Discovery of new 2-(3-(naphthalen-2-yl)-4,5-dihydro-1H-pyrazol-1-yl)thiazole derivatives with potential analgesic and anti-inflammatory activities: In vitro, in vivo and in silico investigations.

Joining the global demand for the discovery of potent NSAIDs with minimized ulcerogenic effect, new pyrazole clubbed thiazole derivatives 5a-o were designed and synthesized. The new derivatives were initially evaluated for their analgesic activity. Eight compounds 5a, 5c, 5d, 5e, 5f, 5h, 5m, and 5o showed higher activity than Indomethacin (potency = 105-130 % vs. 100 %). Subsequently, they were picked for further evaluation of their anti-inflammatory activity, ulcerogenic liability as well as toxicological studies. Derivatives 5h and 5m showed a potential % edema inhibition after 3 h (79.39 % and 72.12 %, respectively), with a promising safety profile and low ulcer indices (3.80 and 3.20, respectively). The two compounds 5h and 5m were subjected to in vitro COX-1 and COX-2 inhibition assay. The candidate 5h showed nearly equipotent COX-1 inhibition (IC50 = 38.76 nM) compared to the non-selective reference drug Indomethacin (IC50 = 35.72 nM). Compound 5m expressed significant inhibitory activities and a higher COX-2 selectivity index (IC50 = 87.74 nM, SI = 2.05) in comparison with Indomethacin (SI = 0.52), with less selectivity than Celecoxib (SI = 8.31). Simulation docking studies were carried out to gain insights into the binding interaction of compounds 5h and 5m in the vicinity of COX-1 and COX-2 enzymes that illustrated the importance of pyrazole clubbed thiazole core in hydrogen bonding interactions. The thiazole motif of compounds 5h and 5m exhibited a well orientation toward COX-1 Arg120 key residue by hydrogen bonding interactions. Compound 5h revealed an additional arene-cation interaction with Arg120 that could rationalize its superior COX-1 inhibitory activity. Compounds 5h and 5m overlaid the co-crystallized ligand Celecoxib I differently in the active site of COX-2. Compound 5m showed an enhanced accommodation with binding energy of - 6.13 vs. - 1.70 kcal/mol of compounds 5h. The naphthalene ring of compound 5m adopted the Celecoxib I benzene sulfonamide region that is stabilized by hydrogen-arene interactions with the hydrophobic sidechains of the key residues Ser339 and Phe504. Further, the core structure of compound 5m, pyrazole clubbed thiazole, revealed deeper hydrophobic interactions with Ala513, Leu517 and Val509 residues. Finally, a sensitive and accurate UPLC-MS/MS method was developed for the simultaneous estimation of some selected promising pyrazole derivatives in rat plasma. Accordingly, compounds 5h and 5m were suggested to be promising potent analgesic and anti-inflammatory agents with improved safety profiles and a novel COX isozyme modulation activity.

In-process volumetric sensing of defects in multiple parts during powder bed fusion using ultrasound.

This letter reports on the integration of eight ultrasonic transducers into a build substrate for individual in-process monitoring of eight parts fabricated using powder bed fusion additive manufacturing. Ultrasound is shown to be able to sense poor fusion of parts to the substrate and also sensitivity to porosity. This technique demonstrates the utility of ultrasound as one of a few techniques able to interrogate the volume of additively manufactured parts during the process. Additionally, the ability to measure several parts during a single build can be used for efficient process parameter development studies, as the ultrasonic measurements can offer rapid information about part quality and integrity.

Insights into targeting SARS-CoV-2: design, synthesis, in silico studies and antiviral evaluation of new dimethylxanthine derivatives.

