Characterization of Immune Cell Populations of Cutaneous Neurofibromas in Neurofibromatosis 1.

Cutaneous neurofibromas (cNFs) are characteristic of neurofibromatosis 1 (NF1), yet their immune microenvironment is incompletely known. A total of 61 cNFs from 10 patients with NF1 were immunolabeled for different types of T cells and macrophages, and the cell densities were correlated with clinical characteristics. Eight cNFs and their overlying skin were analyzed for T cell receptor CDR domain sequences, and mass spectrometry of 15 cNFs and the overlying skin was performed to study immune-related processes. Intratumoral T cells were detected in all cNFs. Tumors from individuals younger than the median age of the study participants (33 years), growing tumors, and tumors smaller than the data set median showed increased T cell density. Most samples displayed intratumoral or peritumoral aggregations of CD3-positive cells. T cell receptor sequencing demonstrated that the skin and cNFs host distinct T cell populations, whereas no dominant cNF-specific T cell clones were detected. Unique T cell clones were fewer in cNFs than in skin, and mass spectrometry suggested lower expression of proteins related to T cell-mediated immunity in cNFs than in skin. CD163-positive cells, suggestive of M2 macrophages, were abundant in cNFs. Human cNFs have substantial T cell and macrophage populations that may be tumor-specific.

Myocardial T1 mapping by cardiac magnetic resonance imaging shows early myocardial changes in treatment-naive patients with active rheumatoid arthritis and positive autoantibodies.

OBJECTIVES: We aimed to study whether myocardial changes are already detectable by cardiac magnetic resonance (CMR) imaging at the time of rheumatoid arthritis (RA) diagnosis. METHODS: This single-centre prospective study included 39 treatment-naive patients with early rheumatoid arthritis (ERA, symptom duration <1 year) without any history of heart disease, and 38 age- and sex-matched healthy volunteers. The disease severity was assessed with clinical evaluation (Disease Activity Score-28 for Rheumatoid Arthritis with CRP (DAS28-CRP) score) and serological testing (rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPA)). The ERA patients were classified into group A (DAS28-CRP score ≥3.2, positive RF and ACPA; n=17) and group B (not fulfilling the group A criteria). The ERA patients and healthy controls underwent 1.5T CMR. RESULTS: Group A patients had significantly higher myocardial global T1 relaxation times than the healthy controls, 987 [965, 1003] ms vs. 979 [960, 991] ms (median [IQR]; p=0.041). A significant difference in T1 was found in the basal, mid inferior and mid anterolateral segments. In a multivariate analysis, prolonged global T1 relaxation time was independently associated with female sex (95% CI [5.62, 51.31] ms, p=0.016), and group A status (95% CI [4.65, 39.01] ms p=0.014). CONCLUSIONS: At the time of diagnosis, ERA patients with a higher disease activity (DAS28-CRP score ≥3.2) and both positive RF and ACPA showed prolonged T1 relaxation times in basal myocardial segments. These segments could be most susceptible to the development of myocardial fibrosis, and a segmental reporting style could be useful when estimating the first signs of myocardial fibrosis.

Three-dimensional magnetic resonance cholangiography is superior to two-dimensional single-shot magnetic resonance cholangiography for visualization and image quality of the feline and canine biliary tract: A postmortem study.

