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Abstract Background To compare image quality, metal artifacts, and diagnostic confidence of conventional computed tomography (CT) images of unilateral total hip arthroplasty patients (THA) with deep learning-based metal artifact reduction (DL-MAR) to conventional CT and 130-keV monoenergetic images with and without orthopedic metal artifact reduction (O-MAR). Methods Conventional CT and 130-keV monoenergetic images with and without O-MAR and DL-MAR images of 28 unilateral THA patients were reconstructed. Image quality, metal artifacts, and diagnostic confidence in bone, pelvic organs, and soft tissue adjacent to the prosthesis were jointly scored by two experienced musculoskeletal radiologists. Contrast-to-noise ratios (CNR) between bladder and fat and muscle and fat were measured. Wilcoxon signed-rank tests with Holm-Bonferroni correction were used. Results Significantly higher image quality, higher diagnostic confidence, and less severe metal artifacts were observed on DL-MAR and images with O-MAR compared to images without O-MAR (p

Abstract Background Double inversion recovery (DIR) MRI has the potential to accentuate the synovium without using contrast agents, as it allows simultaneous signal suppression of fluid and fat. The purpose of this study was (1) to compare DIR MRI to conventional contrast-enhanced (CE) MRI for delineation of the synovium in the knee in children with juvenile idiopathic arthritis (JIA) and (2) to assess the agreement between DIR MRI and CE-MRI regarding maximal synovial thickness measurements. Results In this prospective study, 26 children with JIA who consecutively underwent 3.0-T knee MRI between January 2018 and January 2021 were included (presence of knee arthritis: 13 [50%]; median age: 14 years [interquartile range [IQR]: 11–17]; 14 girls). Median confidence to depict the synovium (0–100 mm visual analogue scale; scored by 2 readers [consensus based]) was 88 (IQR: 79–97) for DIR MRI versus 100 (IQR: 100–100) for CE-MRI (p value =

Objectives To develop and validate a protocol for MRI assessment of the distal radial and ulnar periphyseal area in gymnasts and non-gymnasts.Methods Twenty-four gymnasts with wrist pain, 18 asymptomatic gymnasts and 24 non-gymnastic controls (33 girls) underwent MRI of the wrist on a 3T scanner. Sequences included coronal proton density-weighted images with and without fat saturation, and three-dimensional water-selective cartilage scan and T2 Dixon series. Skeletal age was determined using hand radiographs. Three experienced musculoskeletal radiologists established a checklist of possible (peri)physeal abnormalities based on literature and clinical experience. Five other musculoskeletal radiologists and residents evaluated 30 MRI scans (10 from each group) using this checklist and reliability was determined using the intraclass correlation coefficient (ICC) and Fleiss’ kappa. A final evaluation protocol was established containing only items with fair to excellent reliability.Results Twenty-seven items were assessed for reliability. Intra-rater and inter-rater agreement was good to excellent (respective ICCs 0.60–0.91 and 0.60–0.78) for four epiphyseal bone marrow oedema-related items, physeal signal intensity, metaphyseal junction and depth of metaphyseal intrusions. For physeal thickness, thickness compared with proximal physis of first metacarpal, metaphyseal intrusions, physeal connection of intrusions and metaphyseal bone marrow signal intensity, intra-rater agreement was fair to excellent (ICC/kappa 0.55–0.85) and inter-rater agreement was fair (ICC/kappa 0.41–0.59). Twelve items were included in the final protocol.Conclusion The Amsterdam MRI assessment of the Physis protocol facilitates patient-friendly and reliable assessment of the (peri)physeal area in the radius and ulna.