Aiming to achieve efficient activity against severe acute respiratory syndrome coronavirus (SARS-CoV-2), the expansion of the structure- and ligand-based drug design approaches was adopted, which has been recently reported by our research group. Purine ring is a corner stone in the development of SARS-CoV-2 main protease (Mpro) inhibitors. The privileged purine scaffold was elaborated to achieve additional affinity based on hybridization and fragment-based approaches. Thus, the characteristic pharmacophoric features that are required for the inhibition of Mpro and RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2 were utilized along with the crystal structure information of both targets. The designed pathways involved rationalized hybridization with large sulfonamide moieties and a carboxamide fragment for the synthesis of ten new dimethylxanthine derivatives. The synthesis was performed under diverse conditions to afford N-alkylated xanthine derivatives, and cyclization afforded tricyclic compounds. Molecular modeling simulations were used to confirm and gain insights into the binding interactions at both targets' active sites. The merit of designed compounds and the in silico studies resulted in the selection of three compounds that were evaluated in vitro to estimate their antiviral activity against SARS-CoV-2 (compounds 5, 9a and 19 with IC50 values of 38.39, 8.86 and 16.01 µM, respectively). Furthermore, oral toxicity of the selected antiviral candidates was predicted, in addition to cytotoxicity investigations. Compound 9a showed IC50 values of 8.06 and 3.22 µM against Mpro and RdRp of SARS-CoV-2, respectively, in addition to promising molecular dynamics stability in both target active sites. The current findings encourage further specificity evaluations of the promising compounds for confirming their specific protein targeting.

Shared thoughts and practices on some modifiable cancer risk factors.

OBJECTIVE: Numerous cancer-causing factors are inversely correlated with health literacy. The current study's objective was to evaluate the Saudi community's knowledge, attitude, and behavior regarding certain carcinogens. SUBJECTS AND METHODS: To perform this descriptive study, a cross-sectional survey was carried out in Hail City, Northern Saudi Arabia, between September 2020 and November 2020. In the city of Hail, about 450 volunteers have expressed interest in taking part in the study. RESULTS: A total of 165 individuals smoked cigarettes and drank alcohol, respectively (67%) and 42 (9%). Negative attitudes toward cigarette smoking, alcohol consumption, radiation exposure, genetic predisposition, some viruses, some bacterial infection, some parasites, and fungi were 85/450 (19%), 209/450 (46.4%), 206/450 (45.8%), 322/450 (71.6%), 297/450 (66%), 375/450 (83.3%), 403/450 (89.6%), and 405/450 (90%), in that order. CONCLUSIONS: Some cancer-causing substances are widely used in the Saudi community. Lack of understanding and a negative attitude toward some carcinogens are widespread, necessitating immediate interventions at the community and health affairs levels.

Personal caution about some cancer-related lifestyle habits in Northern Saudi Arabia.

OBJECTIVE: The present study aimed at assessing community familiarity with cancer-related lifestyle habits in Northern Saudi Arabia. SUBJECTS AND METHODS: This descriptive cross-sectional study involved a community-based sample of 442 civilians living in Hail, Northern Saudi Arabia. Data were collected during the period between October and November 2020. Data were randomly collected from different public gathering places regardless of age or sex. RESULTS: Higher nescience percentages were associated with physical inactivity followed by obesity and fast food, representing 328/390 (84%), 311/390 (80%), and 263/390 (67%), respectively. CONCLUSIONS: Northern Saudi Arabia has a high negative attitude toward cancer risk factors, necessitating the implementation of community-based health education and cancer awareness programs. Level of education and age have no significant role in the level of cancer awareness.

A Perspective Study on the RTK, PI3K, B-Raf, CDK and the Multi-Protein Targeting in Medicinal Chemistry.

The cellular signaling pathway components that control the different stages of cell maturation such as RTK, PI3K, B-Raf, and CDK represent crucial antitumor drug targets. The isoform diversity of these components revealed multi-divergent vents for cancer cells to develop several resistance mechanisms against these new selective drug targets. This review article illustrates the complex nature of cancer, moreover, molecular tracing of tumor resistance towards certain signaling pathways was presented. Several crucial interventions in this regard for antitumor agents' development were pointed out. The antitumor activities of several cancer chemotherapies targeting kinases were also discussed with a special focus on the structural bases for the design of protein kinase inhibitors. Additionally, a focused literature survey about the various targeted multi-kinase inhibition approaches as a mean to overcome cancer resistance was also included.

Correlation of Call Burden and Sleep Deprivation with Physician Burnout, Driving Crashes, and Medical Errors among US Neurointerventionalists.

