Subgrouping of facilitatory or inhibitory conditioned pain modulation responses in patients with chronic knee pain. Explorative analysis from a multicentre trial.

BACKGROUND: Facilitatory and inhibitory conditioned pain modulation (CPM) responses are observed in healthy volunteers and chronic pain patients, but the clinical implications for phenotyping are unknown. This study aimed to subgroup and compare chronic knee pain patients according to their CPM responses. METHODS: This explorative, cross-sectional study included 127 patients with chronic knee pain (osteoarthritis or following total knee arthroplasty). Individual CPM responses were categorized as facilitatory (test stimuli pain intensity increased when conditioning stimuli were applied), as inhibitory (test stimuli pain intensity decreased) or as no change (defined as less than 5.3% change in pain intensity). Outcomes were clinical pain intensities, temporal summation, widespread pain, self-reported physical function, PainDETECT questionnaire and Pain Quality Assessment Scale. Data were analysed as comparisons between the inhibitory and the facilitatory groups and using multivariate linear regression models. RESULTS: Fifty-four patients had facilitatory CPM responses, 49 had inhibitory CPM responses, and 24 showed no change in CPM response. A between-group difference was observed for self-reported physical function, with the facilitatory CPM group reporting better function (54.4 vs. 46.0, p = 0.028) and the facilitatory CPM group reported more deep pain sensations (3.2 vs. 2.0, p = 0.021). The remaining outcomes showed no between-group differences. Higher clinical pain intensity and facilitated temporal summation were associated in the facilitated CPM group but not in the inhibitory CPM group. CONCLUSION: These explorative findings indicated that quantitative clinical and experimental differences exist between facilitatory or inhibitory CPM responses in a chronic knee pain patient population. Differences in patients' CPM responses should be further investigated to unravel possible clinical importance. SIGNIFICANCE: Our findings confirm that conditioned pain modulation consist of inhibitory and facilitatory responders among a patient population with chronic knee pain. This explorative study indicates that patients with either facilitatory or inhibitory conditioned pain modulation could exhibit differences in pain outcomes. Subgrouping of chronic pain patients depending on individual conditioned pain modulation responses could be considered in phenotyping patients prior to inclusion in clinical trials or used for personalizing the management regime.

Recommendations for the delivery of therapeutic exercise for people with knee and/or hip osteoarthritis. An international consensus study from the OARSI Rehabilitation Discussion Group.

OBJECTIVE: To develop evidence-informed recommendations to support the delivery of best practice therapeutic exercise for people with knee and/or hip osteoarthritis (OA). DESIGN: A multi-stage, evidence-informed, international multi-disciplinary consensus process that included: 1) a narrative literature review to synthesise existing evidence; 2) generation of evidence-informed proposition statements about delivery of exercise for people with knee and/or hip OA by an international multi-disciplinary expert panel, with statements refined and analysed thematically; 3) an e-Delphi survey with the expert panel to gain consensus on the most important statements; 4) a final round of statement refinement and thematic analysis to group remaining statements into domains. RESULTS: The expert panel included 318 members (academics, health care professionals and exercise providers, patient representatives) from 43 countries. Final recommendations comprised 54 specific proposition statements across 11 broad domains: 1) use an evidence-based approach; 2) consider exercise in the context of living with OA and pain; 3) undertake a comprehensive baseline assessment with follow-up; 4) set goals; 5) consider the type of exercise; 6) consider the dose of exercise; 7) modify and progress exercise; 8) individualise exercise; 9) optimise the delivery of exercise; 10) focus on exercise adherence; and 11) provide education about OA and the role of exercise. CONCLUSION: The breadth of issues identified as important by the international diverse expert panel highlights that delivering therapeutic exercise for OA is multi-dimensional and complex.

The role of interleukin-18 in the diagnosis and monitoring of hemophagocytic lymphohistiocytosis/macrophage activation syndrome - a systematic review.