Magnetic resonance cholangiography (MRC) is an established diagnostic tool for noninvasive assessment of the biliary tract in humans. It has also been found to be feasible in companion animals, but no published studies have compared MRC sequences in veterinary medicine. The present study is part of a prospective, observational, analytical investigation on MR cholangiopancreatography performed on the donated bodies of 12 cats and eight dogs. The main aim of this study was to compare the images of 2D-SSh-TSE-MRC and 3D-TSE-MRC sequences for visualization and image quality of the feline and canine biliary tract. Both sequences are T2-weighted and noncontrast. Three independent readers scored the visibility of four segments of the biliary tract, namely the gallbladder (GB), cystic duct, common bile duct (CBD), and extrahepatic ducts, and the image quality of the two MRC sequences using five-point Likert scales. Wilcoxon signed-rank test was used to compare the scores between the MRC sequences separately for cats and dogs. Inter- and intraobserver agreements were measured using Gwet's AC2 with linear weighting. The 3D-TSE-MRC images were scored significantly higher than the 2D-SSh-TSE-MRC for both visibility and image quality (P < .001-.016 for cats, P = .008-.031 for dogs); the only exception was GB in dogs. In both cats and dogs, interobserver agreement for segment visibility and image quality ranged from slight to substantial in 2D-SSh-TSE-MRC and from poor to almost perfect in 3D-TSE-MRC. Most of the assessments (73% for segment visibility and 66% for image quality) had substantial to almost perfect intraobserver agreement. Findings from the current study support the use of 3D-TSE-MRC over 2D-SSh-TSE-MRC for evaluation of the feline and canine biliary tract, but further studies on live animals are warranted.

Hemoglobin mass and performance responses during 4 weeks of normobaric "live high-train low and high".

PURPOSE: To investigate whether 4 weeks of normobaric "live high-train low and high" (LHTLH) causes different hematological, cardiorespiratory, and sea-level performance changes compared to living and training in normoxia during a preparation season. METHODS: Nineteen (13 women, 6 men) cross-country skiers competing at the national or international level completed a 28-day period (∼18 h day-1 ) of LHTLH in normobaric hypoxia of ∼2400 m (LHTLH group) including two 1 h low-intensity training sessions per week in normobaric hypoxia of 2500 m while continuing their normal training program in normoxia. Hemoglobin mass (Hbmass ) was assessed using a carbon monoxide rebreathing method. Time to exhaustion (TTE) and maximal oxygen uptake (VO2max ) were measured using an incremental treadmill test. Measurements were completed at baseline and within 3 days after LHTLH. The control group skiers (CON) (seven women, eight men) performed the same tests while living and training in normoxia with ∼4 weeks between the tests. RESULTS: Hbmass in LHTLH increased 4.2 ± 1.7% from 772 ± 213 g (11.7 ± 1.4 g kg-1 ) to 805 ± 226 g (12.5 ± 1.6 g kg-1 ) (p < 0.001) while it was unchanged in CON (p = 0.21). TTE improved during the study regardless of the group (3.3 ± 3.4% in LHTLH; 4.3 ± 4.8% in CON, p < 0.001). VO2max did not increase in LHTLH (61.2 ± 8.7 mL kg-1 min-1 vs. 62.1 ± 7.6 mL kg-1 min-1 , p = 0.36) while a significant increase was detected in CON (61.3 ± 8.0-64.0 ± 8.1 mL kg-1 min-1 , p < 0.001). CONCLUSIONS: Four-week normobaric LHTLH was beneficial for increasing Hbmass but did not support the short-term development of maximal endurance performance and VO2max when compared to the athletes who lived and trained in normoxia.

Cardiac output and arteriovenous oxygen difference contribute to lower peak oxygen uptake in patients with fibromyalgia.