We investigated a possible involvement of the sympathetic nervous system in the parallel increase of renin, cyclooxygenase-2 (COX-2), and neuronal nitric oxide synthase (nNOS) gene expression in the juxtaglomerular apparatus of rat kidneys induced by salt deficiency. Therefore, we determined the effects of renal denervation and the [beta]-adrenoreceptor antagonist metoprolol (50 mg/kg body wt po, twice a day) on renocortical expression of renin, COX-2, and nNOS in rats fed a low-salt (0.02% wt/wt) diet or treated for 1 wk with ramipril (10 mg/kg body wt) in combination with a low-salt diet. We found that a low-salt diet in combination with ramipril strongly increased renocortical mRNA levels of renin, COX-2, and nNOS 9-, 7-, and 2.5-fold, respectively. Treatment with metoprolol did not change basal expression of the three genes or induction of renin and COX-2 gene expression, while induction of nNOS expression was clearly attenuated. Similarly, unilateral renal denervation attenuated induction of nNOS expression but had no effect on all other parameters. These findings suggest that [beta]-adrenergic stimulation is not required for stimulation of renin and COX-2 gene expression in the juxtaglomerular apparatus during salt deficiency. However, [beta]-adrenoreceptor activity or renal nerve activity appears to be required for the full stimulation of nNOS expression by low salt intake or combined with angiotensin-converting enzyme inhibition. cyclooxygenase-2; kidney; renal nerves; neuronal nitric oxide synthase

IntroductionObesity has been linked to vascular dysfunction, cognitive impairment and neurodegenerative diseases. However, experimental models that recapitulate brain pathology in relation to obesity and vascular dysfunction are still lacking.MethodsIn this study we performed the histological and histochemical characterization of brains from Ldlr-/-.Leiden mice, an established model for obesity and associated vascular disease. First, HFD-fed 18 week-old and 50 week-old Ldlr-/-.Leiden male mice were compared with age-matched C57BL/6J mice. We then assessed the effect of high-fat diet (HFD)-induced obesity on brain pathology in Ldlr-/-.Leiden mice and tested whether a treatment with an anti-complement component 5 antibody, a terminal complement pathway inhibitor recently shown to reduce vascular disease, can attenuate neurodegeneration and neuroinflammation. Histological analyses were complemented with Next Generation Sequencing (NGS) analyses of the hippocampus to unravel molecular pathways underlying brain histopathology.ResultsWe show that chow-fed Ldlr-/-.Leiden mice have more severe neurodegeneration and show an age-dependent astrogliosis that is not observed in age-matched C57BL/6J controls. This was substantiated by pathway enrichment analysis using the NGS data which showed that oxidative phosphorylation, EIF2 signaling and mitochondrial dysfunction pathways, all associated with neurodegeneration, were significantly altered in the hippocampus of Ldlr-/-.Leiden mice compared with C57BL/6J controls. Obesity-inducing HFD-feeding did not aggravate neurodegeneration and astrogliosis in Ldlr-/-.Leiden mice. However, brains from HFD-fed Ldlr-/-.Leiden mice showed reduced IBA-1 immunoreactivity and increased CD68 immunoreactivity compared with chow-fed Ldlr-/-.Leiden mice, indicating alteration of microglial immunophenotype by HFD feeding. The systemic administration of an anti-C5 treatment partially restored the HFD effect on microglial immunophenotype. In addition, NGS data of hippocampi from Ldlr-/-.Leiden mice showed that HFD feeding affected multiple molecular pathways relative to chow-fed controls: HFD notably inactivated synaptogenesis and activated neuroinflammation pathways. The anti-C5 treatment restored the HFD-induced effect on molecular pathways to a large extent.ConclusionThis study shows that the Ldlr-/-.Leiden mouse model is suitable to study brain histopathology and associated biological processes in a context of obesity and provides evidence of the potential therapeutic value of anti-complement therapy against obesity-induced neuroinflammation.