BACKGROUND AND PURPOSE: High call frequency can lead to inadequate sleep, fatigue, and burnout, resulting in detrimental effects on physicians and patients. We aimed to assess the correlation between the frequency and burden of neurointerventional surgery calls and sleep deprivation with physician burnout, physical and driving safety, and fatigue-related medical errors. MATERIALS AND METHODS: We sent an online questionnaire to the members of the 2 neurointerventional surgery societies comprising 50 questions and spanning 3 main topics: 1) overnight/weekend call burden, 2) sleeping patterns, and 3) Copenhagen Burnout Inventory. RESULTS: One hundred sixty-four surveys were completed. Most (54%) neurointerventional surgeons reported burnout. Call burden of ≥1 every 3 days and being in practice >10 years were independent predictors of burnout. Thirty-nine percent reported falling asleep at the wheel, 23% reported a motor vehicle crash/near-crash, and 34% reported medical errors they considered related to call/work fatigue. On multivariate logistic regression, high call burden (called-in >3 times/week) was an independent predictor of sleeping at the wheel and motor vehicle crashes. Reporting <4 hours of uninterrupted sleep was an independent predictor of motor vehicle crashes and medical errors. Most neurointerventional surgeons recommended a maximum call frequency of once every 3 days. CONCLUSIONS: Call frequency and burden, number of years in practice, and sleep deprivation are associated with burnout of neurointerventional surgeons, sleeping at the wheel, motor vehicle crashes, and fatigue-related medical errors. These findings contribute to the increasing literature on physician burnout and may guide future societal recommendations related to call burden in neurointerventional surgery.

Identification of Some Promising Heterocycles Useful in Treatment of Allergic Rhinitis: Virtual Screening, Pharmacophore Mapping, Molecular Docking, and Molecular Dynamics.

Rhinitis is an allergic disease that causes troubles and restlessness for patients. In this research work we will focus on finding promising organic molecules with potential ability to target histamine receptor with no sedative side effect. Phalazines and their isosteres, pyrimidines and pyridines have been reported to target H1 receptors, for this reason we have searched for library of these basic scaffolds, this library which has 184 organic molecules will be subjected for further explorations through computer aided drug design techniques. Swiss ADMET will be used to gather these compounds in clusters. Cluster with low potential to penetrate BBB is selected for virtual screening through pharmacophore model. Then molecular docking that revealed the stability of the complex formed between the investigated molecules and H1 receptor. ADMET profile showed three compounds (XVIII), (XX), and (XXI) with no toxicity on liver and no effect on CYP2D6, these three compounds were subjected to molecular dynamic simulations and compound (XVIII) showed the most stable complex with the target protein (H1). Finally, we can say this work helped us to find new compounds with promising potential to target H1 without ability to penetrate BBB, so they can be used as useful candidates in treatment of rhinitis and deserve to be subjected for preclinical and clinical investigations. Supplementary Information: The online version contains supplementary material available at 10.1134/S1068162022330019.

Design, synthesis and anti-Mycobacterium tuberculosis evaluation of new thiazolidin-4-one and thiazolo[3,2-a][1,3,5]triazine derivatives.

In response to the urgent need to encounter infection diseases, and upon increasing concerns about the devastating effects of tuberculosis (TB), the promising thiazolidin-4-one scaffold was used as a starting point to design and synthesize seventeen new compounds, relying on the pharmacophoric features of different anti-Mycobacterium tuberculosis and antibacterial active compounds. Thiazolidin-4-one was elaborated to result in bi-functioning formation, and further ring fusion into a thiazolo[3,2-a][1,3,5]triazine, which was hybridized with different heterocyclic rings and sulfonamide moieties. All the newly synthesized compounds were evaluated for their activity against drug sensitive (DS), multi-drug resistant (MDR) and extensive drug resistant (XDR) Mycobacterium tuberculosis (Mtb) strains. Additionally, their anti-bacterial activity against several bronchitis causing-bacteria (ATCC) and their antifungal activity were assessed. Several compounds showed promising results regarding all of the mentioned assays without any antifungal activities. Particularly, compound 3 showed a promising activity against the three Mtb strains (DS, MDR and XDR) with MIC of 2.49, 9.91 and 39.72 µM, respectively. Furthermore, compound 7c revealed antituberculosis activity with MIC of 2.28, 18.14 and 36.31 µM against DS, MDR and XDR strains, respectively. Both of compounds 3 and 7c surpassed azithromycin on several bronchitis causing-bacteria and showed enhanced inhibitory activity against Mycobacterium tuberculosis enoyl-acyl carrier protein reductase (InhA), with IC50 of 3.90 and 2.47 µM, respectively. The enzymatic activity was augmented by the binding characteristics of 3 and 7c in the InhA active site. Further investigations confirmed their safety on normal cell lines, and promising predicted ADME characteristics.