BACKGROUND: Patients with fibromyalgia (FM) exhibit low peak oxygen uptake ([Formula: see text]O2peak). We aimed to detect the contribution of cardiac output to ([Formula: see text]) and arteriovenous oxygen difference [Formula: see text] to [Formula: see text] from rest to peak exercise in patients with FM. METHODS: Thirty-five women with FM, aged 23 to 65 years, and 23 healthy controls performed a step incremental cycle ergometer test until volitional fatigue. Alveolar gas exchange and pulmonary ventilation were measured breath-by-breath and adjusted for fat-free body mass (FFM) where appropriate. [Formula: see text] (impedance cardiography) was monitored. [Formula: see text] was calculated using Fick's equation. Linear regression slopes for oxygen cost (∆[Formula: see text]O2/∆work rate) and [Formula: see text] to [Formula: see text]O2 (∆[Formula: see text]/∆[Formula: see text]O2) were calculated. Normally distributed data were reported as mean ± SD and non-normal data as median [interquartile range]. RESULTS: [Formula: see text]O2peak was lower in FM patients than in controls (22.2 ± 5.1 vs. 31.1 ± 7.9 mL∙min-1∙kg-1, P < 0.001; 35.7 ± 7.1 vs. 44.0 ± 8.6 mL∙min-1∙kg FFM-1, P < 0.001). [Formula: see text] and C(a-v)O2 were similar between groups at submaximal work rates, but peak [Formula: see text] (14.17 [13.34-16.03] vs. 16.06 [15.24-16.99] L∙min-1, P = 0.005) and C(a-v)O2 (11.6 ± 2.7 vs. 13.3 ± 3.1 mL O2∙100 mL blood-1, P = 0.031) were lower in the FM group. No significant group differences emerged in ∆[Formula: see text]O2/∆work rate (11.1 vs. 10.8 mL∙min-1∙W-1, P = 0.248) or ∆[Formula: see text]/∆[Formula: see text]O2 (6.58 vs. 5.75, P = 0.122) slopes. CONCLUSIONS: Both [Formula: see text] and C(a-v)O2 contribute to lower [Formula: see text]O2peak in FM. The exercise responses were normal and not suggestive of a muscle metabolism pathology. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03300635. Registered 3 October 2017-Retrospectively registered. https://clinicaltrials.gov/ct2/show/NCT03300635 .

Cholangiopancreatography in cats: a post-mortem comparison of MRI with fluoroscopy, corrosion casting and histopathology.

In human medicine, magnetic resonance cholangiopancreatography (MRCP) is a valuable diagnostic tool for hepatobiliary and pancreatic diseases. In veterinary medicine, however, data evaluating the diagnostic value of MRCP are limited. The primary objectives of this prospective, observational, analytical investigation were to assess whether MRCP reliably visualizes the biliary tract and pancreatic ducts in cats without and with related disorders, and whether MRCP images and measurements of the ducts agree with those of fluoroscopic retrograde cholangiopancreatography (FRCP), corrosion casting and histopathology. A secondary objective was to provide MRCP reference diameters for bile ducts, GB, and pancreatic ducts. Donated bodies of 12 euthanized adult cats underwent MRCP, FRCP, and autopsy with corrosion casting of the biliary tract and pancreatic ducts using vinyl polysiloxane. Diameters of the biliary ducts, gallbladder (GB), and pancreatic ducts were measured using MRCP, FRCP, corrosion casts and histopathologic slides. There was an agreement between MRCP and FRCP in measuring diameters of the GB body, GB neck, cystic duct, and common bile duct (CBD) at papilla. Strong positive correlations existed between MRCP and corrosion casting for measuring GB body and neck, cystic duct, and CBD at the extrahepatic ducts' junction. In contrast to the reference methods, post-mortem MRCP did not visualize right and left extrahepatic ducts, and pancreatic ducts in most cats. Based on this study, MRCP with 1.5 Tesla can be regarded as a contributory method to improve the assessment of feline biliary tract and pancreatic ducts when their diameter is >1 mm.

The rare disease neurofibromatosis 1 as a source of hereditary economic inequality: Evidence from Finland.

PURPOSE: This study investigated whether individuals with neurofibromatosis 1 (NF1) fare worse than individuals without NF1 in terms of economic well-being. NF1 is relatively common in the population and provides an informative case of a rare hereditary disease. METHODS: We examined a subset of 692 individuals with verified NF1 from the Finnish total population-based NF1 cohort and compared that with 7407 control individuals matched for age, sex, and municipality during 1997-2014. Economic well-being was operationalized with annual work earnings and total income, including social income transfers. RESULTS: NF1 significantly worsened economic well-being. Low education, increased morbidity, and reduced labor market participation partly explained the effect of NF1. Yet, NF1 was independently associated with lower income even after adjusting for these factors. Furthermore, NF1 had a larger negative effect on income from work than it had on total income, which indicated that the Finnish social security system partly compensated the labor market losses suffered by individuals with NF1. NF1 had a larger impact on economic inequality for men than for women. CONCLUSION: NF1 contributes to economic inequality. A hereditary disease may convey worse economic well-being over several generations.