Damage and disease of nerves activates the complement system. We demonstrated that activation of the terminal pathway of the complement system leads to the formation of the membrane attack complex (MAC) and delays regeneration in the peripheral nervous system. Animals deficient in the complement component C6 showed improved recovery after neuronal trauma. Thus, inhibitors of the MAC might be of therapeutic use in neurological disease. Here, we describe the development, structure, mode of action, and properties of a novel therapeutic monoclonal antibody, CP010, against C6 that prevents formation of the MAC in vivo. The monoclonal antibody is humanized and specific for C6 and binds to an epitope in the FIM1-2 domain of human and primate C6 with sub-nanomolar affinity. Using biophysical and structural studies, we show that the anti-C6 antibody prevents the interaction between C6 and C5/C5b by blocking the C6 FIM1-2:C5 C345c axis. Systemic administration of the anti-C6 mAb caused complete depletion of free C6 in circulation in transgenic rats expressing human C6 and thereby inhibited MAC formation. The antibody prevented disease in experimental autoimmune myasthenia gravis and ameliorated relapse in chronic relapsing experimental autoimmune encephalomyelitis in human C6 transgenic rats. CP010 is a promising complement C6 inhibitor that prevents MAC formation. Systemic administration of this C6 monoclonal antibody has therapeutic potential in the treatment of neuronal disease.

Abstract We present a new approach to tuning-fork-based atomic force microscopy for utilizing advanced “tip-on-chip” probes with high sensitivity and broad compatibility. Usually, such chip-like probes with a size reaching 2 × 2 mm2 drastically perturb the oscillation of the tuning fork, resulting in poor performance in its intrinsic force sensing. Therefore, restoring initial oscillatory characteristics is necessary for regaining high sensitivity. To this end, we developed a new approach consisting of three basic steps: tuning-fork rebalancing, revamping holder-sensor fixation, and electrode reconfiguration. Mass rebalancing allows the tuning fork to recover the frequency and regain high Q-factor values up to 104 in air and up to 4 × 104 in ultra-high vacuum conditions. The floating-like holder-fixation using soft wires significantly reduces energy dissipation from the mounting elements. Combined with the soft wires, reconfigured electrodes provide electrical access to the chip-like probe without intervening in the force-sensing signal. Finally, our easy-to-implement approach allows converting the atomic force microscopy tip from a passive tool to a dedicated microdevice with extended functionality.

Charcot-Marie-Tooth disease type 1A (CMT1A) is the most prevalent hereditary demyelinating neuropathy. This autosomal, dominantly inherited disease is caused by a duplication on chromosome 17p which includes the peripheral myelin protein 22 (PMP22) gene. There is clinical evidence that the disability in CMT1A is to a large extend due to axonal damage rather than demyelination. Over-expression of PMP22 is recently thought to impede cholesterol trafficking causing a total shutdown of local cholesterol and lipid synthesis in the Schwann cells, thus disturbing their ability to remyelinate. But there is a large variety in disease burden between CMT1A patients with the same genetic defect, indicating the presence of modifying factors that affect disease severity. One of these potential factors is the immune system. Several reports have described patients with co-occurrence of CMT1A with chronic inflammatory demyelinating disease or Guillain-Barré syndrome. We have previously shown in multiple animal models that the innate immune system and specifically the terminal complement system is a driver of inflammatory demyelination. To test the contribution of the terminal complement system to neuroinflammation and disease progression in CMT1A, we inhibited systemic complement C6 in two transgenic mouse models for CMT1A, the C3-PMP22 and C3-PMP22 c-JunP0Cre models. Both models over-express human PMP22, and one (C3-PMP22 c-JunP0Cre) also has a Schwann cell-specific knockout of c-Jun, a crucial regulator of myelination controlling autophagy. We found that systemic inhibition of C6 using antisense oligonucleotides affects the neuroinflammation, Rho GTPase and ERK/MAPK signalling pathways in the CMT1A mouse models. The cholesterol synthesis pathway remained unaffected. Analysis of motor function during treatment with C6 antisense oligonucleotides did not reveal any significant improvement in the CMT1A mouse models. This study shows that the contribution of the terminal complement system to progressive loss of motor function in the CMT1A mouse models tested is limited.

