Ultimate Load-Carrying Ability of Rib-Stiffened 2024-T3 and 7075-T6 Aluminium Alloy Panels under Axial Compression

Stringer-stiffened panels made of aluminium alloys are often used as structural elements in the aircraft industry. The load-carrying capacity of this type of structure cannot relieve the reduction in strength in the event of local buckling. In this paper, a method of fabrication of rib-stiffened panels made of EN AW-2024-T3 Alclad and EN AW-7075-T6 Alclad has been proposed using single point incremental forming. Panels made of sheets of different thickness and with different values of forming parameters were tested under the axial compression test. A digital image correlation (DIC)-based system was used to find the distribution of strain in the panels. The results of the axial compression tests revealed that the panels had two distinct buckling modes: (i) The panels buckled halfway up the panel height towards the rib, without any appreciable loss of rib stability, and (ii) the rib first lost stability at half its height with associated breakage, and then the panel was deflected in the opposite direction to the position of the rib. Different buckling modes can be associated with the character of transverse and longitudinal springback of panels resulting from local interaction of the rotating tool on the surface of the formed ribs.     

Vascular complications in steroid treated patients undergoing transfemoral aortic valve implantation

• Steroids if taken chronically or periprocedurally contribute to delayed wound healing and decreased vascular patency
• Access site complications after diagnostic interventional procedures carry significant morbidity, increased cost, and prolonged hospital stay
• TAVI offers high risk surgical candidates with severe aortic stenosis a significant survival advantage

     

Assessment of selected B cells populations in the workers of X-ray departments

Objectives

Workers of X-ray departments are occupationally exposed to long-term low levels of ionizing radiation (LLIR), which may affect their humoral immunity. The aim of the study was to assess the influence of LLIR on the number and proportion of B cells (CD19+), B1 cells (CD5+CD19+) and memory B cells (CD27+CD19+) in peripheral blood of such workers.

Materials and Methods

In the study group of 47 X-ray departments workers and the control group consisting of 38 persons, the number and percentage of CD19+, CD5+CD19+, CD27+CD19+ cells as well as CD5+CD19+/CD19+ and CD27+CD19+/CD19+ cell ratios were assessed using flow cytometry. Additionally, the study group was divided into 2 groups by the length of employment below and over 15 years and analysis adjusted for age and smoking habit was performed.

Results

The total number of CD19+ cells showed significant increase in the group of workers in comparison with the persons from the control group, whereas the percentage of CD5+CD19+ cells as well as CD27+CD19+/CD19+ and CD5+CD19+/CD19+ cell ratios were lower. Percentage, number of CD5+CD19+ cells and CD5+CD19+/CD19+ cell ratio were significantly lower in the workers with length of employment longer than 15 years in comparison with those employed below 15 years. Moreover, we found positive associations between the number of CD19+ cells and employment as well as smoking habit, whereas the number of CD5+CD19+ cells was positively associated with cigarette smoking alone. Percentage of CD5+CD19+ cells as well as CD5+CD19+/CD19+ and CD27+CD19+/CD19+ cell ratios were negatively correlated with employment.

Conclusions

The study suggests association between the suppressive influence of low level ionizing radiation on circulating in peripheral blood, especially of B1 cells as well as of memory B cells, in workers of X-ray units, which is adverse in relation to microbiological threat.     

Novel mGluR5 Positive Allosteric Modulator Improves Functional Recovery,Attenuates Neurodegeneration,and Alters Microglial Polarization after Experimental Traumatic Brain Injury

Traumatic brain injury (TBI) causes microglial activation and related neurotoxicity that contributes to chronic neurodegeneration and loss of neurological function. Selective activation of metabotropic glutamate receptor 5 (mGluR5) by the orthosteric agonist (RS)-2-chloro-5-hydroxyphenylglycine (CHPG), is neuroprotective in experimental models of TBI, and has potent anti-inflammatory effects in vitro. However, the therapeutic potential of CHPG is limited due to its relatively weak potency and brain permeability. Highly potent, selective and brain penetrant mGluR5 positive allosteric modulators (PAMs) have been developed and show promise as therapeutic agents. We evaluated the therapeutic potential of a novel mGluR5 PAM, VU0360172, after controlled cortical impact (CCI) in mice. Vehicle, VU0360172, or VU0360172 plus mGluR5 antagonist (MTEP), were administered systemically to CCI mice at 3 h post-injury; lesion volume, hippocampal neurodegeneration, microglial activation, and functional recovery were assessed through 28 days post-injury. Anti-inflammatory effects of VU0360172 were also examined in vitro using BV2 and primary microglia. VU0360172 treatment significantly reduced the lesion, attenuated hippocampal neurodegeneration, and improved motor function recovery after CCI. Effects were mediated by mGluR5 as co-administration of MTEP blocked the protective effects of VU0360172. VU0360172 significantly reduced CD68 and NOX2 expression in activated microglia in the cortex at 28 days post-injury, and also suppressed pro-inflammatory signaling pathways in BV2 and primary microglia. In addition, VU0360172 treatment shifted the balance between M1/M2 microglial activation states towards an M2 pro-repair phenotype. This study demonstrates that VU0360172 confers neuroprotection after experimental TBI, and suggests that mGluR5 PAMs may be promising therapeutic agents for head injury.