Magnetic resonance imaging safety in patients with abandoned or functioning epicardial pacing leads.

OBJECTIVES: The European Society of Cardiology Guidelines on cardiac pacing from 2021 allow magnetic resonance imaging (MRI) in patients with cardiac implantable electronic devices (CIEDs) but do not recommend MRI in patients with epicardial pacing leads. The clinical dilemma remains whether performing an MRI in patients with CIED and epicardial leads is safe. We aimed to evaluate the safety of performing an MRI in patients with CIED and abandoned or functioning epicardial pacing leads. METHODS: We included all adult patients who underwent clinically indicated MRIs with CIED and functioning or abandoned epicardial leads in a single tertiary hospital between November 2011 and October 2019. The data were retrospectively collected. RESULTS: Twenty-six MRIs were performed on 17 patients with functioning or abandoned epicardial pacing leads. Sixty-nine percent of the MRI scans (18/26) were conducted on patients with functioning epicardial pacing leads. A definite adverse event occurred in one MRI scan. This was a transient elevation of the pacing threshold in a patient with a functioning epicardial ventricular pacing lead implanted 29 years previously. An irreversible atrial pacing lead impedance elevation was detected 6 months after the MRI in another patient; the association with the previous MRI remained unclear. No adverse events were detected in MRIs performed on patients with modern (implanted in 2000 or later) functioning epicardial leads. CONCLUSIONS: MRIs in patients with CIED and modern functioning epicardial pacing leads were performed without detectable adverse events. Further large-scale studies are necessary to confirm MRI safety in patients with epicardial pacing leads. KEY POINTS: • Currently, MRI in patients with cardiac implantable electronic devices (CIEDs) and functioning or abandoned epicardial pacing leads is not recommended. • MRIs in patients with CIED and modern functioning epicardial leads (implanted in 2000 or later) were performed without detectable adverse events in our patient cohort. • Allowing MRI in patients with epicardial pacing leads may significantly improve the diagnostic work-up, especially in specific patient groups, such as patients with congenital heart disease.

Mast Cells in Human Cutaneous Neurofibromas: Density, Subtypes, and Association with Clinical Features in Neurofibromatosis 1.

BACKGROUND: Cutaneous neurofibromas (cNFs) are hallmarks of neurofibromatosis 1 (NF1) and cause the main disease burden in adults with NF1. Mast cells are a known component of cNFs. However, no comprehensive characterization of mast cells in cNFs is available, and their contributions to cNF growth and symptoms such as itch are not known. METHODS: We collected 60 cNFs from ten individuals with NF1, studied their mast cell proteinase content, and compared the mast cell numbers to selected clinical features of the tumors and patients. The tumors were immunolabeled for the mast cell markers CD117, tryptase, and chymase, and the percentage of immunopositive cells was determined using computer-assisted methods. RESULTS: The median proportions of positive cells were 5.5% (range 0.1-14.4) for CD117, 4.0% (1.2-7.0) for tryptase, and 5.0% (1.1-15.9) for chymase. The median densities of cells immunopositive for CD117, tryptase, and chymase were 280, 243, and 250 cells/mm2, respectively. Small tumors, growing tumors, and tumors from patients below the median age of 33 years displayed a high proportion of mast cells. Cells expressing both tryptase and chymase were the predominant mast cell type in cNFs, followed by cells expressing chymase only. CONCLUSION: The results highlight the abundance of mast cells in cNFs and that their number and subtypes clearly differ from those previously reported in unaffected skin.

Haploinsufficiency of the NF1 gene is associated with protection against diabetes.

