Time-dependent Course Research Articles

Relationship Between Quantitative Tracheal Geometry and Clinical Course in Various Types of Vascular Ring.

To investigate the relationship between quantitative tracheal geometry and clinical course among various types of vascular ring and to identify factors correlating with symptom presentation. Patients with vascular ring diagnosed between April 2010 and December 2022 were included. All the patients were classified as type 1 (complete double aortic arch); type 2 (incomplete double aortic arch); type 3 (circumflex aorta); type 4 (right aortic arch and aberrant left subclavian artery with a left retroesophageal diverticulum of Kommerell); or type 5 (mirror-imaged right aortic arch with retroesophageal aortic diverticulum). Their clinical characteristics and quantitative variables on computed tomography (CT) were compared. Of the 50 patients enrolled, those with type 1 tended to have a smaller luminal tracheal diameter at the level of the ring. The median symptom-free survival time was shortest in this group (16.0days [95% confidence interval (CI): 9.4-51.0]), followed by type 3 (138.0days [95% CI: 0.0-851.4]). Type 1 (hazard ratio [HR]: 9.0; 95% CI: 2.3-35.0; P = 0.001), type 3 (HR: 4.2; 95% CI: 1.4-13.2; P = 0.013), and the percentage of tracheal narrowing in the anteroposterior projection (HR: 0.87; 95% CI: 0.78-0.96; P = 0.008) were significantly associated with symptom presentation in the time-dependent course. The aortic arch encircling the entire circumference in type 1 and high-pressure vasculature in front of the vertebral body in types 1 and 3 may contribute to raising the risk of symptom presentation.

Abstract LB063: Anti-tumor activity in preclinical models utilizing a conditional bispecific redirected activation molecule (COBRA) targeting Her2

Abstract Among strategies to recruit cytotoxic T-cells into the tumor micro-environment (TME) are the use of T-cell engager molecules. One such therapeutic modality are molecules that recognize specific tumor associated antigens (TAA) but are activated preferentially in the TME. Conditional Bispecific Redirected Activation molecules (COBRA) are designed to be administered as a prodrug, and cleaved via matrix metalloproteinase to engage with both a tumor TAA and CD3 (Panachi, et.al. MAbs 2020 12(1) 1792130). In this study, we sought to determine the preclinical efficacy of a COBRA molecule targeting the Her2 receptor. Sub-cutaneous xenograft models (SCID mice using adoptive T-cell transfer) were utilized representing various levels of the TAA (HT-55, SNU-16, JIMT-1, and HCC827) to measure both efficacy and mechanism of action (T-cell extravasation). The COBRA molecule was dosed at 0.03, 0.1, 0.3, and 1 mg/kg using a Q3dx7 schedule. A non-cleavable COBRA molecule with the Her2 TAA was included as a control at 1 mg/kg. Efficacy was determined by caliper measurements of sub-cutaneous tumor size twice per week after dosing, and T-cell extravasation into the TME was measured by immunohistochemistry (IHC) at days 10, 19, and termination. IHC data was quantified using HALO imaging software. In our study, we measured dose-dependent tumor regression and/or stasis in all models tested. No anti-tumor activity was measured after dosing with the non-cleavable COBRA molecule. T-cell extravasation as measured by IHC and Halo analysis followed a dose and time dependent course. Comparison of Day 19 T-cell extravasation (one day after the last dose) showed a linear relationship to TAA expression. Our data indicate that treatment with a COBRA molecule in preclinical models with a Her2 TAA results in anti-tumor activity as measured by tumor stasis/regression, and exhibit the expected mechanism of action as evaluated by T-cell extravasation into the TME. Citation Format: Bradley Stringer, Johara Chouitar, Jacqualine Cerbone, Sarah Fortin, Alina Ainbinder, Cassie Kysilovsky, Brittany Scott, Antara Banerjee. Anti-tumor activity in preclinical models utilizing a conditional bispecific redirected activation molecule (COBRA) targeting Her2 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB063.

