Reduced plasma calcitonin gene-related peptide level identified in cluster headache: A prospective and controlled study.

BACKGROUND: The role of calcitonin gene-related peptide (CGRP) in the cyclic pattern of cluster headache is unclear. To acquire biological insight and to comprehend why only episodic cluster headache responds to CGRP monoclonal antibodies, we examined whether plasma CGRP changes between disease states (i.e. bout, remission and chronic) and controls. METHODS: The present study is a prospective case-control study. Participants with episodic cluster headache were sampled twice (bout and remission). Participants with chronic cluster headache and controls were sampled once. CGRP concentrations were measured in plasma with a validated radioimmunoassay. RESULTS: Plasma was collected from 201 participants diagnosed with cluster headache according to the International Classification of Headache Disorders, 3rd edition, and from 100 age- and sex-matched controls. Overall, plasma CGRP levels were significantly lower in participants with cluster headache compared to controls (p < 0.05). In episodic cluster headache, CGRP levels were higher in bout than in remission (mean difference: 17.1 pmol/L, 95% confidence interval = 9.8-24.3, p < 0.0001). CGRP levels in bout were not different from chronic cluster headache (p = 0.266). CONCLUSIONS: Plasma CGRP is unsuitable as a diagnostic biomarker of cluster headache or its disease states. The identified reduced CGRP levels suggest that CGRPs role in cluster headache is highly complex and future investigations are needed into the modulation of CGRP and its receptors.

Effects of power training in older patients with multiple sclerosis on neurodegeneration, neuromuscular function, and physical function. A study protocol for the "power training in older multiple sclerosis patients (PoTOMS) randomized control trial.

Introduction: Approximately one-third of all persons with multiple sclerosis (pwMS) are older, i.e., having an age ≥60 years. Whilst ageing and MS separately elicit deteriorating effects on brain morphology, neuromuscular function, and physical function, the combination of ageing and MS may pose a particular challenge. To counteract such detrimental changes, power training (i.e., a type of resistance exercise focusing on moderate-to-high loading at maximal intended movement velocity) presents itself as a viable and highly effective solution. Power training is known to positively impact physical function, neuromuscular function, as well as brain morphology. Existing evidence is promising but limited to young and middle-aged pwMS, with the effects of power training remaining to be elucidated in older pwMS. Methods: The presented 'Power Training in Older MS patients (PoTOMS)' trial is a national, multi-center, parallel-group, randomized controlled trial. The trial compares 24 weeks of usual care(n = 30) to 24 weeks of usual care and power training (n = 30). The primary outcome is whole brain atrophy rate. The secondary outcomes include changes in brain micro and macro structures, neuromuscular function, physical function, cognitive function, bone health, and patient-reported outcomes. Ethics and dissemination: The presented study is approved by The Regional Ethics Committee (reference number 1-10-72-222-20) and registered at the Danish Data Protection Agency (reference number 2016-051-000001). All study findings will be published in scientific peer-reviewed journals and presented at relevant scientific conferences independent of the results. The www.clinicaltrials.gov identifier is NCT04762342.

Clinical application of bone turnover markers in osteoporosis.

Bone turnover markers (BTM) are highly responsive to initiation and changes in anti-osteoporotic therapy. In contrast to the slow treatment-induced changes in bone mineral density, the fast changes in BTM enable the clinician to adjust treatment management within a short timeframe. This review describes how BTM can be used for treatment monitoring, including monitoring during discontinuation of alendronate and denosumab therapy. In addition, sources of errors and pitfalls when using BTM monitoring will be described.

Dual-release hydrocortisone improves body composition and the glucometabolic profile in patients with secondary adrenal insufficiency.