Abstract Background Traumatic brain injury (TBI) is a major cause of death and disability across all ages. After the primary impact, the pathophysiologic process of secondary brain injury consists of a neuroinflammation response that critically leads to irreversible brain damage in the first days after the trauma. A key catalyst in this inflammatory process is the complement system. Inhibiting the complement system could therefore be a therapeutic target in TBI. Objective To study the safety and efficacy of C1-inhibitor (C1-INH) compared to placebo in patients with TBI. By temporarily blocking the complement system, we hypothesize a decrease in the posttraumatic neuroinflammatory response resulting in a less unfavorable clinical outcome for TBI patients. Methods CIAO@TBI is a multicenter, randomized, blinded, phase II placebo-controlled trial. Adult TBI patients with GCS < 13 requiring intracranial pressure (ICP) monitoring will be randomized, using block randomization, within 12 h after trauma to one dose 6000 IU C1-INH or placebo. A total of 106 patients will be included, and follow-up will occur up to 12 months. The primary endpoints are (1) Therapy Intensity Level (TIL) Scale, (2) Glasgow Outcome Scale-Extended (GOSE) at 6 months, and (3) complication rate during hospitalization. Outcomes will be determined by a trial nurse blinded for the treatment allocation. Analyses will be conducted in an intention-to-treat analysis. Discussion We expect that C1-INH administration will be safe and potentially effective to improve clinical outcomes by reducing neuroinflammation in TBI patients. Trial registration ClinicalTrials.gov NCT04489160. Registered on 27 July 2020. EudraCT 2020-000140-58

The use of corn distillers dried grains with solubles (DDGS) in pig diets is limited due to high fiber concentration. Steeping with exogenous fiber-degrading enzymes (FDE) may improve their feeding value. We evaluated apparent ileal digestibility (AID), standardized ileal digestibility (SID), and apparent total tract digestibility (ATTD) of components and DE content in DDGS steeped without or with two commercial FDE (A and B). Mixture of 350 g of DDGS, FDE (none for control), and 1.5 liters of water was incubated at 40 °C for 24 h with 15 min agitation every 40 min. FDE-A (pure combination) supplied 5,500 U of xylanase and 1,050 U of β-glucanase while FDE-B (multienzyme complex) supplied 1,200 U of xylanase, 150 U of β-glucanase, 500 U of cellulase, and 5,000 U of protease per kg of DDGS plus side activities. Samples were taken at time 0, 4, 8, and 24 h for organic acids and pH measurements. Three semi-purified corn starch–based diets were formulated with steeped DDGS as the sole source of CP. The basal mixture contained 0.2% TiO2 as indigestible marker. Six ileal-cannulated pigs (20 kg BW) were fed the three diets in a replicated 3 × 3 Latin square design to give six replicates per diet. Pigs were fed at 2.8× maintenance energy requirements and had free access to water. In each period, pigs were adjusted to diets for 7 d followed by 2 d for grab fecal and 2 d of 8 h continuous ileal digesta collection. There were no (P > 0.05) treatment and sampling time interaction or treatment effects on pH and lactic concentration. Lactic and acetic acids increased, and pH decreased (P < 0.05) over time points. The AID of CP, NDF, and crude fat and SID of CP were not different (P > 0.05) among treatments. Steeping DDGS with FDE-A had lower (P = 0.01) ATTD of NDF than control but higher (P = 0.001) ATTD of crude fat compared with the control or DDGS steeped with FDE-B. Values for DE content in steeped DDGS were not different (P > 0.05) and amounted to 4,095, 4,039, and 3,974 kcal/kg DM for the control, FDE-A, and FDE-B, respectively. In conclusion, under conditions of the study, steeping DDGS with exogenous enzymes did not improve fiber and energy digestibility. [ABSTRACT FROM AUTHOR]