Pathologic characteristics of human venous in-stent stenosis and stent occlusion

ObjectiveThe objective of this study was to determine the pathologic features of venous in-stent stenosis over time occurring in bare metal stents. MethodsEndovascular biopsy samples were obtained prospectively from venous bare metal stents implanted in 2009 through 2018. All samples were formalin-fixed, paraffin-embedded and stained with hematoxylin and eosin. Samples were examined by a cardiovascular pathologist to estimate the amount of its constituent components, which included fresh thrombus, organizing thrombus, old thrombus, or diffuse intimal thickening (DIT), and pathologic features including calcification, neovascularization, and hemosiderin deposition. This pathologic characterization was correlated with time following stent implantation to discern time-dependence of pathologic evolution of in-stent stenosis using both descriptive statistics and binary logistic regression. ResultsA total of 254 post-stent venograms with biopsies of in-stent contents from 148 unique patients were studied. Fresh thrombus and organizing thrombus were both present across all studied time intervals. Old thrombus was seen beginning at approximately 2 weeks and DIT at approximately 4 weeks. Calcification was a rare finding encountered at later time intervals. The prevalence of each component varied with time: the probability of encountering fresh thrombus (P = .010) and organizing thrombus (P = .008) decreased over time. By contrast, the probability of finding DIT (P = .002) and calcifications (P < .001) increased over time. The presence of old thrombus, neovascularization, or hemosiderin did not demonstrate time dependence. Diffuse intimal thickening was frequently seen along with organizing thrombus as well as independently, and in many instances, these two features were directly merged. ConclusionsThe evolution of human venous in-stent restenosis appears to follow a time-dependent course, suggesting a possible progressive evolution from fresh and organizing thrombus to DIT. Contrasted with the literature on arterial in-stent restenosis, vein in-stent restenosis may have an increased thrombus prevalence (both organizing and old thrombus). DIT is a primary feature of late in-stent stenosis and may explain in part why many of these lesions may not respond to thrombolytic or anticoagulant treatment alone.

The Minimally Clinically Important Difference and Substantial Clinical Benefit in Anterior Cruciate Ligament Reconstruction: A Time-to-Achievement Analysis.

This study examined the time-dependent course of the minimally clinically important difference (MCID) and the substantial clinical benefit (SCB) achievement for International Knee Documentation Committee (IKDC) and Knee Injury and Osteoarthritis Outcome Score (KOOS) subscales following anterior cruciate ligament reconstruction (ACLR). A prospective institutional registry was queried for patients receiving ACLR. The patient-reported outcome measures (PROMs) of interest included the IKDC score and KOOS sub-scales. One hundred forty-three patients (mean±SD age, 30.86±12.78 years; mean±SD body mass index, 25.51±4.64 kg/m2) were included in the analysis. Threshold values for the MCID/SCB were 18.9 of 29.6 on IKDC score, 15.7 of 25.3 on KOOS Symptom, 11.9 of 15.5 on KOOS Pain, 13.3 of 20.0 on KOOS ADL, 25.9 of 35.8 on KOOS Quality of Life (QoL), and 27.0 of 43.0 on KOOS Sport (area under the curve, 0.74-0.91). Overall, MCID achievement rates increased from 28.0% to 42.7% at 6 months to 41.9% to 70.8% at 12 months. Achievement rates of SCB increased from 16.1% to 30.4% at 6 months to 29.3% to 51.8% at 12 months. Statistically significant increases in MCID achievement (chi-square=47.95-79.36, all P<.001) and SCB achievement (chi-square=26.02-53.24, all P<.001) occurred from preoperative to 6-month time points across PROMs. From 6-month to 12-month time points, increases in MCID achievement occurred on IKDC score and KOOS QoL (chi-square=5.53-15.11, P<.001-.009). Statistically significant increases in MCID and SCB achievement occurred from preoperative to 6-month time points across IKDC score and KOOS subscales; however, statistically significant increases in achievement rates from 6 months to 1 year occurred on IKDC score, KOOS QoL, and KOOS Sport. This study underlines the importance of considering psychological factors and rehabilitative milestones when examining the achievement MCID and SCB after ACLR. [Orthopedics. 2021;44(5):299-305.].

Time-dependent shift of the relationship between systolic blood pressure and clinical outcome in acute lacunar stroke.

