Miracle-dz/UniFAR-FTUs huggingface dataset:
Assessment of image-derived risk factors for natural course of unruptured cerebral aneurysms.

OBJECTIVE The goal of this prospective longitudinal study was to test whether image-derived metrics can differentiate unruptured aneurysms that will become unstable (grow and/or rupture) from those that will remain stable. METHODS One hundred seventy-eight patients harboring 198 unruptured cerebral aneurysms for whom clinical observation and follow-up with imaging surveillance was recommended at 4 clinical centers were prospectively recruited into this study. Imaging data (predominantly CT angiography) at initial presentation was recorded. Computational geometry was used to estimate numerous metrics of aneurysm morphology that described the size and shape of the aneurysm. The nonlinear, finite element method was used to estimate uniform pressure-induced peak wall tension. Computational fluid dynamics was used to estimate blood flow metrics. The median follow-up period was 645 days. Longitudinal outcome data on these aneurysm patients-whether their aneurysms grew or ruptured (the unstable group) or remained unchanged (the stable group)-was documented based on follow-up at 4 years after the beginning of recruitment. RESULTS Twenty aneurysms (10.1%) grew, but none ruptured. One hundred forty-nine aneurysms (75.3%) remained stable and 29 (14.6%) were lost to follow-up. None of the metrics-including aneurysm size, nonsphericity index, peak wall tension, and low shear stress area-differentiated the stable from unstable groups with statistical significance. CONCLUSIONS The findings in this highly selected group do not support the hypothesis that image-derived metrics can predict aneurysm growth in patients who have been selected for observation and imaging surveillance. If aneurysm shape is a significant determinant of invasive versus expectant management, selection bias is a key limitation of this study.
Modulation of Tau Phosphorylation by the Kinase PKR: Implications in Alzheimer's Disease

Double‐stranded RNA dependent kinase (PKR) is a pro‐apoptotic kinase that controls protein translation. Previous studies revealed that activated PKR is increased in brains with Alzheimer's disease (AD). Glycogen Synthase Kinase Aβ (GSK‐3β) is responsible for tau phosphorylation and controls several cellular functions also including apoptosis. The goal of this work was to determine if PKR could concurrently trigger GSK‐3β activation, tau phosphorylation and apoptosis. In AD brains, both activated kinases co‐localize with phosphorylated tau in neurons. In SH‐SY5Y cell cultures, tunicamycin and Aβ1‐42 activate PKR, GSK‐3β and induce tau phosphorylation and all these processes are attenuated by PKR inhibitors or PKR siRNA. Our results demonstrate that neuronal PKR co‐localizes with GSK‐3β and tau in AD brains and is able to modulate GSK‐3β activation, tau phosphorylation and apoptosis in neuroblastoma cells exposed to tunicamycin or Aβ. PKR could represent a crucial signaling point relaying stress signals to neuronal pathways leading to cellular degeneration in AD.
Carbon dots of different composition and surface functionalization: cytotoxicity issues relevant to fluorescence cell imaging

Nanoscale carbon particles have emerged as versatile precursors for a new class of highly fluorescent nanomaterials that resemble semiconductor quantum dots. The surface-passivated fluorescent carbon nanoparticles, dubbed ‘carbon dots’, were already demonstrated for their potential optical bioimaging applications in vitro and in vivo. In this study, we conducted a systematic cytotoxicity evaluation on the carbon dots prepared by various combinations of precursor carbon nanoparticles and molecules for the particle surface functionalization. The results suggested that the cytotoxicity of carbon dots was dependent on the selection of surface passivation molecules. Those dots showing more significant cytotoxicity at higher concentrations were also evaluated for their effects on the fluorescence imaging of live cells. The implications of the results on the eventual use of carbon dots as cell imaging agents are discussed.
Cytolysin-Dependent Escape of the Bacterium from the Phagosome Is Required but Not Sufficient for Induction of the Th1 Immune Response against Listeria monocytogenes Infection: Distinct Role of Listeriolysin O Determined by Cytolysin Gene Replacement

