Spectrum of Large and Medium Vessel Vasculitis in Adults: Primary Vasculitides, Arthritides, Connective Tissue, and Fibroinflammatory Diseases.

PURPOSE OF REVIEW To provide a comprehensive overview of the spectrum of large and medium vessel vasculitis in adults with primary vasculitides, arthritides, connective tissue, and fibroinflammatory diseases as well as vasculitis mimics, for an efficient differential diagnosis and initial diagnostic approach. RECENT FINDINGS Imaging has had a tremendous impact on the diagnosis of medium to large vessel vasculitis, now often replacing histopathologic confirmation and identifying new disease manifestations (e.g., intracranial disease in giant cell arteritis; vascular manifestations of IgG4-related disease). Novel diseases or syndromes involving blood vessels have been described (e.g., VEXAS-Syndrome with polychondritis). The use of the terms "medium" or "large" vessel varies considerably between medical specialties. The differential diagnosis of large and medium vessel vasculitis is becoming increasingly complex as new entities or disease manifestations of known inflammatory rheumatic diseases are regularly identified. A more precise and widely recognized definition of the vessel sizes would make future research more comparable

Spectrum of Large- and Medium-Vessel Vasculitis in Adults: Neoplastic, Infectious, Drug-Induced, Autoinflammatory, and Primary Immunodeficiency Diseases.

PURPOSE OF REVIEW To provide a comprehensive review of drugs and neoplastic, infectious, autoinflammatory, and immunodeficiency diseases causing medium- to large-vessel vasculitis in adults with emphasis on information essential for the initial diagnostic process. RECENT FINDINGS Entities with medium- to large-vessel vasculitis as clinical manifestations have been described recently (e.g., adenosine deaminase-2 deficiency, VEXAS-Syndrome), and vasculitis in established autoinflammatory or immunodeficiency diseases is increasingly being identified. In the diagnostic process of medium- to large-vessel vasculitis in adults, a large variety of rare diseases should be included in the differential diagnosis, especially if diagnosis is made without histologic confirmation and in younger patients. Although these disorders should be considered, they will undoubtedly remain rare in daily practice

Changing expectations about speed alters perceived motion direction

SummaryOur perceptions are fundamentally altered by our knowledge of the world. When cloud-gazing, for example, we tend spontaneously to recognize known objects in the random configurations of evaporated moisture. How our brains acquire such knowledge and how it impacts our perceptions is a matter of heated discussion. A topic of recent debate has concerned the hypothesis that our visual system ‘assumes’ that objects are static or move slowly [1] rather than more quickly [1–3]. This hypothesis, or ‘prior on slow speeds’, was postulated because it could elegantly explain a number of perceptual biases observed in situations of uncertainty [2]. Interestingly, those biases affect not only the perception of speed, but also the direction of motion. For example, the direction of a line whose endpoints are hidden (as in the ‘aperture problem’) or poorly visible (for example, at low contrast or for short presentations) is more often perceived as being perpendicular to the line than it really is — an illusion consistent with expecting that the line moves more slowly than it really does. How this ‘prior on slow speeds’ is shaped by experience and whether it remains malleable in adults is unclear. Here, we show that systematic exposure to high-speed stimuli can lead to a reversal of this direction illusion. This suggests that the shaping of the brain's prior expectations of even the most basic properties of the environment is a continuous process

Case Report: Genetic Double Strike: VEXAS and TET2-Positive Myelodysplastic Syndrome in a Patient With Long-Standing Refractory Autoinflammatory Disease.

Somatic genetic mutations involving the innate and inflammasome signaling are key drivers of the pathogenesis of myelodysplastic syndromes (MDS). Herein, we present a patient, who suffered from a long-standing refractory adult-onset autoinflammatory syndrome (AIS), previously interpreted as various distinct rheumatic disorders. Developing pancytopenia and particularly macrocytic anemia prompted the screening for a hematological malignancy, which led to the diagnosis of a TET-2-positive MDS. The impressive and continuously changing range of organ involvement, with remarkable refractoriness to anti-inflammatory treatment, exceeded the common autoinflammatory phenotype of MDS patients. This prompted us to suspect a recently discovered disease, characterized by somatic mutations of the UBA1 gene: the VEXAS (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) syndrome, which was ultimately confirmed by genetic testing. Reevaluation of previous bone marrow biopsies showed the presence of characteristic vacuoles in myeloid- and erythroid progenitor cells. Our case illustrates that the triad of an unresponsive multisystemic autoinflammatory disease, hematological abnormalities and vacuoles in myeloid- and erythroid progenitors in the bone marrow biopsy should prompt screening for the VEXAS syndrome

Gas-induced segregation in Pt-Rh alloy nanoparticles observed by in-situ Bragg coherent diffraction imaging

Bimetallic catalysts can undergo segregation or redistribution of the metals driven by oxidizing and reducing environments. Bragg coherent diffraction imaging (BCDI) was used to relate displacement fields to compositional distributions in crystalline Pt-Rh alloy nanoparticles. 3D images of internal composition showed that the radial distribution of compositions reverses partially between the surface shell and the core when gas flow changes between O2 and H2. Our observation suggests that the elemental segregation of nanoparticle catalysts should be highly active during heterogeneous catalysis and can be a controlling factor in synthesis of electrocatalysts. In addition, our study exemplifies applications of BCDI for in situ 3D imaging of internal equilibrium compositions in other bimetallic alloy nanoparticles