PURPOSE: Studies have suggested improved metabolic profiles in patients with adrenal insufficiency treated with dual-release hydrocortisone (DR-HC) compared with conventional hydrocortisone (C-HC). This study investigates the effect of DR-HC compared with C-HC treatment on five health variables: diurnal salivary cortisol/cortisone, body composition, bone health, glucose metabolism, lipids, and blood pressure. METHODS: Prospective study of 27 participants (24 men) with secondary adrenal insufficiency with measurements during stable C-HC and 16 weeks after treatment switch to DR-HC. OUTCOMES: Diurnal salivary-cortisol/cortisone, body composition assessed by Dual-Energy X-ray absorptiometry scan, bone status indices (serum type I N-terminal procollagen [PINP], collagen type I cross-linked C-telopeptide [CTX], osteocalcin, receptor activator kappa-B [RANK] ligand, osteoprotegerin, and sclerostin), lipids, haemoglobin A1c (HbA1c), and 24-hour blood pressure. RESULTS: After the switch to DR-HC, the diurnal salivary-cortisol area under the curve (AUC) decreased non-significantly (mean difference: -55.9 nmol/L/day, P = 0.06). The salivary-cortisone-AUC was unchanged. Late-evening salivary-cortisol and cortisone were lower (-1.6 and -1.7 nmol/L, P = 0.002 and 0.004). Total and abdominal fat mass (-1.5 and -0.5 kg, P = 0.003 and 0.02), HbA1c (-1.2 mmol/mol, P = 0.02), and osteocalcin decreased (-7.0 µg/L, P = 0.03) whereas sclerostin increased (+41.1 pg/mL, P = 0.0001). The remaining bone status indices, lipids, and blood pressure were unchanged. CONCLUSION: This study suggests that switching to DR-HC leads to lower late-evening cortisol/cortisone exposure and a more favourable metabolic profile and body composition. In contrast, decreased osteocalcin with increasing sclerostin might indicate a negative impact on bones. CLINICAL TRIAL REGISTRATION: EudraCT201400203932.

Protocol for the combined cardiometabolic deep phenotyping and registry-based 20-year follow-up study of the Inter99 cohort.

INTRODUCTION: The population-based Inter99 cohort has contributed extensively to our understanding of effects of a systematic screening and lifestyle intervention, as well as the multifactorial aetiology of type 2 diabetes (T2D) and cardiovascular disease. To understand causes, trajectories and patterns of early and overt cardiometabolic disease manifestations, we will perform a combined clinical deep phenotyping and registry follow-up study of the now 50-80 years old Inter99 participants. METHODS AND ANALYSIS: The Inter99 cohort comprises individuals aged 30-60 years, who lived in a representative geographical area of greater Copenhagen, Denmark, in 1999. Age-stratified and sex-stratified random subgroups were invited to participate in either a lifestyle intervention (N=13 016) or questionnaires (N=5264), while the rest served as a reference population (N=43 021). Of the 13 016 individuals assigned to the lifestyle intervention group, 6784 (52%) accepted participation in a baseline health examination in 1999, including screening for cardiovascular risk factors and prediabetic conditions. In total, 6004 eligible participants, who participated in the baseline examination, will be invited to participate in the deep phenotyping 20-year follow-up clinical examination including measurements of anthropometry, blood pressure, arterial stiffness, cardiometabolic biomarkers, coronary artery calcification, heart rate variability, heart rhythm, liver stiffness, fundus characteristics, muscle strength and mass, as well as health and lifestyle questionnaires. In a subsample, 10-day monitoring of diet, physical activity and continuous glucose measurements will be performed. Fasting blood, urine and faecal samples to be stored in a biobank. The established database will form the basis of multiple analyses. A main purpose is to investigate whether low birth weight independent of genetics, lifestyle and glucose tolerance predicts later common T2D cardiometabolic comorbidities. ETHICS AND DISSEMINATION: The study was approved by the Medical Ethics Committee, Capital Region, Denmark (H-20076231) and by the Danish Data Protection Agency through the Capital Region of Denmark's registration system (P-2020-1074). Informed consent will be obtained before examinations. Findings will be disseminated in peer-reviewed journals, at conferences and via presentations to stakeholders, including patients and public health policymakers. TRIAL REGISTRATION NUMBER: NCT05166447.

Lipid metabolism and functional somatic disorders in the general population. The DanFunD study.