BACKGROUND: The hereditary predisposition to diabetes is only partially explained by genes identified so far. Neurofibromatosis type 1 (NF1) is a rare monogenic dominant syndrome caused by aberrations of the NF1 gene. Here, we used a cohort of 1410 patients with NF1 to study the association of the NF1 gene with type 1 (T1D) and type 2 diabetes (T2D). METHODS: A total of 1410 patients were confirmed to fulfil the National Institutes of Health diagnostic criteria for NF1 by individually reviewing their medical records. The patients with NF1 were compared with 14 017 controls matched for age, sex and area of residence as well as 1881 non-NF1 siblings of the patients with NF1. Register-based information on purchases of antidiabetic medication and hospital encounters related to diabetes were retrieved. The Cox proportional hazards model was used to calculate the relative risk for diabetes in NF1. RESULTS: Patients with NF1 showed a lower rate of T2D when compared with a 10-fold control cohort (HR 0.27, 95% CI 0.17 to 0.43) or with their siblings without NF1 (HR 0.28, 95% CI 0.16 to 0.47). The estimates remained practically unchanged after adjusting the analyses for history of obesity and dyslipidaemias. The rate of T1D in NF1 was decreased although statistically non-significantly (HR 0.58, 95% CI 0.27 to 1.25). CONCLUSION: Haploinsufficiency of the NF1 gene may protect against T2D and probably T1D. Since NF1 negatively regulates the Ras signalling pathway, the results suggest that the Ras pathway may be involved in the pathogenesis of diabetes.

Characterizing geometric distortions of 3D sequences in clinical head MRI.

OBJECTIVE: Phantoms are often used to estimate the geometric accuracy in magnetic resonance imaging (MRI). However, the distortions may differ between anatomical and phantom images. This study aimed to investigate the applicability of a phantom-based and a test-subject-based method in evaluating geometric distortion present in clinical head-imaging sequences. MATERIALS AND METHODS: We imaged a 3D-printed phantom and test subjects with two MRI scanners using two clinical head-imaging 3D sequences with varying patient-table positions and receiver bandwidths. The geometric distortions were evaluated through nonrigid registrations: the displaced acquisitions were compared against the ideal isocenter positioning, and the varied bandwidth volumes against the volume with the highest bandwidth. The phantom acquisitions were also registered to a computed tomography scan. RESULTS: Geometric distortion magnitudes increased with larger table displacements and were in good agreement between the phantom and test-subject acquisitions. The effect of increased distortions with decreasing receiver bandwidth was more prominent for test-subject acquisitions. CONCLUSION: Presented results emphasize the sensitivity of the geometric accuracy to positioning and imaging parameters. Phantom limitations may become an issue with some sequence types, encouraging the use of anatomical images for evaluating the geometric accuracy.

Institutional transition from invasive to non-invasive imaging in children with univentricular heart defects: safety and cost savings.

OBJECTIVES: Patients with univentricular heart defects require lifelong imaging surveillance. Recent advances in non-invasive imaging have enabled replacing these patients' routine catheterisation. Our objective was to describe the safety and cost savings of transition of a tertiary care children's hospital from routine invasive to routine non-invasive imaging of low-risk patients with univentricular heart defects. METHODS: This single-centre cohort study consists of 1) a retrospective analysis of the transition from cardiac catheterisation (n = 21) to CT angiography (n = 20) before bidirectional Glenn operation and 2) a prospective study (n = 89) describing cardiac magnetic resonance before and after the total cavopulmonary connection in low-risk patients with univentricular heart defects. RESULTS: Pre-Glenn: The total length of CT angiography was markedly shorter compared to the catheterisation: 30 min (range: 20-60) and 125 min (range: 70-220), respectively (p < 0.001). Catheterisation used more iodine contrast agents than CT angiography, 19 ± 3.9 ml, and 10 ± 2.4 ml, respectively (p < 0.001). Controlled ventilation was used for all catheterised and 3 (15%) CT angiography patients (p < 0.001). No complications occurred during CT angiography, while they emerged in 19% (4/21) catheterisation cases (p < 0.001). CT angiography and catheterisation showed no significant difference in the radiation exposure. Pre-/post-total cavopulmonary connection: All cardiac magnetic resonance studies were successful, and no complications occurred. In 60% of the cardiac magnetic resonance (53/89), no sedation was performed, and peripheral venous pressure was measured in all cases. Cost analysis suggests that moving to non-invasive imaging yielded cost savings of at least €2500-4000 per patient. CONCLUSION: Transition from routine invasive to routine non-invasive pre-and post-operative imaging is safely achievable with cost savings.

