Non-technical summary Exercise training is a potent stimulus for capillary growth in skeletal muscle, but the precise mechanisms underlying the regulation of capillary growth in muscle remain unclear. We examined the effect of acute exercise and endurance training in male subjects, on a number of compounds believed to either promote or inhibit growth of capillaries in skeletal muscle. The results show that acute exercise increases the gene expression of both capillary growth-promoting and -inhibiting compounds, suggesting that both positive and negative factors are needed for the precise control of growth. Training increased capillary growth but had little effect on gene and protein levels of the capillary growth-promoting and -inhibiting factors, suggesting a similar potential for capillary growth in untrained and trained muscle. The study is one of the first addressing how the balance between a large number of positive and negative factors is affected in human muscle with exercise and training.Abstract This study examined the effect of acute exercise and 4 weeks of aerobic training on skeletal muscle gene and protein expression of pro-and anti-angiogenic factors in 14 young male subjects. Training consisted of 60 min of cycling (∼60% ofV O 2 max ), 3 times/week. Biopsies were obtained from vastus lateralis muscle before and after training. Muscle interstitial fluid was collected during cycling at weeks 0 and 4. Training increased (P < 0.05) the capillary: fibre ratio and capillary density by 23% and 12%, respectively. The concentration of interstitial vascular endothelial growth factor (VEGF) in response to acute exercise increased similarly (>6-fold; P < 0.05) before and after training. Resting protein levels of soluble VEGF receptor-1 in interstitial fluid, and of VEGF, thrombospondin-1 (TSP-1) and tissue inhibitor of matrix metalloproteinase-1 (TIMP1) in muscle were unaffected by training, whereas endothelial nitric oxide synthase protein levels in muscle increased by 50% (P < 0.05). Before and after training, acute exercise induced a similar increase (P < 0.05) in the mRNA level of angiopoietin 2, matrix metalloproteinase 9 and TSP-1. After training, TIMP1 mRNA content increased with exercise (P < 0.05). In conclusion, acute exercise induced a similar increase in the gene-expression of both pro-and anti-angiogenic factors in untrained and trained muscle. We propose that the increase in anti-angiogenic factors with exercise is important for modulation of angiogenesis. The lack of effect of training on basal muscle VEGF protein levels and VEGF secretion during exercise suggests that increased VEGF levels are not a prerequisite for exercise-induced capillary growth in healthy muscle. Abbreviations Ang1, angiopoietin-1; Ang2, angiopoietin-2; BrdU, bromodeoxyuridine; eNOS, endothelial nitric oxide synthase; MMP2, matrix metalloproteinases-2; MMP9, matrix metalloproteinases-9; NO, nitric oxide; PF4, platelet factor-4; sVEGFR-1, soluble VEGF receptor-1; Tie2, angiopoietin receptor-2; TIMP1, tissue inhibitor of MM...

Visceral pain can be difficult to treat with classical mu-opioid agonists and it has been suggested to use opioids with distinct pharmacological profiles. In animal experiments, oxycodone has shown different effects compared to morphine, and clinical observations have shown that oxycodone may occasionally be superior to, e.g., morphine in the treatment of visceral pain. In the current study, we randomised 24 healthy subjects to treatment with either morphine (30 mg), oxycodone (15 mg) or placebo in a crossover study. The experimental pain model involved multi-modal (mechanical, thermal and electrical) pain tests in the skin, muscles and viscera. The pain tests were carried out at baseline and 30, 60 and 90 min after oral administration of the drugs. The model showed effect of the two opioids compared to placebo on all stimulus modalities in all three types of tissues (all P values <0.001). Both opioids attenuated the sensory response mainly to painful stimulations. Morphine and oxycodone were equipotent in pain modulation of the skin and muscles, but oxycodone had superior analgesic effect to both morphine and placebo on the mechanical (P<0.001) and thermal (P<0.001) stimulations of the oesophagus. In conclusion, the multi-modal and tissue-differentiated pain model could link findings from animal experiments to clinical findings. A different pharmacological profile of oxycodone compared to that of morphine was shown, and thus oxycodone may be a useful alternative to morphine in the treatment of visceral pain syndromes.

Goal-directed fluid therapy to near-maximal SV guided by ED adds no extra value to the fluid therapy using zero balance and normal BW in patients undergoing elective colorectal surgery.