OBJECTIVES: Earlier studies on the association between plasma lipid profiles and functional somatic disorders (FSD) are mainly small case control studies hampered by selection bias and do not consider the great overlap between the various FSDs. The aim of the present study was to investigate the associations between various FSDs and plasma lipid profiles (total cholesterol, HDL cholesterol, non-HDL cholesterol and triglycerides) in a large, unselected population. DESIGN: A cross-sectional general population-based study. SETTING: The Danish Study of Functional Somatic Disorders (DanFunD) conducted in 2011-2015 in 10 municipalities in the western part of greater Copenhagen, Denmark. PARTICIPANTS: A total of 8,608 men and women aged 18-76 years were included in the analyses. Various delimitations of FSD such as chronic fatigue, chronic widespread pain, irritable bowel, and bodily distress syndrome were measured using validated self-administrated questionnaires. Lipid parameters were measured from fasting plasma samples using colorimetric slide methods with Vitros 4600/5600 Ortho Clinical Diagnostics. OUTCOME MEASURES: Logistic regression analyses were used to calculate possible associations between plasma lipids and the various delimitations of FSD. Associations are presented by OR (95% CI) and shown in boxplots. RESULTS: We found a positive association between bodily distress syndrome and triglycerides and non-HDL cholesterol and a negative association with HDL-cholesterol, but no consistent association with total cholesterol. A similar pattern was observed for persons with chronic fatigue, and to some degree for persons with chronic widespread pain, whereas persons with irritable bowel did not show a clear association with the lipid profiles. CONCLUSION: This is the first major study on plasma lipid profiles and FSD indicating an association between some delimitations of FSD and an unfavorable lipid profile. Due to the cross-sectional design, it cannot be determined whether the findings are consequences or determinants of FSD. Further studies-preferable prospective studies-are needed.

Meal sugar-protein balance determines postprandial FGF21 response in humans.

Biological mechanisms to promote dietary balance remain unclear. Fibroblast growth factor 21 (FGF21) has been suggested to contribute to such potential regulation considering that FGF21 1) is genetically associated with carbohydrate/sugar and protein intake in opposite directions, 2) is secreted after sugar ingestion and protein restriction, and 3) pharmacologically reduces sugar and increases protein intake in rodents. To gain insight of the nature of this potential regulation, we aimed to study macronutrient interactions in the secretory regulation of FGF21 in healthy humans. We conducted a randomized, double-blinded, crossover meal study (NCT05061485), wherein healthy volunteers consumed a sucrose drink, a sucrose + protein drink, and a sucrose + fat drink (matched sucrose content), and compared postprandial FGF21 responses between the three macronutrient combinations. Protein suppressed the sucrose-induced FGF21 secretion [incremental area under the curve (iAUC) for sucrose 484 ± 127 vs. sucrose + protein -35 ± 49 pg/mL × h, P < 0.001]. The same could not be demonstrated for fat (iAUC 319 ± 102 pg/mL × h, P = 203 for sucrose + fat vs. sucrose). We found no indications that regulators of glycemic homeostasis could explain this effect. This indicates that FGF21 responds to disproportionate intake of sucrose relative to protein acutely within a meal, and that protein outweighs sucrose in FGF21 regulation. Together with previous findings, our results suggests that FGF21 might act to promote macronutrient balance and sufficient protein intake.NEW & NOTEWORTHY Here we test the interactions between sugar, protein, and fat in human FGF21 regulation and demonstrate that protein, but not fat, suppresses sugar-induced FGF21 secretion. This indicates that protein outweighs the effects of sugar in the secretory regulation of FGF21, and could suggest that the nutrient-specific appetite-regulatory actions of FGF21 might prioritize ensuring sufficient protein intake over limiting sugar intake.

The association of vitamin K status with lung function and disease in a general population.

