Abstract
Neutrophils represent one of the first immune cell types recruited to sites of infection, where they can control pathogens by phagocytosis and cytotoxic mechanisms. Intracellular pathogens ...such as
Leishmania major
can hijack neutrophils to establish an efficient infection. However the dynamic interactions of neutrophils with the pathogen and other cells at the site of the infection are incompletely understood. Here, we have investigated the role of Ly6G, a homolog of the human CD177 protein, which has been shown to interact with cell adhesion molecules, and serves as a bona fide marker for neutrophils in mice. We show that Ly6G deficiency decreases the initial infection rate of neutrophils recruited to the site of infection. Although the uptake of
L. major
by subsequently recruited monocytes was tightly linked with the concomitant uptake of neutrophil material, this process was not altered by Ly6G deficiency of the neutrophils. Instead, we observed by intravital 2-photon microscopy that Ly6G-deficient neutrophils entered the site of infection with delayed initial recruitment kinetics. Thus, we conclude that by promoting neutrophils’ ability to efficiently enter the site of infection, Ly6G contributes to the early engagement of intracellular pathogens by the immune system.
JAK2-V617F-positive chronic myeloproliferative neoplasia (CMN) commonly displays dysfunction of integrins and adhesion molecules expressed on platelets, erythrocytes, and leukocytes. However, the ...mechanism by which the 2 major leukocyte integrin chains, β1 and β2, may contribute to CMN pathophysiology remained unclear. β1 (α4β1; VLA-4) and β2 (αLβ2; LFA-1) integrins are essential regulators for attachment of leukocytes to endothelial cells. We here showed enhanced adhesion of granulocytes from mice with JAK2-V617F knockin (JAK2+/VF mice) to vascular cell adhesion molecule 1- (VCAM1-) and intercellular adhesion molecule 1-coated (ICAM1-coated) surfaces. Soluble VCAM1 and ICAM1 ligand binding assays revealed increased affinity of β1 and β2 integrins for their respective ligands. For β1 integrins, this correlated with a structural change from the low- to the high-affinity conformation induced by JAK2-V617F. JAK2-V617F triggered constitutive activation of the integrin inside-out signaling molecule Rap1, resulting in translocation toward the cell membrane. Employing a venous thrombosis model, we demonstrated that neutralizing anti-VLA-4 and anti-β2 integrin antibodies suppress pathologic thrombosis as observed in JAK2+/VF mice. In addition, aberrant homing of JAK2+/VF leukocytes to the spleen was inhibited by neutralizing anti-β2 antibodies and by pharmacologic inhibition of Rap1. Thus, our findings identified cross-talk between JAK2-V617F and integrin activation promoting pathologic thrombosis and abnormal trafficking of leukocytes to the spleen.
The hydrogen evolution reaction (HER) of nanocrystalline Ni–Mo–B alloys was investigated in alkaline solution in comparison with the corresponding crystalline materials and polycrystalline nickel. ...The nanocrystalline alloys, prepared by melt spinning, were investigated towards the HER in 1 M KOH solution at 298 K. An electrochemical activation procedure (cyclic reduction-oxidation pre-treatment) was used to enhance the apparent HER activity. In case of the crystalline Ni–Mo–B master alloys the origin of the activity can mainly be attributed to an increase of the real surface area (roughening) caused by a dissolution of Mo-containing phases. Interestingly, a roughening of nanocrystalline Ni–Mo–B alloys did not occur, probably, because of the very homogenous and fine microstructure of these materials. The higher HER activity of the nanocrystalline Ni–Mo–B alloys is obviously caused by a higher intrinsic activity of the nanocrystalline Ni–Mo–B alloys and a synergistic effect of Mo.
•The HER of nanocrystalline (nc) and polycrystalline Ni–Mo–B alloys was studied.•The origin of the improved activity correlates with the altered microstructure.•The improved HER of polycrystalline alloys originates from Mo phase dissolution.•Activated nc alloys benefit from a higher intrinsic activity (no roughening).