Increased risk for dementia in neurofibromatosis type 1.

PURPOSE: To determine the risk for dementia in neurofibromatosis type 1 (NF1) using a Finnish nationwide cohort of individuals with NF1, and data from national registries. METHODS: A Finnish cohort of 1,349 individuals with confirmed NF1 according to the US National Institutes of Health (NIH) diagnostic criteria was compared with a control cohort of 13,870 individuals matched for age, sex, and area of residence. Dementia-related hospital visits were retrieved from the Finnish Care Register for Health Care using International Classification of Diseases, 10th revision (ICD-10) diagnosis codes G30 and F00-F03. Purchases of antidementia drugs were queried with Anatomical Therapeutic Chemical (ATC) classification code N06D from the drug reimbursement register maintained by the Social Insurance Institution of Finland. The follow-up spanned 1998-2014. RESULTS: Totals of 16 and 165 individuals with at least two dementia-related diagnoses or drug purchases were identified in the NF1 and control cohorts, respectively. The hazard ratio for dementia in NF1 was 1.67 (95% confidence interval [CI] 1.00-2.80, P = 0.050). In an analysis stratified by the type of dementia, the risk for Alzheimer disease was increased in NF1 compared to controls with a hazard ratio of 2.88 (95% CI 1.47-5.66, P = 0.002). CONCLUSION: Dementia and especially Alzheimer disease are previously unrecognized neurological complications of NF1.

p53-Regulated Long Noncoding RNA PRECSIT Promotes Progression of Cutaneous Squamous Cell Carcinoma via STAT3 Signaling.

Long noncoding RNAs (lncRNAs) have emerged as putative biomarkers and therapeutic targets in cancer. The role of lncRNA LINC00346 in cutaneous squamous carcinoma (cSCC) was examined. The expression of LINC00346 was up-regulated in cSCC cells compared with normal human epidermal keratinocytes. Elevated expression of LINC00346 was noted in tumor cells in cSCC tissue sections in vivo, as compared with cSCC in situ, and actinic keratosis by RNA in situ hybridization; and the expression in seborrheic keratosis and normal skin was very low. Immunohistochemical analysis of cSCC tissue sections and functional assays of cSCC cells in culture showed that LINC00346 expression is down-regulated by p53. Knockdown of LINC00346 inhibited invasion of cSCC cells in culture and suppressed growth of human cSCC xenografts in vivo. Knockdown of LINC00346 inhibited expression of activated STAT3 and resulted in down-regulation of the expression of matrix metalloproteinase (MMP)-1, MMP-3, MMP-10, and MMP-13. Based on these observations LINC00346 was named p53 regulated carcinoma-associated STAT3-activating long intergenic non-protein coding transcript (PRECSIT). These results identify PRECSIT as a new p53-regulated lncRNA, which promotes progression of cSCC via STAT3 signaling.

A rare disease and education: Neurofibromatosis type 1 decreases educational attainment.

Rare heritable syndromes may affect educational attainment. Here, we study education in neurofibromatosis 1 (NF1) that is associated with multifaceted medical, social and cognitive consequences. Educational attainment in the Finnish population-based cohort of 1408 individuals with verified NF1 was compared with matched controls using Cox proportional hazards model with delayed entry and competing risk for death. Moreover, models accounting for the effects of cancer at age 15-30 years, parental NF1 and developmental disorders were constructed. Overall, the attainment of secondary education was reduced in individuals with NF1 compared to controls (hazard ratio 0.83, 95%CI 0.74-0.92). History of cancer and developmental disorders were major predictors of lack of secondary education. Individuals with NF1 obtained vocational secondary education more often than general upper secondary education. Consequently, NF1 decreased the attainment of Bachelor's and Master's degrees by 46%-49% and 64%-74%, respectively. Surprisingly, the non-NF1 siblings of individuals with NF1 also had lower educational attainment than controls, irrespective of parental NF1. In conclusion, NF1 is associated with reduced educational attainment and tendency for affected individuals to obtain vocational instead of academic education. Individuals living with NF1, especially those with cancer, developmental disorders or familial NF1, need effective student counseling and learning assistance.