Causal probabilistic networks (CPNs) have proved to be a useful knowledge representation tool for modeling domains where causal relationsin a broad sense -are a natural way of relating domain concepts and where uncertainty is inherited in these relations. The domain is modeled in a CPN by use of a directed graph where the nodes represent concepts in the domain and the arcs represent causal relations. Furthermore, the quantitative relation between a node and its immediate causes is expressed as conditional probabilities. During the last few years, several schemes based on probability theory for incorporating and propagating new information throughout a CPN has emerged. As long as the domain can be modeled by use of a singly connected CPN (i.e., no more than one path between any pair of nodes), the schemes operate directly in the CPN and perform conceptually simple operations in this structure. When it comes to more complicated structures such as multiply connected CPNs (i.e., more than one path is allowed between pairs of nodes), the schemes operate in derived structures where the embedded domain knowledge no longer is as explicit and transparent as in the CPN. Furthermore, the simplicity in the operations is lost also. This report outlines a scheme-the algebra of Bayesian belief universesfor absorbing and propagating evidence in multiply connected CPNs. The scheme provides a secondary structure, a junction tree, and a simple set of algebraic operations between objects in this structure, CollectEvidence and DistributeEvidence. These are the basic tools for making inference in a CPN domain model and yield a calculus as simple as in the case of singly connected CPNs.*This work is supported in part by the EEC ESPRIT programme, project P599.

Experimental pain models for assessment of analgesic effect needs to be reproducible, valid and responding in a uniform way to changes in pain level. The pain system differs in various tissue types and analgesics may have different effects in different tissues. This study assessed the reproducibility of an experimental model using mechanical, thermal and electrical stimulations. Pain was evoked in three tissues: Skin, muscle and viscera. Pain was evoked and assessed in 24 healthy volunteers. The experiment was repeated three times with 30 min. intervals and twice with a weekly interval. Systematic bias, intra-class correlation (ICC) and coefficient of variation (CV) and valid sample sizes for analgesic testing were assessed. The model proved to be feasible. Most tests were unbiased, showing stable means except for the mechanical and thermal stimulation in viscera, which showed decreasing pain thresholds when the tests were repeated with 30 min. intervals. Generally the pain tests showed relatively high CV (mean 71%, range 8-145%). The pain tests showed high ICC's (Ͼ0.80) when repeated on the same day. When the tests were repeated with an interval of one week, ICC was smaller (mean 0.79 range 0.49-0.96). This means that these tests are useful for analgesic testing recruiting useful sample sizes in a crossover (mean 31 range 2-84) and a parallel study (mean 59 range 3-164) design. Application of this experimental pain model in a cross-over study design with appropriate base-line recordings offers a unique opportunity of revealing analgesic effects on pain arising from different tissues.

In this paper we propose a new approach to probabilistic inference on belief networks, global conditioning, which is a simple generalization of Pearl's (1986b) method of loopcutset conditioning. We show that global conditioning, as well as loop-cutset conditioning, can be thought of as a special case of the method of Lauritzen and Spiegelhalter (1988) as refined by Jensen et al (1990a;. Nonetheless, this approach provides new opportunities for parallel processing and, in the case of sequential processing, a tradeoff of time for memory. We also show how a hybrid method (Suermondt and others 1990) combining loop-cutset conditioning with Jensen's method can be viewed within our framework. By exploring the relationships between these methods, we develop a unifying framework in which the advantages of each approach can be combined successfully.

Oxycodone was a stronger analgesic than morphine in several pain modalities in the skin, muscle and oesophagus.

New lineages of SARS-CoV-2 are of potential concern due to higher transmissibility, risk of severe outcomes, and/or escape from neutralizing antibodies. Lineage B.1.1.7 (the Alpha variant) became dominant in early 2021, but the association between transmissibility and risk factors, such as age of primary case and viral load remains poorly understood. Here, we used comprehensive administrative data from Denmark, comprising the full population (January 11 to February 7, 2021), to estimate household transmissibility. This study included 5,241 households with primary cases; 808 were infected with lineage B.1.1.7 and 4,433 with other lineages. Here, we report an attack rate of 38% in households with a primary case infected with B.1.1.7 and 27% in households with other lineages. Primary cases infected with B.1.1.7 had an increased transmissibility of 1.5–1.7 times that of primary cases infected with other lineages. The increased transmissibility of B.1.1.7 was multiplicative across age and viral load.