This study explores the relationship between systolic blood pressure during the acute period of stroke and poor functional outcome in patients with lacunar stroke, emphasizing a possible time-dependent nature of the relationship. Based on multicenter stroke registry data, patients with acute lacunar stroke were identified, and systolic blood pressure levels at eight time points (1, 2, 4, 8, 16, 24, 48, and 72 h) after stroke onset were extracted at the 15 participating centers in South Korea. Poor functional outcome was defined as a three-month modified Rankin Scale score of 2-6. Non-linear restricted cubic spline and linear models were used for assessing the relationship at each time point. A total of 97,349 systolic blood pressure measurements of 3,042 patients were analyzed. At 1 h and 4 h after stroke onset, the relationship between systolic blood pressure and poor outcome showed a non-linear association. The nadir was 155 mmHg at 1 h and 124 mmHg at 4 h. After this time period, a higher systolic blood pressure was associated with a poorer outcome. This linear relationship weakened over time after 12 h (coefficient values of the adjusted linear models: 0.0081 at 8 h, 0.0105 at 12 h, 0.0102 at 24 h, 0.0082 at 48 h, 0.0054 at 72 h). Based on our cohort of large number of lacunar stroke patients, our findings suggest that systolic blood pressure levels may follow a time-dependent course in relation to prediction of outcome at three months. The findings may be valuable for hypothesis generation in association with clinical trial development for blood pressure control in acute stroke patients.

Factors Affecting Patient Outcomes in Acute Appendicitis in Rural Areas: An Observational Cohort Study

The most common surgical emergency both in developed and non-developed countries is acute appendicitis and it has a time-dependent clinical course. In this observational cohort study, we aim to investigate the factors affecting patient outcomes in acute appendicitis at a rural hospital. This observational cohort study was held between November 2012 and May 2014 at a rural hospital. Patients' pre-operative, perioperative, and post-operative data were collected prospectively. Patients were followed-up for 12-months. A total of 151 patients were recorded. Factors significantly associated with complicated cases (abscess/perforation) were referral region as remote towns (OR:7.94, 95%CI [3.46-18.23]; p < 0.001), referral season as winter (OR:2.47, %95CI [1.14-5.36]; p = 0.022), pre-operative hospital delay (OR:6.52, 95%CI [3.49-12.20]; p < 0.001), and duration of referral (OR:1.01, 95%CI [1.00-1.01]; p < 0.001). In the multivariate analysis, only pre-operative hospital delay remained as a significant factor (OR:5.87, 95%CI [2.85 - 12.07]; p < 0.001). Factors affecting length of hospital stay (LoHS) were referral region as remote towns (95%CI, β = 3.10 [2.28-3.93], t = 1.91; p < 0.001), abscess/perforation (95%CI, β = 4.70 [4.04-5.36], t = 14.05; p < 0.001), pre-operative hospital delay (95%CI, β = 1.25 [0.87-1.62], t = 6.58; p < 0.001), and duration of referral (95%CI, β = 0.011 [0.01-0.14], t = 7.34; p < 0.001). In the multivariate analysis, all four factors stayed significant. The rate of complicated appendicitis was significantly high in winter than other seasons for patients referring from remote towns (75% vs 33%, p < 0.001). This observational cohort study is the only study specifically focused on the effect of season and region on abscess/perforation rates, LoHS, and accessibility to hospital in patients with acute appendicitis.

Time Course of Metabolomic Alterations in Cerebrospinal Fluid After Aneurysmal Subarachnoid Hemorrhage.

Object: The aim of this study was to investigate metabolite levels in cerebrospinal fluid (CSF) in their time-dependent course after aneurysmal subarachnoid hemorrhage (aSAH) comparing them to patients harboring unruptured intracranial aneurysms.Methods: Eighty CSF samples of 16 patients were analyzed. The study population included patients undergoing endovascular/microsurgical treatment of ruptured intracranial aneurysms (n = 8), which were assessed for 9 days after aSAH. Control samples were collected from the basal cisterns in elective aneurysm surgery (n = 8). The CSF samples were consecutively collected with extraventricular drain (EVD) placement/intraoperatively, 6 h later, and daily thereafter (day 1–9). The endogenous metabolites were analyzed with a targeted quantitative and quality controlled metabolomics approach using the AbsoluteIDQ®p180Kit. Differences inbetween timepoints and compared to the control group were evaluated.Results: Numerous alterations of amino acid (AA) levels were detected within the first hours after bleeding. The highest mean concentrations occurred 1 week after aSAH. AA levels were continuously increasing over time starting 6 h after aSAH. Taurine concentration was highest briefly after aSAH starting to decrease already after 6 h (vs. day 1–9, p = 0.02). The levels of sphingomyelins/ phosphatidylcholines/ lysophosphatidylcholines/mono-unsaturated fatty acid chain were highly elevated on day 0 (compared to other timepoints or controls, p < 0.01) and decreased over the next several days to concentrations comparable to the control group. Carnitine concentrations were decreased after SAH (vs. day 7, p < 0.01), while they recovered within the next day. The Fischer ratio of branched-chain AA to aromatic AA was lowest immediately after SAH and increased in 7 days (p < 0.001).Conclusion: AA levels in CSF increased overtime and often differ from patients without SAH. There was a peak concentration of structural AA within the first 6 h after aneurysm treatment. Time-dependent alterations of CSF metabolites and compounds may elucidate pathophysiological processes after aSAH, providing potential predictors assessed non-invasively by routine lab testing.