ABSTRACT Listeria monocytogenes evades the antimicrobial mechanisms of macrophages by escaping from the phagosome into the cytosolic space via a unique cytolysin that targets the phagosomal membrane, listeriolysin O (LLO), encoded by hly. Gamma interferon (IFN-γ), which is known to play a pivotal role in the induction of Th1-dependent protective immunity in mice, appears to be produced, depending on the bacterial virulence factor. To determine whether the LLO molecule (the major virulence factor of L. monocytogenes) is indispensable or the escape of bacteria from the phagosome is sufficient to induce IFN-γ production, we first constructed an hly-deleted mutant of L. monocytogenes and then established isogenic L. monocytogenes mutants expressing LLO or ivanolysin O (ILO), encoded by ilo from Listeria ivanovii. LLO-expressing L. monocytogenes was highly capable of inducing IFN-γ production and Listeria-specific protective immunity, while the hly-deleted mutant was not. In contrast, the level of IFN-γ induced by ILO-expressing L. monocytogenes was significantly lower both in vitro and in vivo, despite the ability of this strain to escape the phagosome and the intracellular multiplication at a level equivalent to that of LLO-expressing L. monocytogenes. Only a negligible level of protective immunity was induced in mice against challenge with LLO- and ILO-expressing L. monocytogenes. These results clearly show that escape of the bacterium from the phagosome is a prerequisite but is not sufficient for the IFN-γ-dependent Th1 response against L. monocytogenes, and some distinct molecular nature of LLO is indispensable for the final induction of IFN-γ that is essentially required to generate a Th1-dependent immune response.
Relating Sensation Seeking and the von Restorff Isolation Effect

Sensation seeking was examined in a short-term memory task involving the serial recall of a 10-item list of consonants with (isolated) and without (nonisolated) a distinctively larger item in the fifth position. 126 students were given the Sensation Seeking Scale Form–V and 32 10-item lists to memorize in a 1 by 3 mixed design. Sensation seeking was a between-subject factor and Blocks (Trials 1–16 and 17–32), Isolation (isolated and nonisolated), and Duration (2 sec. and 10 sec.) were within-subject factors. Generally nonisolated lists and the larger letters (the von Restorff Isolation Effect) were better recalled, with the latter being stronger at the shorter duration. Only the high sensation-seeking group showed a Blocks effect for lists with an isolated item such that there was a greater number of items correct per list in Block 1 than in Block 2. This finding is consistent with the argument that higher scores on sensation seeking are associated with greater cortical arousal and better memory for newness and change. Students with high sensation-seeking scores showed superior memory for the isolated list when it contained an isolate if allowed more processing time. It is argued that high sensation-seeking scores were associated with more effective transfer of items from shorter to longer-term memory. A rapid nontime-dependent perceptual process was used to explain the isolation effect. The poorer overall list performance for the lists with the isolate was explained in terms of the intense nature of the isolate.
Complexes between cationic pyridylphenylene dendrimers and ovine prion protein: do hydrophobic interactions matter?

Here, the interactions between cationic pyridylphenylene dendrimers of the second, third and fourth generations and full-length ovine prion protein (PrP) were studied using isothermal titration calorimetry (ITC), dynamic light scattering (DLS), and tryptophan fluorescence measurements. A molecular dynamic (MD) study was performed to predict the most possible binding sites for the dendrimer interactions with the protein. All the dendrimers used acted as effective quenchers of fluorescence of the tryptophan residues. The quenching constants calculated according to the Stern–Volmer equation allowed us to quantitatively estimate the efficiency of the dendrimer–protein interactions. ITC data revealed the driving force of the complexation: electrostatic interactions assisted by hydrophobic interactions. Due to the latter, the dendrimer and PrP form complexes which are stable towards the addition of a salt and of the oppositely charged polymer. These results allowed us to propose the mechanism and the model of the pyridylphenylene dendrimer interactions with full-length PrP.
A Highly Durable RNAi Therapeutic Inhibitor of PCSK9