Circulating free DNA in the plasma of individuals with neurofibromatosis type 1.

Neurofibromatosis type 1 (NF1) is an autosomal dominant syndrome whose characteristic manifestations include benign neurofibromas, yet NF1 is also associated with a high risk of cancer. Measurements of circulating free plasma DNA (cfDNA) are gaining wider applicability in cancer diagnostics, targeting of therapy, and monitoring of therapeutic response. Individuals with NF1 are likely to be followed up using this method, but the effects of NF1 and neurofibromas on cfDNA levels are not known. We studied peripheral blood samples from 19 adults with NF1 and 12 healthy controls. The cfDNA was isolated from plasma with QIAamp Circulating Nucleic Acid Kit and quantified using the Qubit 2.0 Fluorometer. The cfDNA concentration of each sample was normalized relative to the plasma protein concentration. The normalized median concentration of cfDNA in plasma was 19.3 ng/ml (range 6.6-78.6) among individuals with NF1 and 15.9 ng/ml (range 4.8-47.0) among controls (p = .369). Individuals with NF1 who also had plexiform neurofibroma (pNF) showed non-significantly elevated cfDNA concentration compared to individuals with NF1 and without known pNF (median 25.4 vs. 18.8 ng/ml, p = .122). The effect of NF1 on cfDNA seems to be relatively small and NF1 is therefore unlikely to hamper the use of cfDNA-based assays.

Peak flow measurements in patients with severe aortic stenosis: a prospective comparative study between cardiovascular magnetic resonance 2D and 4D flow and transthoracic echocardiography.

BACKGROUND: Aortic valve stenosis (AS) is the most prevalent valvular disease in the developed countries. Four-dimensional (4D) flow cardiovascular magnetic resonance (CMR) is an emerging imaging technique, which has been suggested to improve the evaluation of AS severity compared to two-dimensional (2D) flow and transthoracic echocardiography (TTE). We investigated the reliability of CMR 2D flow and 4D flow techniques in measuring aortic transvalvular peak systolic flow in patients with severe AS. METHODS: We prospectively recruited 90 patients referred for aortic valve replacement due to severe AS (73.3 ± 11.3 years, aortic valve area 0.7 ± 0.1 cm2, and 54/36 tricuspid/bicuspid), and 10 non-valvular disease controls. All the patients underwent echocardiography and 2D flow and 4D flow CMR. Peak flow velocity measurements were compared using Wilcoxon signed rank sum test and Bland-Altman analysis. RESULTS: 4D flow underestimated peak flow velocity in the AS group when compared with TTE (bias - 1.1 m/s, limits of agreement ± 1.4 m/s) and 2D flow (bias - 1.2 m/s, limits of agreement ± 1.6 m/s). The differences between values obtained by TTE (median 4.3 m/s, range 2.7-6.1 m/s) and 2D flow (median 4.5 m/s, range 2.9-6.5 m/s) compared to 4D flow (median 3.1 m/s, range 1.7-5.1 m/s) were significant (p < 0.001). The difference between 2D flow and TTE were insignificant (bias 0.07 m/s, limits of agreement ± 1.5 m/s). In non-valvular disease controls, peak flow velocity was measured higher by 4D flow than 2D flow (1.4 m/s, 1.1-1.7 m/s and 1.3 m/s, 1.1-1.5 m/s, respectively; bias 0.2 m/s, limits of agreement ± 0.16 m/s). CONCLUSIONS: CMR 4D flow significantly underestimates systolic peak flow velocity in patients with severe AS. 2D flow, in turn, estimated the AS velocity accurately, with measured peak flow velocities comparable to TTE.