Six-Sigma Quality Management of Additive Manufacturing.

Quality is a key determinant in deploying new processes, products, or services and influences the adoption of emerging manufacturing technologies. The advent of additive manufacturing (AM) as a manufacturing process has the potential to revolutionize a host of enterprise-related functions from production to the supply chain. The unprecedented level of design flexibility and expanded functionality offered by AM, coupled with greatly reduced lead times, can potentially pave the way for mass customization. However, widespread application of AM is currently hampered by technical challenges in process repeatability and quality management. The breakthrough effect of six sigma (6S) has been demonstrated in traditional manufacturing industries (e.g., semiconductor and automotive industries) in the context of quality planning, control, and improvement through the intensive use of data, statistics, and optimization. 6S entails a data-driven DMAIC methodology of five steps-define, measure, analyze, improve, and control. Notwithstanding the sustained successes of the 6S knowledge body in a variety of established industries ranging from manufacturing, healthcare, logistics, and beyond, there is a dearth of concentrated application of 6S quality management approaches in the context of AM. In this article, we propose to design, develop, and implement the new DMAIC methodology for the 6S quality management of AM. First, we define the specific quality challenges arising from AM layerwise fabrication and mass customization (even one-of-a-kind production). Second, we present a review of AM metrology and sensing techniques, from materials through design, process, and environment, to postbuild inspection. Third, we contextualize a framework for realizing the full potential of data from AM systems and emphasize the need for analytical methods and tools. We propose and delineate the utility of new data-driven analytical methods, including deep learning, machine learning, and network science, to characterize and model the interrelationships between engineering design, machine setting, process variability, and final build quality. Fourth, we present the methodologies of ontology analytics, design of experiments (DOE), and simulation analysis for AM system improvements. In closing, new process control approaches are discussed to optimize the action plans, once an anomaly is detected, with specific consideration of lead time and energy consumption. We posit that this work will catalyze more in-depth investigations and multidisciplinary research efforts to accelerate the application of 6S quality management in AM.

Refractory Stroke Thrombectomy: Prevalence, Etiology, and Adjunctive Treatment in a North American Cohort.

BACKGROUND AND PURPOSE: Acute stroke intervention refractory to mechanical thrombectomy may be due to underlying vessel wall pathology including intracranial atherosclerotic disease and intracranial arterial dissection or recalcitrant emboli. We studied the prevalence and etiology of refractory thrombectomy, the safety and efficacy of adjunctive interventions in a North American-based cohort. MATERIALS AND METHODS: We performed a multicenter, retrospective study of refractory thrombectomy, defined as unsuccessful recanalization, vessel reocclusion in <72 hours, or required adjunctive antiplatelet glycoprotein IIb/IIIa inhibitors, intracranial angioplasty and/or stenting to achieve and maintain reperfusion. Clinical and imaging criteria differentiated etiologies for refractory thrombectomy. Baseline demographics, cerebrovascular risk factors, technical/clinical outcomes, and procedural safety/complications were compared between refractory and standard thrombectomy groups. Multivariable logistic regression analysis was performed to determine independent predictors of refractory thrombectomy. RESULTS: Refractory thrombectomy was identified in 25/302 cases (8.3%), correlated with diabetes (44% versus 22%, P = .02) as an independent predictor with OR = 2.72 (95% CI, 1.05-7.09; P = .04) and inversely correlated with atrial fibrillation (16% versus 45.7%, P = .005). Refractory etiologies were secondary to recalcitrant emboli (20%), intracranial atherosclerotic disease (60%), and/or intracranial arterial dissection (44%). Four (16%) patients were diagnosed with early vessel reocclusion, and 21 patients underwent adjunctive salvage interventions with glycoprotein IIb/IIIa inhibitor infusion alone (32%) or intracranial angioplasty and/or stenting (52%). There were no significant differences in TICI 2b/3 reperfusion efficacy (85.7% versus 90.9%, P = .48), symptomatic intracranial hemorrhage rates (0% versus 9%, P = .24), favorable clinical outcomes (39.1% versus 48.3%, P = .51), or mortality (13% versus 28.3%, P = .14) versus standard thrombectomy. CONCLUSIONS: Refractory stroke thrombectomy is encountered in <10% of cases, independently associated with diabetes, and related to underlying vessel wall pathology (intracranial atherosclerotic disease and/or intracranial arterial dissection) or, less commonly, recalcitrant emboli. Emergent salvage interventions with glycoprotein IIb/IIIa inhibitors or intracranial angioplasty and/or stenting are safe and effective adjunctive treatments.