BACKGROUND Inclisiran (ALN‐PCSsc) is a long‐acting RNA interference (RNAi) therapeutic agent that inhibits the synthesis of proprotein convertase subtilisin–kexin type 9 (PCSK9), a target for the lowering of low‐density lipoprotein (LDL) cholesterol. METHODS In this phase 1 trial, we randomly assigned healthy volunteers with an LDL cholesterol level of at least 100 mg per deciliter in a 3:1 ratio to receive a subcutaneous injection of inclisiran or placebo in either a single‐ascending‐dose phase (at a dose of 25, 100, 300, 500, or 800 mg) or a multiple‐dose phase (125 mg weekly for four doses, 250 mg every other week for two doses, or 300 or 500 mg monthly for two doses, with or without concurrent statin therapy); each dose cohort included four to eight participants. Safety, the side‐effect profile, and pharmacodynamic measures (PCSK9 level, LDL cholesterol level, and exploratory lipid variables) were evaluated. RESULTS The most common adverse events were cough, musculoskeletal pain, nasopharyngitis, headache, back pain, and diarrhea. All the adverse events were mild or moderate in severity. There were no serious adverse events or discontinuations due to adverse events. There was one grade 3 elevation in the γ‐glutamyltransferase level, which was considered by the investigator to be related to statin therapy. In the single‐dose phase, inclisiran doses of 300 mg or more reduced the PCSK9 level (up to a least‐squares mean reduction of 74.5% from baseline to day 84), and doses of 100 mg or more reduced the LDL cholesterol level (up to a least‐squares mean reduction of 50.6% from baseline). Reductions in the levels of PCSK9 and LDL cholesterol were maintained at day 180 for doses of 300 mg or more. All multiple‐dose regimens reduced the levels of PCSK9 (up to a least‐squares mean reduction of 83.8% from baseline to day 84) and LDL cholesterol (up to a least‐squares mean reduction of 59.7% from baseline to day 84). CONCLUSIONS In this phase 1 trial, no serious adverse events were observed with inclisiran. Doses of 300 mg or more (in single or multiple doses) significantly reduced levels of PCSK9 and LDL cholesterol for at least 6 months. (Funded by Alnylam Pharmaceuticals and the Medicines Company; ClinicalTrials.gov number, NCT02314442.)
Lithium treatment and glucose tolerance in manic‐melancholic patients

Intravenous glucose tolerance was measured in manic‐melancholic patients given one daily lithium‐dose for relapse prevention. It was found that glucose tolerance was increased for some hours after each lithium administration. In the first week of treatment glucose disposal rate was increased up to 12 h after lithium ingestion. In long‐term treated patients glucose tolerance was increased 2 h after administration but not 12 h after.
The Cooperative Italian FLIN Study Group: prevalence and clinico-pathological features of colorectal laterally spreading tumors

Background and study aims: Laterally spreading tumors (LSTs) are increasingly recognized as important precursors of colorectal carcinoma. The clinical behavior of these large nonpolypoid lesions is still uncertain. The aim of the present study was to assess prevalence and clinico-pathological features of LSTs in a large Italian cohort of patients. Methods: The study was a subgroup analysis of a large database of patients undergoing total colonoscopy. The database originated from a multicenter cross-sectional observational study involving 80 centers throughout Italy. Results: Data from 27 400 total colonoscopies were analyzed. Precancerous lesions were detected in 5609 patients. Of these, LSTs were identified in 254 patients (4.5%; 95% confidence interval [CI] 3.5–6.2). Granular-type LSTs (G-LSTs) accounted for 83% of the cases (211/254). LSTs were predominant in the proximal colon (154, 60.6%). A total 231 lesions were endoscopically removed, with histology being available for 242. Neoplasia was confirmed in 225 lesions (93.4%) (143 low grade adenoma, 76 high grade adenoma, and six submucosal cancer). The six cases of submucosally invasive carcinoma were diagnosed in five G-LST and one nongranular LST (NG-LST). The risk of containing advanced histology was not increased in G-LST compared with NG-LST (odds ratio [OR] 1.55, 95%CI 0.73–3.27); it was significantly higher in lesions with large nodules (OR 3.09, 95%CI 1.05–9.04; P = 0.041) or depressed surface (OR 4.27, 95%CI 1.24–14.61; P = 0.021). Conclusions: LSTs represent approximately 5% of all precancerous colorectal lesions in the Italian population and are prevalent in the proximal colon. These lesions are no more likely to harbor advanced histology than similar-sized polypoid lesions. Large nodularity or depressed surface are risk factors for advanced histology.
MODELING GAMMA-RAY BURST X-RAY FLARES WITHIN THE INTERNAL SHOCK MODEL