Indirect fixation of coronoid process fractures of the ulna, especially arthroscopically, offers the possibility to avoid extensive medial surgical approaches. However, optimal placement of K-wires ...for cannulated screw fixation is technically challenging. The aim of the present study was to present guide values for K-wire placement for indirect screw fixation of coronoid tip (COT) and anteromedial facet (AMF) fractures of the ulna.
Computed tomography scans of the elbows of 197 patients with an uninjured ulna were identified and evaluated following a standard measuring protocol. Optimal placement of K-wires was defined as the bisector between the anterior and articular cortex while respecting a 1.6-mm safe zone for each placement. This placement of the K-wires in the COT and the AMF was analyzed by measuring the wire angulation in relation to the posterior ulnar cortex (AUC), the distance from the entry point to the posterior olecranon edge (DPE), and the intraosseous length (IOL). Because the coronoid has a curved shape, measurements of the COT and AMF were expected to differ significantly. Sex was also expected to influence measurements. To determine whether this optimal placement of K-wires can be reliably identified, interobserver and intraobserver reliabilities were evaluated.
To address tip fragments, we determined a mean AUC of 64°, DPE of 36 mm, and IOL of 38 mm. Regarding wire placement toward the AMF, the means for the AUC, DPE, and IOL were 79°, 27 mm, and 33 mm, respectively. Statistically significant differences were found between the COT and the AMF for the AUC, DPE, and IOL. Our measuring protocol showed good interobserver and intraobserver reliability.
K-wire placement toward the COT demands a smaller angle, a longer IOL, and a more distal entry point than wires placed toward AMF. These differences reflect the curved and complex anatomy of the coronoid.
This measuring algorithm can be used to plan osteosynthesis, and the obtained reference values can help understand the coronoid’s complex anatomy.
Respiratory failure in the acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic is hypothesized to be driven by an overreacting innate immune response, where the complement system is a key ...player. In this prospective cohort study of 39 hospitalized coronavirus disease COVID-19 patients, we describe systemic complement activation and its association with development of respiratory failure. Clinical data and biological samples were obtained at admission, days 3 to 5, and days 7 to 10. Respiratory failure was defined as PO₂/FiO₂ ratio of ≤40 kPa. Complement activation products covering the classical/lectin (C4d), alternative (C3bBbP) and common pathway (C3bc, C5a, and sC5b-9), the lectin pathway recognition molecule MBL, and antibody serology were analyzed by enzyme-immunoassays; viral load by PCR. Controls comprised healthy blood donors. Consistently increased systemic complement activation was observed in the majority of COVID-19 patients during hospital stay. At admission, sC5b-9 and C4d were significantly higher in patients with than without respiratory failure (P = 0.008 and P = 0.034). Logistic regression showed increasing odds of respiratory failure with sC5b-9 (odds ratio 31.9, 95% CI 1.4 to 746, P = 0.03) and need for oxygen therapy with C4d (11.7, 1.1 to 130, P = 0.045). Admission sC5b-9 and C4d correlated significantly to ferritin (r = 0.64, P < 0.001; r = 0.69, P < 0.001). C4d, sC5b-9, and C5a correlated with antiviral antibodies, but not with viral load. Systemic complement activation is associated with respiratory failure in COVID-19 patients and provides a rationale for investigating complement inhibitors in future clinical trials.
The purpose of this study was to investigate the primary stability and displacement tendencies of an external fixation system in 2 different configurations in comparison to locking plate fixation in ...a 3-part proximal humeral fracture model.
Twenty-one fresh-frozen human cadaveric proximal humeral specimens were divided into 3 groups of 7 stripped specimens. An unstable 3-part fracture of the proximal humerus was set. Construct A consisted of the Galaxy Fixation Shoulder System, with fixation in accordance with the manufacturer's recommended technique (3 pairs of threaded wires). Construct B was fixed with an additional pair of threaded wires according to the recommendations of Gumina et al (4 pairs of threaded wires). The remaining 7 specimens were fixed with a locking plate. By use of an optical motion capture system, relative motion at the fracture site and failure load were evaluated during a cyclic loading protocol.