Signaling pathways in human osteoclasts differentiation: ERK1/2 as a key player.

Little is known about the signaling pathways involved in the differentiation of human osteoclasts. The present study evaluated the roles of the Ras/PI3K/Akt/mTOR, Ras/Raf/MEK1/2/ERK1/2, calcium-PKC, and p38 signaling pathways in human osteoclast differentiation. Mononuclear cells were isolated from the peripheral blood of control persons and patients with neurofibromatosis 1 (NF1), and the cells were differentiated into osteoclasts in the presence of signaling pathway inhibitors. Osteoclast differentiation was assessed using tartrate-resistant acid phosphatase 5B. Inhibition of most signaling pathways with chemical inhibitors decreased the number of human osteoclasts and disrupted F-actin ring formation, while the inhibition of p38 resulted in an increased number of osteoclasts, which is a finding contradictory to previous murine studies. However, the p38 inhibition did not increase the bone resorption capacity of the cells. Ras-inhibitor FTS increased osteoclastogenesis in samples from control persons, but an inhibitory effect was observed in NF1 samples. Inhibition of MEK, PI3K, and mTOR reduced markedly the number of NF1-deficient osteoclasts, but no effect was observed in control samples. Western blot analyses showed that the changes in the phosphorylation of ERK1/2 correlated with the number of osteoclasts. Our results highlight the fact that osteoclastogenesis is regulated by multiple interacting signaling pathways and emphasize that murine and human findings related to osteoclastogenesis are not necessarily equivalent.

Metal artifacts in intraoperative O-arm CBCT scans.

BACKGROUND: Cone-beam computed tomography (CBCT) has become an increasingly important medical imaging modality in orthopedic operating rooms. Metal implants and related image artifacts create challenges for image quality optimization in CBCT. The purpose of this study was to develop a robust and quantitative method for the comprehensive determination of metal artifacts in novel CBCT applications. METHODS: The image quality of an O-arm CBCT device was assessed with an anthropomorphic pelvis phantom in the presence of metal implants. Three different kilovoltage and two different exposure settings were used to scan the phantom both with and without the presence of metal rods. RESULTS: The amount of metal artifact was related to the applied CBCT imaging protocol parameters. The size of the artifact was moderate with all imaging settings. The highest applied kilovoltage and exposure level distinctly increased artifact severity. CONCLUSIONS: The developed method offers a practical and robust way to quantify metal artifacts in CBCT. Changes in imaging parameters may have nonlinear effects on image quality which are not anticipated based on physics.

Variability in hemoglobin mass response to altitude training camps.

The present study investigated whether athletes can be classified as responders or non-responders based on their individual change in total hemoglobin mass (tHb-mass) following altitude training while also identifying the potential factors that may affect responsiveness to altitude exposure. Measurements were completed with 59 elite endurance athletes who participated in national team altitude training camps. Fifteen athletes participated in the altitude training camp at least twice. Total Hb-mass using a CO rebreathing method and other blood markers were measured before and after a total of 82 altitude training camps (1350-2500 m) in 59 athletes. In 46 (56%) altitude training camps, tHb-mass increased. The amount of positive responses increased to 65% when only camps above 2000 m were considered. From the fifteen athletes who participated in altitude training camps at least twice, 27% always had positive tHb-mass responses, 13% only negative responses, and 60% both positive and negative responses. Logistic regression analysis showed that altitude was the most significant factor explaining positive tHb-mass response. Furthermore, male athletes had greater tHb-mass response than female athletes. In endurance athletes, tHb-mass is likely to increase after altitude training given that hypoxic stimulus is appropriate. However, great inter- and intra-individual variability in tHb-mass response does not support classification of an athlete permanently as a responder or non-responder. This variability warrants efforts to control numerous factors affecting an athlete's response to each altitude training camp.