X-ray afterglow light curves have been collected for over 400 Swift gamma-ray bursts (GRBs) with nearly half of them having X-ray flares superimposed on the regular afterglow decay. Evidence suggests that gamma-ray prompt emission and X-ray flares share a common origin and that at least some flares can only be explained by long-lasting central engine activity. We have developed a shell model code to address the question of how X-ray flares are produced within the framework of the internal shock model. The shell model creates randomized GRB explosions from a central engine with multiple shells and follows those shells as they collide, merge, and spread, producing prompt emission and X-ray flares. We pay special attention to the time history of central engine activity, internal shocks, and observed flares, but do not calculate the shock dynamics and radiation processes in detail. Using the empirical Ep–Eiso (Amati) relation with an assumed Band function spectrum for each collision and an empirical flare temporal profile, we calculate the gamma-ray (Swift/BAT band) and X-ray (Swift/XRT band) lightcurves for arbitrary central engine activity and compare the model results with the observational data. We show that the observed X-ray flare phenomenology can be explained within the internal shock model. The number, width, and occurring time of flares are then used to diagnose the central engine activity, putting constraints on the energy, ejection time, width, and number of ejected shells. We find that the observed X-ray flare time history generally reflects the time history of the central engine, which reactivates multiple times after the prompt emission phase with progressively reduced energy. The same shell model predicts an external shock X-ray afterglow component, which has a shallow decay phase due to the initial pile-up of shells onto the blast wave. However, the predicted X-ray afterglow is too bright as compared with the observed flux level, unless ϵe is as low as 10−3.
Cross-sectional study on knowledge of chronic kidney disease among medical outpatient clinic patients.

BACKGROUND Chronic kidney disease (CKD) is a major health concern worldwide. There are limited studies which look into the actual knowledge level of CKD among the general population both locally and internationally. This study aims to assess the knowledge level of CKD among patients in a secondary hospital in Malaysia. METHODS Consecutive sampling of patients attending the Medical Outpatient Clinic was performed in this crosssectional study. Respondents were given self-administered questionnaires which contain questions on demographic characteristics and knowledge on CKD. RESULTS Out of 300 respondents, 78.6% (n=236) of the respondents completed the questionnaire. Majority of respondents (73.7%, n=174) scored less than 4 out of 7 marks on knowledge on CKD. Respondents who were younger, males, having higher education status, professionals/executives and earned higher monthly income were more likely to have a higher mean knowledge score of CKD. Respondents who have heard of CKD were also significantly associated with higher mean knowledge score of CKD. CONCLUSION The study findings suggest that our Malaysian population is still inadequately informed on CKD, especially those who are at risk of developing CKD and its complications, and also among those of the lower socioeconomic group. In order for successful primary and secondary prevention of CKD, more importance should be placed on increasing awareness on CKD among these atrisk groups.
Functional effects of myoblast implantation into histoincompatible mice with or without immunosuppression.