Efficient antimony removal by self-assembled core-shell nanocomposite of Co3O4@rGO and the analysis of its adsorption mechanism

Co3O4@rGO were facilely prepared by template free self-assemble in this study. The morphology of Co3O4@rGO was actiniaria-like core-shell structural nanocomposites. The formation mechanism of Co3O4@rGO core-shell nanocomposite was discussed according to its significant time-dependent morphology evolution course. To evaluate the application potential of Co3O4@rGO, its adsorption performance toward highly toxic antimony ions were studied. The Co3O4@rGO nanocomposite exhibit high anti-interference ability and high adsorption ability. The maximum adsorption capacities towards Sb(III) and Sb(V) are 151.04 and 165.51 mg/g, respectively. River water samples containing antimony violating the limit were used to evaluate the practical application of Co3O4@rGO, and high performance was achieved. The EU and China limits for antimony in drinking water can be met by using mesoporous Co3O4@rGO treating the actual river water samples with original antimony concentration lower than 50 μg/L. Adsorption isotherm, adsorption kinetics, pH and co-existing ions effects were also studied in details. The results indicate that mesoporous Co3O4@rGO is an excellent adsorbent for antimony removal. Mesoporous Co3O4@rGO nanocomposite is a potential candidate for antimony removal from waste water.

Prospective observational evaluation of radiation-induced late taste impairment kinetics in oropharyngeal cancer patients: Potential for improvement over time?

Background and purposeTaste impairment is a common radiation-induced toxicity in head and neck cancer (HNC) patients acutely. However, data on the potential for recovery and the time dependent course of late taste impairment are limited. Materials and methodsAs part of an IRB-approved observational prospective study, HNC patients underwent serial surveys including the MD Anderson Symptom Inventory - Head and Neck module (MDASI-HN). For our analysis, we extracted MDASI-HN taste item results from oropharyngeal cancer patients treated with intensity-modulated radiotherapy or volumetric modulated arc therapy and at least two taste assessments after ≥1 year from end of radiotherapy (RT). Results1214 MDASI taste items from 326 patients between 1 and 13 years post-RT were included. Median prescribed dose to the high-dose clinical target volume (CTV1) was 66.0 Gy, with 180 patients (55%) receiving chemotherapy. Taste markedly improved in the first years from end of RT, but plateaued after year 5. In patients with taste assessment in subsequent years, a significant reduction in taste impairment was found from the second to the third year (p = 0.001) and tended towards significance from the third to the fourth year (p = 0.058). Multivariate analysis revealed treatment site as significant factor in the sixth year from RT and CTV1 dose and age in the seventh year. ConclusionRadiation-induced taste impairment may improve over an extended time interval, but becomes relatively stable from year 5 post-RT. Direct characterization of RT-induced taste impairment and the calculation of normal tissue complication probability should include consideration of the time-dependent course in taste recovery.

Clinical and structural aspects of tracheal stenosis and a novel embryological hypothesis of left pulmonary artery sling.