Model-Based Feedforward Control of Part Height in Directed Energy Deposition.

Control of the geometric accuracy of a metal deposit is critical in the repair and fabrication of complex components through Directed Energy Deposition (DED). This paper developed and experimentally evaluated a model-based feedforward control of laser power with the objective of achieving the targeted part height in DED. Specifically, based on the dynamic model of melt-pool geometry derived from our prior work, a nonlinear inverse-dynamics controller was derived in a hatch-by-hatch, layer-by-layer manner to modulate the laser power such that the melt-pool height was regulated during the simulated build process. Then, the laser power trajectory from the simulated closed-loop control under the nonlinear inverse-dynamics controller was implemented as a feedforward control in an Optomec Laser-Engineered Net Shape (LENS) MR-7 system. This paper considered the deposition of L-shaped structures of Ti-6AL-4V as a case study to illustrate the proposed model-based controller. Experimental validation showed that by applying the proposed model-based feed-forward control for laser power, the resulting build had 24-42% reduction in the average build height error with respect to the target build height compared to applying a constant laser power through the entire build or applying a hatch-dependent laser power strategy, for which the laser power values were obtained from experimental trial and error.

Design, synthesis and in silico insights of new 7,8-disubstituted-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione derivatives with potent anticancer and multi-kinase inhibitory activities.

Aiming to obtain an efficient anti-proliferative activity, structure- and ligand-based drug design approaches were expanded and utilized to design and refine a small compound library. Subsequently, thirty-two 7,8-disubstituted-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione derivatives were selected for synthesis based on the characteristic pharmacophoric features required for PI3K and B-Raf oncogenes inhibition. All the synthesized compounds were evaluated for their in vitro anticancer activity. Compounds 17 and 22c displayed an acceptable potent activity according to the DTP-NCI and were further evaluated in the NCI five doses assay. To validate our design, compounds with the highest mean growth inhibition percent were screened against the target PI3Kα and B-RafV600E to confirm their multi-kinase activity. The tested compounds showed promising multi-kinase activity. Compounds 17 and 22c anticancer effectiveness and multi-kinase activity against PI3Kα and B-RafV600E were consolidated by the inhibition of B-RafWT, EGFR and VEGFR-2 with IC50 in the sub-micromolar range. Further investigations on the most potent compounds 17 and 22c were carried out by studying their safety on normal cell line, in silico profiling and predicted ADME characteristics.

Robotic assisted eTEP ventral hernia repair: Brazilian early experience.

PURPOSE: The enhanced view totally extraperitoneal (eTEP) concept first applied to inguinal hernias has become an important tool in the armamentarium of ventral hernia repair. The purpose of this report is to date the first brazilian robotic-assisted eTEP ventral hernia repair case series. METHODS: A review of a prospectively maintained database was conducted in patients who underwent robotic-assisted enhanced view totally extraperitoneal (eTEP) for ventral hernia repair between June 2018 and January 2020. Patients demographics, preoperative hernia characteristics, intraoperative variables and postoperative outcomes were evaluated. RESULTS: Our review identified 74 patients submitted to the procedure. Thirty-one patients (41.8%) presented primary ventral hernias (PVHs) and 43 patients (58.2%) presented incisional hernias (IHs). Female patients were predominant in both groups PVHs and IHs with 17 (22.9%) and 22 (29.7%) respectively, with a total of 39 patients (52.7%). Mean BMI was 29.1 kg/m2 (range 21.3-48.0 kg/m2) with higher mean BMI rates of 30.3 kg/m2 in the IHs group (range 22-48 years). A lateral dock setup was utilized in 55 cases (74.4%), having the inferior and superior dock setup in 18 (24.3%) and 1 (1.3%) cases respectively. Mean console time was 148.3 (range 75-277 min) and 192.6 min (range 66-301 min) in the PVHs and IHs groups respectively. There were no intraoperative complications or conversions. Average length of stay was 1.5 days. Four patients were readmitted within 30 days of surgery. There were no reoperation or cases of intraparietal herniation in this cohort. No hernia recurrence was verified during the mean 230.7 days of follow up in both groups. CONCLUSION: We present the first brazilian series to-date of the robotic assisted eTEP approach for ventral hernia repairs. Although long term outcomes require further analysis, its feasibility and reproducibility in experienced surgeons hands are evident, with safe and acceptable early postoperative outcomes.