1. The goals of this study were to evaluate the immunogenicity of myogenic cells (MCs) (1) immediately after implantation into regenerating muscles, and (2) following their maturation under initial immunosuppression. Implanted mouse soleus muscles were evaluated by isometric tension recordings in vitro followed by histological investigations on frozen sections. 2. Implantation of non‐histocompatible myoblasts into cryodamaged soleus muscles of CBA/J mice induced immune rejection which caused large and permanent deficits in muscle force: 4‐42 weeks postimplantation maximal tetanic tension was 50‐60% that of intact or regenerated cryodamaged control muscles without tendency for recovery or histological signs of muscle regeneration. Specific tension (force per unit muscle weight) was also significantly reduced. 3. On frozen sections, only 62 +/‐ 12% of the total area was desmin‐positive, that is, occupied by muscle fibres, versus 90 +/‐ 4% in regenerated and 92 +/‐ 3% in intact muscles. Also, the total number of muscle fibre profiles was significantly reduced. 4. Under immune suppression with cyclosporin A (CsA), large muscles developed within 4 weeks. Following CsA withdrawal, muscle weight and force, in addition to desmin‐positive areas on cross‐sections, gradually declined over several months despite continual regeneration, indicating retarded immune rejection. 5. Initial application of CsA for 8 weeks after implantation, instead of 4 weeks, did not result in better survival of the implants, nor did a higher initial dose of CsA (100 instead of 50 mg kg‐1 day‐1). Prolonged continuous application of a reduced dose (25 mg kg‐1 day‐1) did not prevent muscle wasting but caused an additional delay. 6. It is concluded that histoincompatible myoblasts are highly immunogenic and that immune rejection causes large and permanent muscle deficits indicating elimination of host muscle tissue. Initial transient immunosuppression protects the incompatible cells, but after withdrawal, prolonged immune rejection and retarded muscle wasting occur.
Extraneural pathologic prion protein in sporadic Creutzfeldt-Jakob disease.

BACKGROUND In patients with sporadic Creutzfeldt-Jakob disease, pathologic disease-associated prion protein (PrPSc) has been identified only in the central nervous system and olfactory-nerve tissue. Understanding the distribution of PrPSc in Creutzfeldt-Jakob disease is important for classification and diagnosis and perhaps even for prevention. METHODS We used a highly sensitive method of detection--involving the concentration of PrPSc by differential precipitation with sodium phosphotungstic acid, which increased the sensitivity of Western blot analysis by up to three orders of magnitude--to search for PrPSc in extraneural organs of 36 patients with sporadic Creutzfeldt-Jakob disease who died between 1996 and 2002. RESULTS PrPSc was present in the brain tissue of all patients. In addition, we found PrPSc in 10 of 28 spleen specimens and in 8 of 32 skeletal-muscle samples. Three patients had PrPSc in both spleen and muscle specimens. Patients with extraneural PrPSc had a significantly longer duration of disease and were more likely to have uncommon molecular variants of sporadic Creutzfeldt-Jakob disease than were patients without extraneural PrPSc. CONCLUSIONS Using sensitive techniques, we identified extraneural deposition of PrPSc in spleen and muscle samples from approximately one third of patients who died with sporadic Creutzfeldt-Jakob disease. Extraneural PrPSc appears to correlate with a long duration of disease.
Polymorphisms and pancreatic cancer risk: a meta-analysis

Increasing evidence suggests that variants of common and low-penetrance genes are involved in pancreatic cancer (PC) carcinogenesis. We undertook a meta-analysis of published studies to assess evidence regarding the risk associated with these genes. Medline, Web of Science, ProQuest, Google Scholar, and international conference proceedings were searched and citations in relevant primary and review articles were collected. The studies that we considered eligible included all reports that investigated an association between genetic polymorphisms and PC. We identified 23 studies that evaluated the risk effects on PC of common alleles for 13 gene polymorphisms. A significant association was recognized between ALDH 2*1*2 polymorphisms and PC [odds ratio (OR)=1.37, 95% confidence interval (CI)=1.07–1.75, P=0.01] based on only two studies. Although the overall results for MTHFR T677T are negative, sensitivity analysis stratified by ethnic background showed a significant association between Caucasian and MTHFR T677T polymorphisms and PC (OR=1.66, 95% CI=1.10–2.52, P=0.02). The risk for PC was higher in individuals with MTHFR C677T or TT polymorphisms and a smoking habit (OR=2.52, 95% CI=1.05–6.09, P=0.04). These findings lead us to support the hypothesis that MTHFR T677T and ALDH 2*1*2 polymorphisms may play a carcinogenetic role in PC and represent the candidates for low-penetrance susceptibility alleles identified to date. Although their genetic risks are modest, the high frequency in the population shows that they may have a considerable impact on the incidence of PC. Definite conclusions will be contingent on studies with a larger sample size that determine the risk estimates associated with other variants, gene–gene, and gene–environment interactions.