Plate osteosynthesis showed the highest cyclic load to failure (895 ± 239 N; range, 597-1135 N), followed by construct B (692 ± 121 N; range, 432-788 N) and construct A (350 ± 190 N; range, 139-615 N). Statistically significant differences were found between plating and construct A (P < .001), between plating and construct B (P = .031), and between construct B and construct A (P = .013). Relative motion at the fracture site, in terms of change in distance during cyclic loading, was lowest with construct B measured at the peak load of 395 N after 11 steps (1.73 ± 1.98 mm; range, 0.53-5.96 mm) and highest with construct A (8.46 ± 10.67 mm; range, 2.26-20.79 mm). Angular change measured at the peak load after 11 steps was lowest with construct B (1.19° ± 0.36°; range, 0.59°-1.7°) and highest with construct A (2.44° ± 1.63°; range, 0.77°-4.04°). Statistically significant differences were found between construct A and construct B and between construct A and plating at various steps of cyclic loading.
In this biomechanical study of unstable 3-part proximal humeral fractures, locking plate osteosynthesis demonstrated the highest possible load application. External fixator application with 8 threaded wires (construct B) revealed the least relative motion at the fracture site, without a statistically significant difference compared with locking plates. It therefore represents another valid technique for treatment regarding primary stability. The use of external fixator application with 6 threaded wires (construct A) resulted in the lowest stability and the highest rates of displacement.
Summary Background Cervical dystonia is managed mainly by repeated botulinum toxin injections. We aimed to establish whether pallidal neurostimulation could improve symptoms in patients not ...adequately responding to chemodenervation or oral drug treatment. Methods In this randomised, sham-controlled trial, we recruited patients with cervical dystonia from centres in Germany, Norway, and Austria. Eligible patients (ie, those aged 18–75 years, disease duration ≥3 years, Toronto Western Spasmodic Torticollis Rating Scale TWSTRS severity score ≥15 points) were randomly assigned (1:1) to receive active neurostimulation (frequency 180 Hz; pulse width 120 μs; amplitude 0·5 V below adverse event threshold) or sham stimulation (amplitude 0 V) by computer-generated randomisation lists with randomly permuted block lengths stratified by centre. All patients, masked to treatment assignment, were implanted with a deep brain stimulation device and received their assigned treatment for 3 months. Neurostimulation was activated in the sham group at 3 months and outcomes were reassessed in all patients after 6 months of active treatment. Treating physicians were not masked. The primary endpoint was the change in the TWSTRS severity score from baseline to 3 months, assessed by two masked dystonia experts using standardised videos, analysed by intention to treat. This trial is registered with ClinicalTrials.gov , number NCT00148889. Findings Between Jan 19, 2006, and May 29, 2008, we recruited 62 patients, of whom 32 were randomly assigned to neurostimulation and 30 to sham stimulation. Outcome data were recorded in 60 (97%) patients at 3 months and 56 (90%) patients at 6 months. At 3 months, the reduction in dystonia severity was significantly greater with neurostimulation (–5·1 points SD 5·1, 95% CI −7·0 to −3·5) than with sham stimulation (−1·3 2·4, −2·2 to −0·4, p=0·0024; mean between-group difference 3·8 points, 1·8 to 5·8) in the intention-to-treat population. Over the course of the study, 21 adverse events (five serious) were reported in 11 (34%) of 32 patients in the neurostimulation group compared with 20 (11 serious) in nine (30%) of 30 patients in the sham-stimulation group. Serious adverse events were typically related to the implant procedure or the implanted device, and 11 of 16 resolved without sequelae. Dysarthria (in four patients assigned to neurostimulation vs three patients assigned to sham stimulation), involuntary movements (ie, dyskinesia or worsening of dystonia; five vs one), and depression (one vs two) were the most common non-serious adverse events reported during the course of the study. Interpretation Pallidal neurostimulation for 3 months is more effective than sham stimulation at reducing symptoms of cervical dystonia. Extended follow-up is needed to ascertain the magnitude and stability of chronic neurostimulation effects before this treatment can be recommended as routine for patients who are not responding to conventional medical therapy. Funding Medtronic.