To identify the imaging features peculiar to congenital tracheal stenosis (CTS) complicated with left pulmonary artery sling (LPAS) with the aim of presenting a hypothesis of tracheal stenosis embryology in LPAS. We retrospectively reviewed CTS patients (with complete cartilaginous rings) admitted between April 2010 and July 2018. All the patients were classified into the LPAS or non-LPAS group, and their clinical characteristics and qualitative variables on computed tomography (CT) imaging were compared. Of the 72 patients enrolled, 61 had bilateral lungs. Among the bilateral lung patients, 26 (43%) had LPAS. The tracheal bifurcation was significantly deeper, the stenotic region was longer, and the bronchial angle (especially in the right) was wider, in the LPAS group. The cut-off values for the thoracic vertebral level at the tracheal bifurcation (>4.8), subcarinal angle (>118.1), and right bronchial angle (>61.9) were useful for diagnosing suspected cases of LPAS. In the time-dependent course, LPAS complicated with a congenital heart defect was a statistically significant risk factor of respiratory symptoms (hazard ratio, 3.01; 95% confidence interval, 1.23-7.37; P = .02). The CT findings described here should immediately raise suspicion of LPAS on chest X-ray and also suggest tracheal "squeezing and milking" by the surrounding vessels in the embryo. Patients with LPAS complicated with a heart defect should be followed carefully to determine the optimal timing of intervention.

Monitoring and Process Control of Anaerobic Digestion Plants

AbstractNo abstract.

Severe acute stent malapposition follow-up: 3-month and 12-month serial quantitative analyses by optical coherence tomography

BackgroundOptical coherence tomography (OCT) was used to assess serial changes in severe acute stent malapposition (ASM) after drug-eluting stent (DES) implantation. MethodsThe maximal depth and axial lengths of ASM after DES implantation were serially quantified at percutaneous coronary intervention (PCI), and at 3 and 12-month follow-up, for 100 lesions in 96 patients. Severe ASM was defined as a maximal malapposed depth ≥400 μm or maximal malapposed axial length ≥1 mm. ResultsOf the 100 lesions, 23 lesions (23%) had a severe ASM depth at PCI. At 3 months, the maximal depth decreased to <400 μm in 12 of 23 lesions (52%). At 12 months, the maximal depth further decreased to <400 μm in 8 of the remaining 11 lesions (73%). Similarly, of 53 lesions (53%) with a severe ASM length at PCI, the maximal length decreased to 0 mm in 26 (49%) but remained severe in 17 lesions (32%) at 3 months. At 12 months, 9 of the 17 remaining lesions (53%) further decreased to 0 mm. The cut-off values for the maximal malapposed depth and length to predict the absence of stent malapposition at 12 months were 565 μm at PCI and 165 μm at 3 months, and were 2.7 mm at PCI and 0.1 mm at 3 months, respectively. ConclusionHalf of the severe ASM cases resolved within 3 months, and another half resolved during 3–12 months of follow-up. Our findings provide a better understanding of the time-dependent natural course of severe ASM using OCT.

Time-dependent course of gastric ulcer healing and molecular markers profile modulated by increased gastric mucosal content of carbon monoxide released from its pharmacological donor

Background and purposeBesides hydrogen sulfide (H2S) and nitric oxide (NO), carbon monoxide (CO) contributes to the maintenance of gastric mucosal integrity. We investigated increased CO bioavailability effects on time-dependent dynamics of gastric ulcer healing mediated by particular growth factors, anti-inflammatory and molecular pathways. Experimental approachWistar rats with gastric ulcers induced by serosal acetic acid application (day 0) were treated i.g. throughout 3, 6 or 14 days with vehicle or CO-releasing tricarbonyldichlororuthenium (II) dimer (CORM-2, 2.5 mg/kg). Gross and microscopic alterations in gastric ulcer size and gastric blood flow (GBF) at ulcer margin were determined by planimetry, histology and laser flowmetry, respectively. Gastric mRNA/protein expressions of platelet derived growth factors (PDGFA-D), insulin-like growth factor (IGF-1), epidermal growth factor (EGF), hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGFA) and their receptors, heme oxygenases (HMOX), nuclear factor (erythroid-derived 2)-like 2 (Nrf-2), cyclooxygenase (COX-2), hypoxia inducible factor (HIF)-1α, anti-inflammatory annexin-1 and transforming growth factor (TGF-β1) were assessed by real-time PCR or Western blot. TGF-β1-3 and IL-10 plasma concentration were measured using Luminex platform. Prostaglandin E2 content at ulcer margin was assessed by ELISA. Key resultsCORM-2 decreased ulcer area and increased GBF after 6 and 14 days of treatment comparing to vehicle. CO donor upregulated HGF, HGFr, VEGFR1, VEGFR2, TGF-β1, annexin-1 and maintained increased IGF-1, PDGFC and EGF expression at various time-intervals of ulcer healing. TGF-β3 and IL-10 plasma concentration were significantly increased after COMR-2 vs. vehicle. ConclusionsCO time-dependently accelerates gastric ulcer healing and raises GBF at ulcer margin by mechanism involving subsequent upregulation of anti-inflammatory, growth promoting and angiogenic factors response, not observed physiologically.