Introduction: Matrix Gla protein (MGP) is an inhibitor of lung tissue calcification. The plasma level of dephosphorylated-uncarboxylated MGP (dp-ucMGP) is a biomarker of vitamin K status. The present study assessed whether lower vitamin K status (reflected by higher dp-ucMGP) was associated with lung function and lung disease/symptoms. Methods: A general population sample of 4092 individuals, aged 24 to 77 years, underwent a health examination including questionnaires, spirometry and measurements of plasma dp-ucMGP. Associations of dp-ucMGP with lung function and self-reported disease/symptoms were estimated using regression models adjusted for age, sex and height. Associations were expressed as ß-estimates or odds ratios (ORs) per doubling in dp-ucMGP. Results: Lower vitamin K status (higher dp-ucMGP) was associated with lower forced expiratory volume in 1 s (FEV1) (98 mL; 95% CI: 54-141 mL) and lower forced vital capacity (FVC) (136 mL; 95% CI: 85-187 mL). Dp-ucMGP was not associated with the FEV1/FVC ratio (0.0 percentage points higher than the expected value; 95% CI: -1.0-1.0). Furthermore, lower vitamin K status was associated with COPD (OR 2.24, 95% CI: 1.53-3.27), wheezing (OR 1.81, 95% CI: 1.44-2.28) and asthma (OR 1.44, 95% CI: 1.12-1.83). Conclusion: Lower vitamin K status was associated with lower ventilatory capacity (lower FEV1 and FVC), and with higher risk of self-reported asthma, COPD and wheezing. Vitamin K status was not associated with airflow obstruction (FEV1/FVC ratio).

Cutaneous vascular calcifications in patients with chronic kidney disease and calcific uremic arteriolopathy: a cross-sectional study.

INTRODUCTION: Calcific uremic arteriolopathy is a life-threatening cutaneous condition in patients with chronic kidney disease. Often, clinical diagnosis is accompanied by histopathologic evaluations demonstrating vascular calcium deposits. We aimed to investigate the presence of cutaneous calcifications in non-lesional tissue in patients with chronic kidney disease, and the relation to systemic vascular calcification. METHODS: We investigated the presence of cutaneous vascular calcifications in non-lesional skin biopsies from patients with current or previous calcific uremic arteriolopathy and patients with different stages of chronic kidney disease without calcific uremic arteriolopathy, and explored their association with vascular calcification in other vascular beds. Systemic vascular calcification was examined by mammography and lumbar X-ray. RESULTS: Thirty-nine adults were enrolled (current or previous calcific uremic arteriolopathy, n = 9; end-stage chronic kidney disease, n = 12; chronic kidney disease stage 3b-4, n = 12; healthy controls, n = 6). All calcific uremic arteriolopathy patients had end-stage kidney disease. Cutaneous vascular calcifications were not present in any of the non-lesional skin punch biopsies. Breast arterial calcification was demonstrated in patients with calcific uremic arteriolopathy (75%) and chronic kidney disease (end-stage 67% and stage 3b-4 25%, respectively), but in none of the controls. All chronic kidney disease patients had systemic calcification on lumbar X-ray (median score 21, 22, and 15 in patients with calcific uremic arteriolopathy, end-stage kidney disease and chronic kidney disease stage 3b-4). The serum calcification propensity was significantly different between groups. DISCUSSION: Despite a high burden of systemic vascular calcification, cutaneous calcium deposits in non-lesional tissue could not be demonstrated histopathologically in patients with chronic kidney disease (with or without current or previous calcific uremic arteriolopathy). Further studies to determine whether these findings are representative or attributed to other factors are warranted.

Bone health, body composition and physical fitness dose-response effects of 16 weeks of recreational team handball for inactive middle-to-older-aged males - A randomised controlled trial.

