had only a slight and insignificant effect. It was concluded that the blockade of 5-HT reuptake could only partly explain the efficacy of amitriptyline in tension-type headache, and that also other actions of amitriptyline, e.g. reduction of central sensitization, were involved. Finally, the plasma 5-HT level, the platelet 5-HT level and the number of platelet 5-HT transporters were found to be normal in chronic tension-type headache. On the basis of the present and previous studies, a pathophysiological model for tension-type headache is presented. According to the model, the main problem in chronic tension-type headache is central sensitization at the level of the spinal dorsal horn/trigeminal nucleus due to prolonged nociceptive inputs from pericranial myofascial tissues. The increased nociceptive input to supraspinal structures may in turn result in supraspinal sensitization. The central neuroplastic changes may affect the regulation of peripheral mechanisms and thereby lead to, for example, increased pericranial muscle activity or release of neurotransmitters in the myofascial tissues. By such mechanisms the central sensitization may be maintained even after the initial eliciting factors have been normalized, resulting in the conversion of episodic into chronic tension-type headache. Future basic and clinical research should aim at identifying the source of peripheral nociception in order to prevent the development of central sensitization and at ways of reducing established sensitization. This may lead to a much needed improvement in the treatment of chronic tension-type headache and other chronic myofascial pain conditions.