Blockade of NEAT1 represses inflammation response and lipid uptake via modulating miR-342-3p in human macrophages THP-1 cells.

Atherosclerosis has been recognized as a chronic inflammation process induced by lipid of the vessel wall. Oxidized low-density lipoprotein (ox-LDL) can drive atherosclerosis progression involving macrophages. Recently, long noncoding RNAs (lncRNAs) have been reported to play critical roles in atherosclerosis development. In our current study, we focused on the biological roles of lncRNA NEAT1 in atherosclerosis progress. Here, we found that ox-LDL was able to trigger human macrophages THP-1 cells, a human monocytic cell line, apoptosis in a dose-dependent and time-dependent course. In addition, we observed that NEAT1 was significantly increased in THP-1 cells incubated with ox-LDL and meanwhile miR-342-3p was greatly decreased. Then, NEAT1 was silenced by transfection of small interfering RNA (siRNA) of NEAT1 into THP-1 cells. As exhibited, CD36, oil-red staining levels, total cholesterol (TC), total cholesterol (TG) levels and THP-1 cell apoptosis were obviously repressed by knockdown of NEAT1. Furthermore, inhibition of NEAT1 contributed to the repression of inflammation in vitro. Interleukin 6 (IL-6), IL-1β, cyclooxygenase-2 (COX-2) and tumour necrosis factor-alpha (TNF-α) protein levels were remarkably depressed by NEAT1 siRNA in THP-1 cells. By using bioinformatics analysis, miR-342-3p was predicted as a downstream target of NEAT1 and the correlation between them was confirmed in our study. Moreover, overexpression of miR-342-3p could also greatly suppress inflammation response and lipid uptake in THP-1 cells. Knockdown of NEAT1 and miR-342-3p mimics inhibited lipid uptake in THP-1 cells. In conclusion, we implied that blockade of NEAT1 repressed inflammation response through modulating miR-342-3p in human macrophages THP-1 cells and NEAT1 may offer a promising strategy to treat atherosclerotic cardiovascular diseases.

Gastrointestinal digestion of hazelnut allergens on molecular level: Elucidation of degradation kinetics and resistant immunoactive peptides using mass spectrometry

Allergy to hazelnut seeds ranks among the most prevalent food allergies in Europe. The aim of this study was to elucidate the gastrointestinal digestion of hazelnut allergens on molecular level. Hazelnut flour was digested in vitro following the Infogest consensus model. For six allergenic proteins, the time-dependent course of digestion was monitored by SDS-PAGE and HPLC-MS/MS, and degradation products were characterized by a bottom-up proteomics approach. Depending on the molecular structure, a specific biochemical fate was observed for each allergen, and degradation kinetics were traced back to the peptide level. 1183peptides were characterized, including 130 peptides that carry known IgE-binding epitopes and may represent sensitizers for hazelnut allergy. The kinetics of peptide formation and degradation were determined by label-free quantification and follow a complex multi-stage mechanism. We present a comprehensive survey on the gastrointestinal digestion of a relevant allergenic food on level of the peptidome, including the first systematic characterization and quantification of degradation products. This provides information on the differential resistance of plant food allergens and their structural elements undergoing digestion and forms the basis for a deeper understanding of the molecular principles responsible for sensitization to food allergy.