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening, hyperinflammatory disorder, characterized by multiorgan failure, fever and cytopenias. The diagnosis of HLH and its subtype Macrophage Activation Syndrome (MAS) remains a challenge. Interleukin 18 (IL-18) is emerging as a potential biomarker for HLH/MAS but is currently not a part of diagnostic criteria. This systematic review aimed to assess the potential role of IL-18 in the diagnosis and monitoring of HLH and MAS, and was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. PubMed and Embase were searched on 30 January 2020. Studies included all subtypes of HLH and a range of underlying disorders in both children and adults. A total of 14 studies were included. Generally, serum IL-18 was elevated in both primary and secondary HLH (> 1000 pg/ml) compared with other inflammatory conditions and with healthy individuals; thus, serum IL-18 may be able to discriminate between HLH and other inflammatory conditions. Significantly increased IL-18 (> 10 000 pg/ml) was also consistently described in MAS compared with other subtypes of HLH. The ability of IL-18 to distinguish MAS from systemic juvenile idiopathic arthritis (JIA) is less unambiguous, as IL-18 levels > 100 000 pg/ml were described in sJIA patients both with and without MAS. IL-18 may help to differentiate between HLH subtypes and other inflammatory conditions. As HLH and MAS are rare disorders, only few and relatively small studies exist on the subject. Larger, prospective multi-center studies are called for to assess the diagnostic precision of IL-18 for HLH and MAS.

PO-20 - Crosstalk between the lectin pathway and haemostasis in patients with pulmonary cancer.

INTRODUCTION: Recent research has focused on the complement system in cancer, including the lectin pathway of complement activation. Mannose-binding lectin (MBL), a key activator of the lectin pathway, can bind to tumor cell surfaces in vitro, and lectin pathway activation is increased in several types of cancer. The exact role of the complement system in cancer is currently discussed. However, one possible consequence of the increased complement activation could be contribution to the increased thrombosis risk which cancer patients experience. Proteins of the lectin pathway can activate coagulation and impair fibrinolysis in vitro, but the significance of this in a clinical setting is not well understood. AIM: We aim to investigate associations between lectin pathway and haemostatic activation in patients with lung cancer undergoing thoracoscopic surgery. MATERIALS AND METHODS: Patients with lung cancer (n=60) eligible for thoracoscopic tumor resection were included as part of a randomized controlled trial, the COPPVATS project (EudraCT no: 2012-002409-23), conducted at the Department of Thoracic Surgery, Aarhus University Hospital. Exclusion criteria were arterial or venous thrombosis within the last three months, other systemic disease than cancer, and anticoagulant treatment prior to inclusion. Blood samples were obtained the day before surgery, perioperatively, and on the 1st and 2nd postoperative days. Laboratory analyses on the complement system include MBL, MBL-associated protease (MASP)-1 and -2, MBL-MASP complex, ficolin-1, -2, and -3 and complement factor C3b. Haemostasis was evaluated with routine coagulation parameters (INR, APTT, fibrinogen, fibrin d-dimer), platelet function, and tissue factor-induced thrombin generation. RESULTS: Recruitment of the study subjects is concluded, and laboratory work is in progress. The complement analyses and data processing will be performed during early spring 2016, so that results will be ready for presentation on the conference. CONCLUSIONS: The present project will provide new knowledge on lectin pathway activation and the pathogenesis of thrombosis in cancer patients. In the long term, this will help improve the individual risk assessment and lead to new studies on thromboprophylaxis and treatment in conditions with increased complement activation.

Genomic sequence and analysis of EhV-99B1, a new coccolithovirus from the Norwegian fjords.

Coccolithoviruses are giant dsDNA viruses that infect Emiliania huxleyi, the most ubiquitous marine microalga. Here, we present the genome of the latest coccolithovirus strain to be sequenced, EhV-99B1, and compare it with two other coccolithovirus genomes (EhV-86 and EhV-163). EhV-99B1 shares a pairwise nucleotide identity of 98% with EhV-163 (the two strains were isolated from the same Norwegian fjord but in different years), and just 96.5% with EhV-86 (isolated in the same spring as EhV-99B1 but in the English Channel). We confirmed and extended the list of relevant genomic differences between these EhVs from the Norwegian fjord and EhVs from the English Channel, namely the removal/insertions of: a phosphate permease, an endonuclease, a transposase, and two specific tRNAs. As a whole, this study provided new clues and insights into the diversity and mechanisms driving the evolution of these large oceanic viruses, in particular those processes involving selfish genetic elements.

Phylogenetic analysis of members of the Phycodnaviridae virus family, using amplified fragments of the major capsid protein gene.