GUide sheath Advancement and aspiRation in the Distal petrocavernous internal carotid artery (GUARD) Technique during Thrombectomy Improves Reperfusion and Clinical Outcomes.

BACKGROUND AND PURPOSE: Adjunctive techniques to stent retriever thrombectomy include balloon-guide catheters and/or distal access catheters for aspiration. We describe a novel technique using a flexible, 6 French 088 distal guide sheath advanced past the skull base to augment mechanical thrombectomy. We studied the relative safety and efficacy of this technique in the setting of a combined stent retriever-distal access catheter aspiration thrombectomy protocol. MATERIALS AND METHODS: We performed a retrospective case-control study of intracranial internal carotid artery or M1-M2 middle cerebral artery occlusions requiring mechanical thrombectomy. Patients were divided into 2 groups based on thrombectomy techniques: conventional stent retriever with distal access catheter aspiration without (standard) and with adjunctive GUide sheath Advancement and aspiRation in the Distal petrocavernous internal carotid artery (GUARD). Using propensity score matching, we compared procedural safety, reperfusion efficacy using the modified Thrombolysis in Cerebral Infarction scale and clinical outcomes with the modified Rankin Scale. RESULTS: In comparing the GUARD (45 patients) versus standard (45 matched case controls) groups, there were no significant differences in demographics, NIHSS presentations, IV rtPA use, median onset-to-groin puncture times, procedural complications, symptomatic intracranial hemorrhage, or mortality. The GUARD group demonstrated significantly higher successful mTICI ≥2b reperfusion rates (98% versus 80%, P = .015) and improved functional mRS ≤2 outcomes (67% versus 43%, P = .04), with independent effects of the GUARD technique confirmed in a multivariable logistic regression model. CONCLUSIONS: The GUARD technique during mechanical thrombectomy with combined stent retrieval-distal access catheter aspiration is safe and effective in improving reperfusion and clinical outcomes.

Diagnostic Accuracy of High-Resolution Black-Blood MRI in the Evaluation of Intracranial Large-Vessel Arterial Occlusions.

BACKGROUND AND PURPOSE: 3D high-resolution black-blood MRI or MR vessel wall imaging allows evaluation of the intracranial arterial wall and extraluminal pathology. We investigated the diagnostic accuracy and reliability of black-blood MRI for the intraluminal detection of large-vessel arterial occlusions. MATERIALS AND METHODS: We retrospectively identified patients with intracranial arterial occlusions, confirmed by CTA or DSA, who also underwent 3D black-blood MRI with nonenhanced and contrast-enhanced T1 sampling perfection with application-optimized contrasts by using different flip angle evolution (T1 SPACE) sequences. Black-blood MRI findings were evaluated by 2 independent and blinded neuroradiologists. Large-vessel intracranial arterial segments were graded on a 3-point scale (grades 0-2) for intraluminal baseline T1 hyperintensity and contrast enhancement. Vessel segments were considered positive for arterial occlusion if focal weak (grade 1) or strong (grade 2) T1-hyperintense signal and/or enhancement replaced the normal intraluminal black-blood signal. RESULTS: Thirty-one patients with 38 intracranial arterial occlusions were studied. The median time interval between black-blood MRI and CTA/DSA reference standard studies was 2 days (range, 0-20 days). Interobserver agreement was good for T1 hyperintensity (κ = 0.63) and excellent for contrast enhancement (κ = 0.89). High sensitivity (100%) and specificity (99.8%) for intracranial arterial occlusion diagnosis was observed with either intraluminal T1 hyperintensity or contrast-enhancement imaging criteria on black-blood MRI. Strong grade 2 intraluminal enhancement was maintained in >80% of occlusions irrespective of location or chronicity. Relatively increased strong grade 2 intraluminal T1 hyperintensity was noted in chronic/incidental versus acute/subacute occlusions (45.5% versus 12.5%, P = .04). CONCLUSIONS: Black-blood MRI with or without contrast has high diagnostic accuracy and reliability in evaluating intracranial large-vessel arterial occlusions with near-equivalency to DSA and CTA.