Biotransformation in the zebrafish embryo –temporal gene transcription changes of cytochrome P450 enzymes and internal exposure dynamics of the AhR binding xenobiotic benz[a]anthracene

Not much is known about the biotransformation capability of zebrafish (Danio rerio) embryos. For understanding possible toxicity differences to adult fish, it might be crucial to understand the biotransformation of chemicals in zebrafish embryos i.e. as part of toxicokinetics.The biotransformation capabilities were analysed for two different stages of zebrafish embryos in conjunction with the internal concentrations of a xenobiotic. Zebrafish embryos of the late cleavage/early blastula period (2–26 hpf) and the early pharyngula period (26–50 hpf) were exposed for 24 h to the AhR binding compound benz[a]anthracene (BaA). Time dependent changes in cyp transcription (cyp1a, cyp1b1, cyp1c1 and cyp1c2) as well as concentration & time-dependent courses of BaA in the fish embryo and the exposure medium were analysed. Additionally, the CYP mediated formation of biotransformation products was investigated.We found correlations between transcriptional responses and the internal concentration for both exposure types. These correlations were depending on the start of the exposure i.e. the age of the exposed embryo. While no significant induction of the examined gene transcripts was observed in the first 12 h of exposure beginning in the blastula period a correlation was apparent when exposure started later i.e. in the pharyngula period. A significant induction of cyp1a was detected already after 1.5 h of BaA exposure. Gene transcripts for cyp1b1, cyp1c1 and cyp1c2 showed expressions distinctly different from cyp1a and were, in general, less inducible by BaA in both exposure windows. The toxicokinetic analysis showed that the biotransformation capability was fivefold higher in the older fish embryos. Biotransformation products of phase I reactions were found between 32 hpf and 50 hpf and were tentatively identified as benz[a]anthracene-phenol and benz[a]anthracene-dihydrodiol-epoxide.In conclusion, not only duration but also onset of exposure in relation to the developmental stage of zebrafish embryos is important in the analysis and interpretation of effects due to different biotransformation capabilities.

Spinal Cord Injury Pain Instrument and painDETECT questionnaire: Convergent construct validity in individuals with Spinal Cord Injury.

Neuropathic pain (NeuP) is a frequent sequel of spinal cord injury (SCI). The SCI Pain Instrument (SCIPI) was developed as a SCI-specific NeuP screening tool. A preliminary validation reported encouraging results requiring further evaluation in terms of psychometric properties. The painDETECT questionnaire (PDQ), a commonly applied NeuP assessment tool, was primarily validated in German, but not specifically developed for SCI and not yet validated according to current diagnostic guidelines. We aimed to provide convergent construct validity and to identify the optimal item combination for the SCIPI. The PDQ was re-evaluated according to current guidelines with respect to SCI-related NeuP. Prospective monocentric study. Subjects received a neurological examination according to the International Standards for Neurological Classification of SCI. After linguistic validation of the SCIPI, the IASP-grading system served as reference to diagnose NeuP, accompanied by the PDQ after its re-evaluation as binary classifier. Statistics were evaluated through ROC-analysis, with the area under the ROC curve (AUROC) as optimality criterion. The SCIPI was refined by systematic item permutation. Eighty-eight individuals were assessed with the German SCIPI. Of 127 possible combinations, a 4-item-SCIPI (cut-off-score=1.5/sensitivity=0.864/specificity=0.839) was identified as most reasonable. The SCIPI showed a strong correlation (rsp =0.76) with PDQ. ROC-analysis of SCIPI/PDQ (AUROC=0.877) revealed comparable results to SCIPI/IASP (AUROC=0.916). ROC-analysis of PDQ/IASP delivered a score threshold of 10.5 (sensitivity=0.727/specificity=0.903). The SCIPI is a valid easy-to-apply NeuP screening tool in SCI. The PDQ is recommended as complementary NeuP assessment tool in SCI, e.g. to monitor pain severity and/or its time-dependent course. In SCI-related pain, both SCIPI and PainDETECT show strong convergent construct validity versus the current IASP-grading system. SCIPI is now optimized from a 7-item to an easy-to-apply 4-item screening tool in German and English. We provided evidence that the scope for PainDETECT can be expanded to individuals with SCI.

Regional glucose hypometabolic spread within the primary motor cortex is associated with amyotrophic lateral sclerosis disease progression: A fluoro-deoxyglucose positron emission tomography study.