Algal viruses are considered ecologically important by affecting host population dynamics and nutrient flow in aquatic food webs. Members of the family Phycodnaviridae are also interesting due to their extraordinary genome size. Few algal viruses in the Phycodnaviridae family have been sequenced, and those that have been have few genes in common and low gene homology. It has hence been difficult to design general PCR primers that allow further studies of their ecology and diversity. In this study, we screened the nine type I core genes of the nucleocytoplasmic large DNA viruses for sequences suitable for designing a general set of primers. Sequence comparison between members of the Phycodnaviridae family, including three partly sequenced viruses infecting the prymnesiophyte Pyramimonas orientalis and the haptophytes Phaeocystis pouchetii and Chrysochromulina ericina (Pyramimonas orientalis virus 01B [PoV-01B], Phaeocystis pouchetii virus 01 [PpV-01], and Chrysochromulina ericina virus 01B [CeV-01B], respectively), revealed eight conserved regions in the major capsid protein (MCP). Two of these regions also showed conservation at the nucleotide level, and this allowed us to design degenerate PCR primers. The primers produced 347- to 518-bp amplicons when applied to lysates from algal viruses kept in culture and from natural viral communities. The aim of this work was to use the MCP as a proxy to infer phylogenetic relationships and genetic diversity among members of the Phycodnaviridae family and to determine the occurrence and diversity of this gene in natural viral communities. The results support the current legitimate genera in the Phycodnaviridae based on alga host species. However, while placing the mimivirus in close proximity to the type species, PBCV-1, of Phycodnaviridae along with the three new viruses assigned to the family (PoV-01B, PpV-01, and CeV-01B), the results also indicate that the coccolithoviruses and phaeoviruses are more diverged from this group. Phylogenetic analysis of amplicons from virus assemblages from Norwegian coastal waters as well as from isolated algal viruses revealed a cluster of viruses infecting members of the prymnesiophyte and prasinophyte alga divisions. Other distinct clusters were also identified, containing amplicons from this study as well as sequences retrieved from the Sargasso Sea metagenome. This shows that closely related sequences of this family are present at geographically distant locations within the marine environment.

Fetal antigen 1 in healthy adults and patients with pituitary disease: relation to physiological, pathological, and pharmacological GH levels.

Immunohistochemical analysis of the distribution of human fetal antigen 1 (FA1) in adult human tissues has demonstrated a strong association between FA1 and (neuro)endocrine structures. In the anterior pituitary gland FA1 was colocalized with GH, and the present study was performed to evaluate a possible relationship between GH and FA1. FA1 and GH levels were measured during a 24-h period at 20-min intervals. In contrast to the known GH peaks during 24-h sampling, there was no detectable FA1 peak. The FA1 responses to placebo were not significantly different from the responses to the combination of pyridostigmine and GHRH. No significant difference was found between basal FA1 (nanograms per ml) levels [median (minimum-maximum)] in healthy adults [n = 40; 28.6 ng/ml (12.5-72.0)], acromegalic patients [n = 11; 31.0 ng/ml (21.6-56.3)], and patients with GH deficiency [n = 22; 32.1 ng/ml (13.4-108.7)]. FA1 levels were significantly reduced, in the six of seven acromegalic GH responders to octreotide, from [median (minimum-maximum)] 30.6 ng/ml (20.0-43.1) to 20.3 (13.9-30.2; P < 0.02). There was no significant change during placebo. FA1 levels were significantly increased compared with placebo values during 3 months of GH therapy. The increase in FA1 levels was significantly higher than the change during placebo (P < 0.003). In conclusion, a common secretory and stimulatory pathway for FA1 and GH in healthy adults has been ruled out. However, we found that pharmacologically induced changes in GH levels during weeks to months had a corresponding direct or indirect effect on FA1 levels in patients with GH deficiency or acromegaly. However, a direct effect of octreotide on FA1 levels, independent of GH levels, has not been ruled out.

Maximal oxygen uptake, muscle strength and walking speed in 85-year-old women: effects of increased physical activity.