In this study we aimed at analysing the effects of different weekly exercise volumes (1, 2 or 3 times 60-min) on bone health, body composition and physical fitness of inactive middle-to-older-aged males, after 16 weeks of recreational team handball (RTH). Fifty-four men (68 ± 4 years, stature 169 ± 6 cm; body mass 78.4 ± 10.7 kg; fat mass 27.1 ± 5.3%; BMI 27.4 ± 2.9 kg/m2; VO2peak 27.3 ± 4.8 mL/min/kg) were randomised into three intervention groups (TH1, n = 13; TH2, n = 15; or TH3, n = 12, performing 1, 2 and 3 weekly 60-min training sessions, respectively), and a control group (CG, n = 14). The training sessions consisted mainly of RTH matches played as small-sided and formal game formats (4v4, 5v5, 6v6 or 7v7) with adapted rules. Matches' mean and peak heart rate (HR) ranged from 78-80% and 86-89%HRmax, respectively, and distance covered from 4676 to 5202 m. A time x group interaction was observed for procollagen type-1 amino-terminal propeptide (P1NP), osteocalcin (OC), carboxy-terminal type-1 collagen crosslinks (CTX), sclerostin, upper and lower body dynamic strength, right arm fat mass, left and right arm, right leg and android total mass (TM; p ≤ 0.047) with the greatest effects being shown for TH2 and TH3 groups. Post-intervention group differences were observed in CTX, left arm and right leg TM (TH3 > TH1), P1NP (TH2 > CG), OC, right arm TM (TH3 > CG), upper (CG < TH1, TH2 and TH3) and lower body dynamic strength (CG < TH1 and TH3) (p ≤ 0.047). RTH was effective in enhancing bone health, body composition and physical fitness in middle-to-older-aged males, especially for the intervention groups that performed 2-3 weekly training sessions.ClinicalTrials.gov ID: NCT05295511.Trial registration: ClinicalTrials.gov identifier: NCT05295511.HighlightsAfter 16 weeks of recreational team handball small-sided and formal matches, inactive middle-to-older-aged males improved bone health, body composition and physical fitness, by performing 1, 2 or 3 60-min weekly sessions, however, greater improvements were shown in the groups that performed 2 or 3 weekly training sessions.Training intensity was similar across the intervention groups that performed recreational team handball for 1, 2 or 3 60-min weekly sessions, which means that training volume is most likely to be the reason for the different health effects shown.The very high fun levels reported by all intervention groups shows that recreational team handball is a social and fun exercise modality for middle-to-older-aged males, with potential to intrinsically motivate the participants and assure long-term adherence to exercise.

Study protocol of the InterVitaminK trial: a Danish population-based randomised double-blinded placebo-controlled trial of the effects of vitamin K (menaquinone-7) supplementation on cardiovascular, metabolic and bone health.

INTRODUCTION: Vitamin K has been suggested to have protective effects against progression of vascular calcification and development of cardiovascular disease (CVD). However, few well-powered randomised controlled trials have examined whether vitamin K prevents progression of vascular calcification in individuals from the general population. The aim of the InterVitaminK trial is to investigate the effects of vitamin K supplementation (menaquinone-7, MK-7) on cardiovascular, metabolic, respiratory and bone health in a general ageing population with detectable vascular calcification. METHODS AND ANALYSIS: The InterVitaminK trial is a randomised, double-blinded, placebo-controlled, trial. A total of 450 men and women aged 52-82 years with detectable coronary artery calcification (CAC), but without manifest CVD, will be randomised (1:1) to receive daily MK-7 (333 µg/day) or placebo tablets for 3 years. Health examinations are scheduled at baseline, and after 1, 2 and 3 years of intervention. Health examinations include cardiac CT scans, measurements of arterial stiffness, blood pressure, lung function, physical function, muscle strength, anthropometric measures, questionnaires on general health and dietary intake, and blood and urine sampling. The primary outcome is progression of CAC from baseline to 3-year follow-up. The trial has 89% power to detect a between-group difference of at least 15%. Secondary outcomes are bone mineral density, pulmonary function and biomarkers of insulin resistance. ETHICS AND DISSEMINATION: Oral MK-7 supplementation is considered safe and has not been found to cause severe adverse events. The Ethical Committee of the Capital Region (H-21033114) approved the protocol. Written informed consent is obtained from all participants and the trial is conducted in accordance with the Declaration of Helsinki II. Both negative and positive findings will be reported. TRIAL REGISTRATION NUMBER: NCT05259046.