Buckle fractures of the distal forearm are a common fracture entity in children treated conservatively. Diagnostics primarily include radiographs in 2 planes. Inadequate images may occur in the ...mostly very young patients. Therefore, additional lateral radiographs are often obtained to assess a possible angular tilt. The aim of this study is to investigate whether a strictly lateral x-ray image has an influence on fracture management.
Seventy-three children with buckle fractures of the distal forearm were included in this retrospective analysis. All cases were analyzed by quality of radiographs, necessity to obtain an additional lateral radiograph, and what influence on fracture management resulted. Follow-up was performed 2 to 4 weeks after immobilization.
Thirty-five girls and 38 boys with a mean age of 7.16 years were included; 40 had fractured right and 33 had fractured left arms, respectively. Isolated distal radius fractures occurred in 48 cases, isolated distal ulna fractures in 6 cases, and both bones in 19 cases. Initial radiographic images were evaluated as inadequate in 25 cases. In each of those cases, an additional lateral image was obtained by fluoroscopy without resulting in an alternated fracture management protocol, which was chosen conservatively in each case and resulted in excellent clinical outcome at follow-up examination.
Based on our results, the acquisition of additional lateral radiographs seems to be unnecessary in the diagnostic procedure of buckle fractures of the distal forearm, in case a possible palmar or dorsal angulation cannot be entirely assessed on the initial set of radiographs. An additional lateral image had no influence on fracture management, which was chosen conservatively in every case and led to excellent clinical results.Level of evidence: level III.
Nitric oxide (NO) is an important antimicrobial effector but also prevents unnecessary tissue damage by shutting down the recruitment of monocyte-derived phagocytes. Intracellular pathogens such as ...Leishmania major can hijack these cells as a niche for replication. Thus, NO might exert containment by restricting the availability of the cellular niche required for efficient pathogen proliferation. However, such indirect modes of action remain to be established. By combining mathematical modeling with intravital 2-photon biosensors of pathogen viability and proliferation, we show that low L. major proliferation results not from direct NO impact on the pathogen but from reduced availability of proliferation-permissive host cells. Although inhibiting NO production increases recruitment of these cells, and thus pathogen proliferation, blocking cell recruitment uncouples the NO effect from pathogen proliferation. Therefore, NO fulfills two distinct functions for L. major containment: permitting direct killing and restricting the supply of proliferation-permissive host cells.
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•Direct killing of L. major by NO occurs only during the peak of the immune response•Efficient L. major proliferation requires newly recruited monocyte-derived cells•Loss of NO production increases both pathogen proliferation and monocyte recruitment•NO dampens L. major proliferation indirectly, limiting the pathogen’s cellular niche
Besides direct antimicrobial activity, nitric oxide (NO) can inhibit the entry of inflammatory cells into infected tissues. Intracellular pathogens can hijack such cells as niches for proliferation. Formaglio et al. show that restriction of proliferation-permissive host cell recruitment by NO represents a mechanism that controls Leishmania major infection.
Invertebrate nervous systems are highly disparate between different taxa. This is reflected in the terminology used to describe them, which is very rich and often confusing. Even very general terms ...such as 'brain', 'nerve', and 'eye' have been used in various ways in the different animal groups, but no consensus on the exact meaning exists. This impedes our understanding of the architecture of the invertebrate nervous system in general and of evolutionary transformations of nervous system characters between different taxa.
We provide a glossary of invertebrate neuroanatomical terms with a precise and consistent terminology, taxon-independent and free of homology assumptions. This terminology is intended to form a basis for new morphological descriptions. A total of 47 terms are defined. Each entry consists of a definition, discouraged terms, and a background/comment section.
The use of our revised neuroanatomical terminology in any new descriptions of the anatomy of invertebrate nervous systems will improve the comparability of this organ system and its substructures between the various taxa, and finally even lead to better and more robust homology hypotheses.
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