Electronic supplementary material

The online version of this article (doi:10.1007/s13311-014-0298-6) contains supplementary material, which is available to authorized users.     

Comparison of efficacy from two different dosing regimens of bortezomib: an exposure–response analysis

Bortezomib is a first-in-class proteasome inhibitor, approved for the treatment of multiple myeloma. The originally approved dosing schedule of bortezomib results in significant toxicities that require dose interruptions and discontinuations. Consequentially, less frequent dosing has been explored to optimise bortezomib’s benefit–risk profile. Here, we performed exposure–response analysis to compare the efficacy of the original bortezomib dosing regimen with less frequent dosing of bortezomib over nine 6-week treatment cycles using data from the VISTA clinical trial and the control arm of the ALCYONE clinical trial. The relationship between cumulative bortezomib dose and clinical response was evaluated with a univariate logit model. The median cumulative bortezomib dose was higher in ALCYONE versus VISTA (42·2 vs. 38·5 mg/m²) and ALCYONE patients stayed on treatment longer (mean: 7·2 vs. 5·8 cycles). For all endpoints and regimens, probability of clinical response correlated with cumulative bortezomib dose. Similar to results observed for VISTA, overall survival was longer in ALCYONE patients with ≥ 39·0 versus < 39·0 mg/m² cumulative dose (hazard ratio, 0·119; P < 0·0001). Less frequent bortezomib dosing results in comparable efficacy, and a higher cumulative dose than the originally approved bortezomib dosing schedule, which may be in part be due to reduced toxicity and fewer dose reductions/interruptions.     

Factors and processes modulating phenotypes in neuronopathic lysosomal storage diseases

Lysosomal storage diseases are inherited metabolic disorders caused by genetic defects causing deficiency of various lysosomal proteins, and resultant accumulation of non-degraded compounds. They are multisystemic diseases, and in most of them (>70 %) severe brain dysfunctions are evident. However, expression of various phenotypes in particular diseases is extremely variable, from non-neuronopathic to severely neurodegenerative in the deficiency of the same enzyme. Although all lysosomal storage diseases are monogenic, clear genotype-phenotype correlations occur only in some cases. In this article, we present an overview on various factors and processes, both general and specific for certain disorders, that can significantly modulate expression of phenotypes in these diseases. On the basis of recent reports describing studies on both animal models and clinical data, we propose a hypothesis that efficiency of production of compounds that cannot be degraded due to enzyme deficiency might be especially important in modulation of phenotypes of patients suffering from lysosomal storage diseases.     

Influence of magnetic field strength and image registration strategy on voxel‐based morphometry in a study of Alzheimer's disease

Multi‐centre data repositories like the Alzheimer's Disease Neuroimaging Initiative (ADNI) offer a unique research platform, but pose questions concerning comparability of results when using a range of imaging protocols and data processing algorithms. The variability is mainly due to the non‐quantitative character of the widely used structural T1‐weighted magnetic resonance (MR) images. Although the stability of the main effect of Alzheimer's disease (AD) on brain structure across platforms and field strength has been addressed in previous studies using multi‐site MR images, there are only sparse empirically‐based recommendations for processing and analysis of pooled multi‐centre structural MR data acquired at different magnetic field strengths (MFS). Aiming to minimise potential systematic bias when using ADNI data we investigate the specific contributions of spatial registration strategies and the impact of MFS on voxel‐based morphometry in AD. We perform a whole‐brain analysis within the framework of Statistical Parametric Mapping, testing for main effects of various diffeomorphic spatial registration strategies, of MFS and their interaction with disease status. Beyond the confirmation of medial temporal lobe volume loss in AD, we detect a significant impact of spatial registration strategy on estimation of AD related atrophy. Additionally, we report a significant effect of MFS on the assessment of brain anatomy (i) in the cerebellum, (ii) the precentral gyrus and (iii) the thalamus bilaterally, showing no interaction with the disease status. We provide empirical evidence in support of pooling data in multi‐centre VBM studies irrespective of disease status or MFS. Hum Brain Mapp 35:1865–1874, 2014. © 2013 Wiley Periodicals, Inc.