Multicomponent recreational team handball training improves global health status in postmenopausal women at the long term - A randomised controlled trial.

We studied the long-term effects of a multicomponent exercise training protocol (recreational team handball training, RTH) on global health status in inactive postmenopausal women. Participants (n = 45; age 65 ± 6 years, stature 157 ± 6 cm, body mass 66.2 ± 9.4 kg, fat mass 41.4 ± 5.5%, VO2peak 25.7 ± 3.6 mL/min/kg) were randomised into a control group (CG; n = 14) and a multicomponent exercise training group (EXG; n = 31, performing two to three weekly 60-min RTH sessions). Attendance was 2.0 ± 0.4 sessions/week (first 16 weeks) and 1.4 ± 0.5 (following 20 weeks) and mean heart rate (HR) loading was 77 and 79% of maximal HR (p = .002) for the first 16 and the following 20 weeks, respectively. Cardiovascular, bone, metabolic health, body composition and physical fitness markers were evaluated at baseline, and after 16 and 36 weeks. An interaction (p ≤ .046) was shown for the 2-h oral glucose tolerance test, HDL, Yo-Yo intermittent endurance level 1 test (YYIE1) and knee strength, in favour of EXG. At 36 weeks, YYIE1 and knee strength were higher (p ≤ .038) for EXG vs CG. Also, within-group improvements (p ≤ .043) were observed after 36 weeks for EXG in VO2peak, lumbar spine bone mineral density, lumbar spine bone mineral content, P1NP, osteocalcin, total cholesterol, HDL, LDL, body mass, android fat mass, YYIE1, knee strength, handgrip strength and postural balance. At 36 comparatively to 16 weeks, EXG showed an increase (p ≤ .036) in fasting blood glucose, HDL, knee strength and handgrip strength, and a decrease (p ≤ .025) in LDL. Collectively, this multicomponent exercise training (RTH) induces beneficial changes in global health status in postmenopausal women.HighlightsWe evaluated the long-term effects of a recreational team handball-based multicomponent training on broad-spectrum health and physical fitness markers of inactive postmenopausal women.Improvements in VO2peak and aerobic performance achieved after 16 weeks of training were maintained at 36 weeks.The 20-week extension of the training intervention resulted in further improvements in lipid profile markers and physical fitness variables.Recreational team handball could be suggested as an effective and safe strategy to counteract postmenopausal health-related constrains.

Automated Interlaboratory Comparison of Therapeutic Drug Monitoring Data and Its Use for Evaluation of Published Therapeutic Reference Ranges.

Therapeutic drug monitoring is a tool for optimising the pharmacological treatment of diseases where the therapeutic effect is difficult to measure or monitor. Therapeutic reference ranges and dose-effect relation are the main requirements for this drug titration tool. Defining and updating therapeutic reference ranges are difficult, and there is no standardised method for the calculation and clinical qualification of these. The study presents a basic model for validating and selecting routine laboratory data. The programmed algorithm was applied on data sets of antidepressants and antipsychotics from three public hospitals in Denmark. Therapeutic analytical ranges were compared with the published therapeutic reference ranges by the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP) and in additional literature. For most of the drugs, the calculated therapeutic analytical ranges showed good concordance between the laboratories and to published therapeutic reference ranges. The exceptions were flupentixol, haloperidol, paroxetine, perphenazine, and venlafaxine + o-desmethyl-venlafaxine (total plasma concentration), where the range was considerably higher for the laboratory data, while the calculated range of desipramine, sertraline, ziprasidone, and zuclopenthixol was considerably lower. In most cases, we identified additional literature supporting our data, highlighting the need of a critical re-examination of current therapeutic reference ranges in Denmark. An automated approach can aid in the evaluation of current and future therapeutic reference ranges by providing additional information based on big data from multiple laboratories.

Changes in RANKL and TRAcP 5b after discontinuation of denosumab suggest RANKL mediated formation of osteoclasts results in the increased bone resorption.