Activation of the <i>gluteus maximus</i> during performance of the back squat, split squat and barbell hip thrust and the relationship with maximal sprinting

The purpose of this research was to compare muscle activation of the gluteus maximus and ground reaction force between the barbell hip thrust, back squat, and split squat and to determine the relationship between these outcomes and vertical and horizontal forces during maximal sprinting. Twelve male team sport athletes (age 25.0 ± 4.0 years, stature 184.1 ± 6.0 cm, body mass 82.2 ± 7.9 kg) performed separate movements of the three strength exercises at a load equivalent to their individual three repetition maximum. The ground reaction force was measured using force plates and the electromyography (EMG) activity of the upper and lower gluteus maximus was recorded in each leg and expressed as percentage of the maximum voluntary isometric contraction (MVIC). Participants then completed a single sprint on a non-motorized treadmill for the assessment of maximal velocity, horizontal and vertical forces. Although ground reaction force was lower, peak EMG activity in the gluteus maximus was higher in the hip thrust than the back squat (p = 0.024; 95%CI = 4 – 56%MVIC) and split squat (p = 0.016; 95%CI = 6 – 58%MVIC). Peak sprint velocity was correlated with both anterior-posterior horizontal force (r = 0.72) and peak ground reaction force during the barbell hip thrust (r = 0.69) but no other variables. The increased activation of gluteus maximus during the barbell hip thrust and the relationship with maximal running speed suggests that this movement may be optimal for training this muscle group in comparison to the back squat and split squat

Quantitative ultrasound to monitor the vascular response to tocilizumab in giant cell arteritis.

OBJECTIVES To characterize the effect of ultra-short glucocorticoids followed by Tocilizumab monotherapy on the intima-media thickness (IMT) in GCA. METHODS 18 GCA patients received 500mg methylprednisolone intravenously on days 0-2, followed by Tocilizumab (8mg/kg) intravenously on day 3 and thereafter weekly subcutaneous Tocilizumab injections (162 mg) over 52 weeks. Ultrasound of temporal (TA), axillary (AA) and subclavian (SA) arteries was performed at baseline, on days 2-3, at week 4, 8, 12, 24 and 52. The largest IMT of all segments and IMT at landmarks of AA/SA were recorded. IMT was scaled by mean normal values and averaged. Each segment was classified according to diagnostic cut-offs. RESULTS 16 patients had TA and 6 had extracranial large artery involvement. The IMT showed a sharp decline on day 2/3 in the TA and AA/SA. In TA, this was followed by an increase to baseline levels at week 4 and a subsequent slow decrease, which was paralleled by decreasing symptoms and achievement of clinical remission. The AA/SA showed a new signal of vasculitis at week 4 in three patients with an IMT increase up to week 8. CONCLUSIONS Glucocorticoid pulse therapy induced a transient decrease of the IMT in TA and AA/SA. Tocilizumab monotherapy resulted in a slow and steady decrease in IMT of the TA and a smaller and delayed effect on the AA/SA. The data strongly support a remission-inducing effect of Tocilizumab and argue for an important role of ultrasound in monitoring disease activity in GCA

Triple negative breast cancers express receptors for LHRH and are potential therapeutic targets for cytotoxic LHRH-analogs, AEZS 108 and AEZS 125

Background Triple negative breast cancer (TNBC) is a distinct subtype of breast cancer burdened with a dismal prognosis due to the lack of effective therapeutic agents. Receptors for LHRH (luteinizing hormone-releasing hormone) can be successfully targeted with AEZS-108 [AN-152], an analog of LHRH conjugated to doxorubicin. Our study evaluates the presence of this target LHRH receptor in human specimens of TNBC and investigates the efficacy and toxicity of AEZS-108 in vivo. We also studied in vitro activity of AEZS-125, a new LHRH analog conjugated with the highly potent natural compound, Disorazol Z. Methods 69 human surgical specimens of TNBC were investigated for LHRH-R expression by immunohistochemistry. Expression of LHRH-R in two TNBC cell lines was evaluated by real time RT-PCR. Cytotoxicity of AEZS-125 was evaluated by Cell Titer Blue cytoxicity assay. LHRH- receptor expression was silenced with an siRNA in both cell lines. For the in vivo experiments an athymic nude mice model xenotransplanted with the cell lines, MDA-MB-231 and HCC 1806, was used. The animals were randomised to three groups receiving solvent only (d 1, 7, 14, i.v.) for control, AEZS-108 (d 1, 7, 14, i.v.) or doxorubicin at an equimolar dose (d 1, 7, 14, i.v.). Results In human clinical specimens of TNBC, expression of the LHRH-receptor was present in 49% (n = 69). HCC 1806 and MDA-MB-231 TNBC cells expressed mRNA for the LHRH-receptor. Silencing of the LHRH-receptor significantly decreased the cytotoxic effect of AEZS-108. MDA-MB-231 and HCC 1806 tumors xenografted into nude mice were significantly inhibited by treatment with AEZS-108; doxorubicin at equimolar doses was ineffective. As compared to AEZS 108, the Disorazol Z – LHRH conjugate, AEZS-125, demonstrated an increased cytotoxicity in vitro in HCC 1806 and MDA-MB-231 TNBC; this was diminished by receptor blockade with synthetic LHRH agonist (triptorelin) pretreatment. Conclusion The current study confirms that LHRH-receptors are expressed by a significant proportion of TNBC and can be successfully used as homing sites for cytotoxic analogs of LHRH, such as AEZS-108 and AEZS-125