ObjectiveHere we investigate the process of neurodegeneration in amyotrophic lateral sclerosis (ALS). The relationship between the cortical field spreading of glucose metabolic decreases in the primary motor cortex (PMC) and the progression of corresponding extremity dysfunction was evaluated using [18F] fluoro-deoxyglucose (FDG)-positron emission tomography (PET).MethodsPatients with ALS underwent [18F] FDG-PET and the resulting datasets were individually contrasted against healthy controls using the NEUROSTAT software. The extent ratio was defined as the proportion of pixels with a significant Z-score decrease within regions of the primary motor cortex (precentral gyrus or paracentral lobule) opposite to the impaired upper extremities (UEs) or lower extremities (LEs), respectively. Clinical symptoms in all extremities were assessed using an upper motor neuron (UMN) score and the MRC (Medical Research Council) sum score upon physical examination. Cross-sectional correlations were analysed between clinical symptoms, the duration of these symptoms, and the extent ratio.ResultsNineteen regions of the primary motor cortex corresponding to symptomatic limb in 10 participants were evaluated. In the corresponding region of the primary motor cortex, the extent ratio increased (same meaning as hypometabolic area spread) in association with symptom duration (rs = 0.5, p = 0.03). Neither UMN nor lower motor neuron (LMN) scores were correlated with symptom duration. Three out of 19 impaired regions did not show upper motor neuron (UMN) signs upon physical examination. The extent ratio and UMN score-controlled symptom duration were partially correlated (rs = 0.5, p = 0.05).ConclusionsIn patients with ALS, glucose metabolism decreased in the impaired side of the primary motor cortex depending on the clinical symptom progression in the corresponding extremities, regardless of the presence of clinical UMN signs. A decrement in glucose metabolism on FDG-PET corresponding to symptoms in the primary motor cortex might be an indicator of the time-dependent course of ALS neurodegeneration.

Dynamics of metal-humate complexation equilibria as revealed by isotope exchange studies – a matter of concentration and time

Complexation with dissolved humic matter can be crucial in controlling the mobility of toxic or radioactive contaminant metals. For speciation and transport modelling, a dynamic equilibrium process is commonly assumed, where association and dissociation run permanently. This is, however, questionable in view of reported observations of a growing resistance to dissociation over time. In this study, the isotope exchange principle was employed to gain direct insight into the dynamics of the complexation equilibrium, including kinetic inertisation phenomena.Terbium(III), an analogue of trivalent actinides, was used as a representative of higher-valent metals. Isotherms of binding to (flocculated) humic acid, determined by means of 160Tb as a radiotracer, were found to be identical regardless of whether the radioisotope was introduced together with the bulk of stable 159Tb or subsequently after pre-equilibration for up to 3months. Consequently, there is a permanent exchange of free and humic-bound Tb since all available binding sites are occupied in the plateau region of the isotherm. The existence of a dynamic equilibrium was thus evidenced. There was no indication of an inertisation under these experimental conditions.If the small amount of 160Tb was introduced prior to saturation with 159Tb, the expected partial desorption of 160Tb occurred at much lower rates than observed for the equilibration process in the reverse procedure. In addition, the rates decreased with time of pre-equilibration. Inertisation phenomena are thus confined to the stronger sites of humic molecules (occupied at low metal concentrations). Analysing the time-dependent course of isotope exchange according to first-order kinetics indicated that up to 3years are needed to attain equilibrium. Since, however, metal–humic interaction remains reversible, exchange of metals between humic carriers and mineral surfaces cannot be neglected on the long time scale to be considered in predictive transport models.

Psychogenic Stroke Mimics and Thrombolysis: Ready to Take the Risk?

Stroke is one of the leading cause of disability and death all over the world with a time dependent course and prognosis; during ages different new advances in acute treatment have changed the emergency approach of this cerebrovascular diseases. More rapidly the symptoms are recognized and more prompt thrombolysis treatment may consent vessel recanalization and neurological deficit regression. Early diagnosis is mandatory; unfortunately conditions that can mimic a focal neurological deficit are common in the acute stage. Stroke mimics can account for up to 5% of all acute stroke presentations. Mimics are more frequent in those under 50 years of age, without any particular medical history. The rate of false-positive diagnoses of ischemic stroke labeled “stroke mimic” ranges from 1.3% to 25% in patients not treated with thrombolysis, among all mimics “psychogenic stroke” are increasing in the last decades. In the emergency department is quite difficult to discriminate real stroke from psychogenic stroke mimic but physicians have to decide in a short period which treatment start quickly. Our aim is to review the neurological signs in the rapid short examination in the emergency in order to define stroke mimic from real stroke and the most appropriate approach.