Formation processes for large ejecta and interactions with melt pool formation in powder bed fusion additive manufacturing.

Ejecta with a size much larger than the mean particle size of feedstock powder have been observed in powder bed fusion additive manufacturing, both during post-process sieving and embedded within built components. However, their origin has not been adequately explained. Here, we test a hypothesis on the origin of large (much larger than the mass-median-diameter of feedstock powder) ejecta-that, in part, they result from stochastic, inelastic collisions of ejecta and coalescence of partially-sintered agglomerates. The hypothesis is tested using direct observation of ejecta behavior, via high-speed imaging, to identify interactions between ejecta and consequences on melt pool formation. We show that stochastic collisions occur both between particles which are nearly-simultaneously expelled from the laser interaction zone and between particles ejected from distant locations. Ejecta are also shown to perturb melt pool geometry, which is argued to be a potential cause of lack-of-fusion flaws.

Exposure to aluminum, aluminum + manganese and acid pH triggers different antioxidant responses in gills and liver of Astyanax altiparanae (Teleostei: Characiformes: Characidae) males.

Exposure to aluminum (Al) and aluminum + manganese (Mn) can trigger an increase in reactive oxygen species (ROS) and modify the activity of oxidative defense enzymes. This study investigated whether exposure to Al and Al + Mn at acid pH for 24 and 96 h causes oxidative stress evidenced by antioxidants and oxidative damage in the gills and liver of sexually mature Astyanax altiparanae males. The fish were subsequently immersed in metal-free water for 24 and 96 h to see whether they recovered from the effects of these metals. Exposure to an acid pH boosted the activity of gill superoxide dismutase (SOD) at 96 h and the fish did not recover when immersed for the same period in water at neutral pH. Exposure to Al increased glutathione (GSH) levels (24 h) in the gills, returning to control levels during the recovery period, showing the efficiency of the antioxidant system in preventing lipid peroxidation of the gills and liver. Mn did not modify the activity of the enzymes studied, but did trigger late hepatic lipid peroxidation during the recovery period. The group exposed to Al + Mn exhibited several alterations, including increased concentration of GSH, as well as higher GPx and GR activity in the gills. Despite the defensive responses triggered by acute exposure, during the recovery period there were alterations in catalase (96 h) and an increase in hepatic metallothionein (24 h), but this did not prevent hepatic lipid peroxidation. Al and Al + Mn produced different effects, and the timing of enzymatic and non-enzymatic antioxidant defenses also differed.

Monocytes of patients with unstable angina express high levels of chemokine and pattern-recognition receptors.

BACKGROUND AND AIMS: Macrophages derived from monocytes play an important role in atherosclerosis progression. Subpopulations of circulating classical, intermediate, and non-classical monocytes possess distinct functions and phenotypes, and participate in the pathogenesis of disease. The aim of this study was to compare the quantity and phenotypes of circulating monocyte subpopulations in patients with established atherosclerosis and healthy control individuals. Additionally, the study aimed to provide insight into the functional activity of monocytes against a heat shock protein (HSP60). METHODS: Chemokine and pattern recognition receptors in monocyte subsets obtained from peripheral blood of acute and chronic coronary artery disease patients and controls were quantified by flow cytometry. Furthermore, monocytes from healthy controls were stimulated in vitro with HSP60, and the cytokines produced by them were evaluated by flow cytometry. RESULTS: Eighteen controls (C), 34 individuals with risk factors for cardiovascular disease (RF), 32 patients with stable angina (SA), and 16 patients with unstable angina (UA) were enrolled in the study. The absolute count of intermediate monocytes was found to be increased in patients of the UA group; high frequencies of the chemokine receptors CCR2, CCR5, and CX3CR1 were also observed in this subpopulation. Moreover, the pattern recognition receptors TLR2 and TLR4 were more frequent in intermediate monocytes from the UA group. Furthermore, the intermediate monocytes from healthy individuals produced IL-12p70 after stimulation with HSP60. CONCLUSIONS: Our results show that intermediate monocytes of UA patients exhibited an enhanced expression of the receptors involved in the recognition of damage-associated molecular patterns (DAMPs) and enhancement of the migratory function. Hence, they might contribute to the propagation and progression of inflammation observed in atherosclerosis, especially in the acute setting.