This study explores the effect of regular training on blood pressure, maximal oxygen uptake, maximal isometric muscle strength, and walking speed in the very old. A total of 55 community-dwelling women, 85-year-old, were enrolled in a training group (N = 22) or a control group (N = 33). These groups were reduced to 19 and 26 subjects, respectively, after the training period. Training was performed once a week over eight months, and consisted of various exercises with particular attention to movements important for everyday activities. Training reduced diastolic blood pressure (p < 0.05), and showed a similar trend for systolic blood pressure. Measurements of maximal oxygen uptake before the start of the training (15 mL min-1 kg-1) revealed a level close to the presumed limit for independent living (13 mL min-1 kg-1). Training improved VO2 max by 18% (p < 0.05), whereas the control group experienced a trend towards a reduction. Maximal isometric muscle strength of both the right and left leg showed a tendency to increase with training, but no significant changes were evident in the trunk flexor and extensor muscles. The training group showed a significant increase of 17% in maximal walking speed after the training period. However, one year later, without training, this improvement was reduced to 8% (p < 0.05). No major changes were observed in the control group for any of these parameters. This study demonstrates a maximal oxygen capacity in very old community-dwelling women close to a threshold level indicating dependency. Furthermore, 8 months of regular training appears to lower blood pressure, and to increase maximal oxygen uptake and maximal walking speed. This suggests that physical reactivation of the very old may reduce the risk for acquiring age-related diseases associated with an elevated blood pressure, and may improve parameters crucial for independence.

Simple numerical chromosome aberrations characterize pituitary adenomas.

Although pituitary adenomas are among the most frequent intracranial neoplasms, only very few have been cytogenetically analyzed. We have short-term cultured and karyotyped 28 consecutive pituitary adenomas (16 clinically nonfunctioning adenomas and 12 clinically functioning adenomas), finding a normal karyotype in 22, whereas 6 had clonal chromosome aberrations (5 nonfunctioning pituitary adenomas and 1 prolactinoma). The abnormal karyotypes were relatively simple. Most anomalies were numerical, with a structural rearrangement, t(6;19), being found in only one tumor. The most common aberrations were trisomy 7 (3 adenomas), trisomy 9 (2 adenomas), trisomy 12 (2 adenomas), trisomy 20 (2 adenomas), and loss and gain in 2 separate clones of one X chromosome (2 adenomas).

Body composition in 85 year-old women: effects of increased physical activity.

This study explores whether regular training alters body composition and resting metabolism in the very old. A total of 55 community-dwelling women, 85 years old, were enrolled in a training group (N = 22) and a control group (N = 33). Training was performed once a week for eight months, and consisted of various exercises with particular attention to movements important for everyday activities. Before, immediately after, and one year after cessation of training, body composition was evaluated both by an impedance measurement and a whole body scan by dual-photon X-ray absorptiometry. Resting metabolism, assessed as energy expenditure at rest, was measured with standardized protocols by analyzing oxygen consumption and carbon dioxide production. Height declined in both groups throughout the study. Immediately after the training period, body weight showed a trend towards reduced levels in the training group, and an opposite trend in the control group. The control group showed an increased body mass index (p < 0.05) related to an increase in fat mass immediately after the training period; these parameters were unaltered in the training group. A reduction in fat free mass (p < 0.05) and bone mineral content (p < 0.05), and unaltered energy expenditure at rest were evident in both groups during the course of the study. These results suggest that regular training can counteract the age-related accumulation of fat in the very old. Physical reactivation, therefore, may possess an important potential for reducing morbidity in the very old by lowering fat mass, and thereby reducing the risk of acquiring several age-related diseases.

Significant envenomation by Aurelia aurita, the moon jellyfish.

The case of a patient envenomated by Aurelia aurita, who developed significant local cutaneous lesions and immunospecific serum antibodies is reported. The lesions required more than ten days to heal. The patient developed significant cross-reacting antibodies to Chrysaora quinquecirrha antigens.

Glycosylated hemoglobin A1 used in quality-control of diabetes care: a cross-sectional study in an outpatient clinic.

HBA1 was used to evaluate the quality of treatment and regulation in 163 insulin treated diabetes patients. The mean of HBA1 in all patients was 11.2 +/- 2.4%. Only 24% of the patients had HBA1 values below the mean + 3 SD of non diabetics. Patients with high values of HBA1 were controlled and treated more intensively than those with lower or normal values. They were also seen more frequently at the outpatient clinic, their insulin doses were larger, and they took more frequent insulin injections. 63% of the patients practised home monitoring of blood glucose, but they were not better controlled than those, who did not. In some of the patients conspicuous discrepancies were found between high HBA1 percentages and low blood glucose values measured at the outpatient clinic. It is concluded, that home monitoring of blood glucose, frequent visits to an outpatient clinic, and 2 daily insulin injections do not appreciably improve diabetes control, and that other approaches are needed, e.g., greater co-operation by the patients in frequent adjustments of treatment between clinic visits.

Colchicine alters the nerve birefringence response.

The internal perfusion of squid axons with colchicine reversibly and selectively reduces the transient sodium current and the birefringence response to a brief depolarizing voltage pulse.