In patients discontinuing long-term denosumab, RANKL levels are high 6 months after the last denosumab injection. Nine and 12 months after the last denosumab injection RANKL levels are lower, but TRAcP 5b levels are higher, suggesting that accumulated RANKL increases the number of active osteoclasts. PURPOSE: The rapid increase in bone turnover occurring when discontinuing long-term treatment with denosumab (DMAB), an antibody that neutralizes receptor activator of nuclear factor kappa-B ligand (RANKL) is not fully understood. We aimed to investigate the mechanisms underlying the rebound activation of bone resorption by measuring tartrate-resistant acid phosphatase 5b (TRAcP 5b), RANKL, osteoprotegerin (OPG), C-terminal collagen crosslinks (CTX), and procollagen type I N-propeptide (P1NP) in patients discontinuing long-term DMAB. METHODS: Sixty-one patients with BMD T-score > - 2.5 at the spine and hip discontinuing long-term DMAB were randomized to treatment with zoledronate (ZOL) 6 months (6 M group, n = 20), 9 months (9 M group, n = 20) or 12 months after the last DMAB injection or when bone turnover was high (12 M group, n = 21). Bone turnover markers were measured immediately before initiation of ZOL treatment. RESULTS: We found higher CTX and PINP in the 9 M and 12 M groups compared to the 6 M group (p < 0.001). In the 6 M group, TRAcP 5b was lower and RANKL higher than in the other two groups (p < 0.001). TRAcP 5b correlated negatively with RANKL (R = - 0.54), and time since the last DMAB injection correlated positively with CTX (R = 0.56), PINP (R = 0.72), TRAcP 5b (R = 0.51) and negatively with RANKL (R = - 0.70) (p < 0.001 for all). We found no difference in OPG between groups. CONCLUSION: Following discontinuation of long-term DMAB, we find high levels of RANKL, which most likely result in an increase in the number of active osteoclasts (illustrated by TRAcP5b) causing an increased bone turnover.

Repeated measures of hypocretin-1 in Danish and Italian patients with narcolepsy and in controls.

STUDY OBJECTIVES: The assay currently used worldwide to measure cerebrospinal fluid hypocretin-1 (CSF-hcrt-1) for diagnosing narcolepsy uses a competitive radioimmunoassay with polyclonal anti-hcrt-1 antibodies. This assay detects multiple hypocretin-1 immunoreactive species in the CSF that are all derived from full-length hcrt-1. We aimed to revalidate CSF-hcrt-1 cut-offs for narcolepsy type 1 (NT1) diagnosis and to evaluate temporal changes in CSF-hcrt-1 levels in patients suspected of having central hypersomnia. METHOD: We carried out a repeat lumbar puncture with a mean follow-up of 4.0 years, to measure CSF-hcrt-1 in patients suspected of having central hypersomnia in a follow-up study. Data from CSF samples of patients with NT1 and of controls without known hypersomnia, from the Italian-Stanford and Danish populations, were examined using a receiver-operating characteristic analysis. RESULTS: The optimal CSF-hcrt-1 cut-offs for identifying NT1 were 129 pg/ml and 179 pg/ml for the Italian-Stanford and Danish populations, respectively. The sensitivity was 0.93-0.99 and the specificity was 1. Follow-up lumbar puncture measurements of CSF-hcrt-1 were obtained from 73 patients. 30 of 32 patients with low CSF-hcrt-1 levels continued to be categorized as low, with an unaltered diagnosis; two patients showed a marked increase in CSF-hcrt-1, attaining normal values at follow-up. One of these patients relapsed to low CSF-hcrt-1 after follow-up. All 41 patients with normal CSF-hcrt-1 at baseline had normal CSF-hcrt-1 at follow-up. CONCLUSION: CSF-hcrt-1 measurement can provide an accurate test for diagnosing NT1, although it is important to validate the CSF-hcrt-1 cut-off for specific testing locations. Stable CSF-hcrt-1 levels support the already established prognosis of narcolepsy as permanent once the disorder has fully developed.