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Nanosecond pulsed electric fields (nsPEF) induce apoptotic pathways in human cancer cells. The potential therapeutic effective of nsPEF has been reported in cell lines and in xenograft animal tumor model. The present study investigated the ability of nsPEF to cause cancer cell death in vivo using carcinogen-induced animal tumor model, and the pulse duration of nsPEF was only 7 and 14 nano second (ns). An nsPEF generator as a prototype medical device was used in our studies, which is capable of delivering 7-30 nanosecond pulses at various programmable amplitudes and frequencies. Seven cutaneous squamous cell carcinoma cell lines and five other types of cancer cell lines were used to detect the effect of nsPEF in vitro. Rate of cell death in these 12 different cancer cell lines was dependent on nsPEF voltage and pulse number. To examine the effect of nsPEF in vivo, carcinogen-induced cutaneous papillomas and squamous cell carcinomas in mice were exposed to nsPEF with three pulse numbers (50, 200, and 400 pulses), two nominal electric fields (40 KV/cm and 31 KV/cm), and two pulse durations (7 ns and 14 ns). Carcinogen-induced cutaneous papillomas and squamous carcinomas were eliminated efficiently using one treatment of nsPEF with 14 ns duration pulses (33/39 = 85%), and all remaining lesions were eliminated after a 2nd treatment (6/39 = 15%). 13.5% of carcinogen-induced tumors (5 of 37) were eliminated using 7 ns duration pulses after one treatment of nsPEF. Associated with tumor lysis, expression of the anti-apoptotic proteins Bcl-xl and Bcl-2 were markedly reduced and apoptosis increased (TUNEL assay) after nsPEF treatment. nsPEF efficiently causes cell death in vitro and removes papillomas and squamous cell carcinoma in vivo from skin of mice. nsPEF has the therapeutic potential to remove human squamous carcinoma.

Well-mixed lean SI engine operation can provide improvements of the fuel economy relative to that of traditional well-mixed stoichiometric SI operation. This work examines the use of two methods for improving the stability of lean operation, namely multi-pulse transient plasma ignition and intake air preheating. These two methods are compared to standard SI operation using a conventional high-energy inductive ignition system without intake air preheating. E85 is the fuel chosen for this study. The multi-pulse transient plasma ignition system utilizes custom electronics to generate 10 kHz bursts of 10 ultra-short (12ns), high-amplitude pulses (200 A). These pulses were applied to a custom spark plug with a semi-open ignition cavity. High-speed imaging reveals that ignition in this cavity generates a turbulent jet-like early flame spread that speeds up the transition from ignition to the main combustion event. Performance testing shows that lean operation with heated intake air enables a 17% improvement of fuel economy atϕ= 0.59 for both ignition systems, relative to that of stoichiometric operation. Moreover, multi-pulse transient plasma ignition offers more stable ultra-lean operation, with IMEPnvariability less than 5% down toϕ= 0.49. The ability to operate stably at such lean conditions is attributed to a more stable flame initiation offered by both the increased charge temperature and the multi-pulse transient plasma ignition that allows a later spark timing due to the very fast transition to fully turbulent deflagration.

Nanosecond, megavolt-per-meter, pulsed electric fields induce phosphatidylserine (PS) externalization, intracellular calcium redistribution, and apoptosis in Jurkat T-lymphoblasts, without causing immediately apparent physical damage to the cells. Intracellular calcium mobilization occurs within milliseconds of pulse exposure, and membrane phospholipid translocation is observed within minutes. Pulsed cells maintain cytoplasmic membrane integrity, blocking propidium iodide and Trypan blue. Indicators of apoptosis—caspase activation and loss of mitochondrial membrane potential—appear in nanoelectropulsed cells at later times. Although a theoretical framework has been established, specific mechanisms through which external nanosecond pulsed electric fields trigger intracellular responses in actively growing cells have not yet been experimentally characterized. This report focuses on the membrane phospholipid rearrangement that appears after ultrashort pulse exposure. We present evidence that the minimum field strength required for PS externalization in actively metabolizing Jurkat cells with 7-ns pulses produces transmembrane potentials associated with increased membrane conductance when pulse widths are microseconds rather than nanoseconds. We also show that nanoelectropulse trains delivered at repetition rates from 2 to 2000 Hz have similar effects, that nanoelectropulse-induced PS externalization does not require calcium in the external medium, and that the pulse regimens used in these experiments do not cause significant intra- or extracellular Joule heating.

Nanosecond, megavolt-per-meter electric pulses cause permeabilization of cells to small molecules, programmed cell death (apoptosis) in tumor cells, and are under evaluation as a treatment for skin cancer. We use nanoelectroporation and fluorescence imaging to construct two-dimensional maps of the electric field associated with delivery of 15 ns, 10 kV pulses to monolayers of the human prostate cancer cell line PC3 from three different electrode configurations: single-needle, five-needle, and flat-cut coaxial cable. Influx of the normally impermeant fluorescent dye YO-PRO-1 serves as a sensitive indicator of membrane permeabilization. The level of fluorescence emission after pulse exposure is proportional to the applied electric field strength. Spatial electric field distributions were compared in a plane normal to the center axis and 15-20 μm from the tip of the center electrode. Measurement results agree well with models for the three electrode arrangements evaluated in this study. This live-cell method for measuring a nanosecond pulsed electric field distribution provides an operationally meaningful calibration of electrode designs for biological applications and permits visualization of the relative sensitivities of different cell types to nanoelectropulse stimulation. PACS Codes: 87.85.M-

This cross-sectional study of the general population of Telemark County, Norway, aimed to identify risk factors associated with poor asthma control as defined by the Asthma Control Test (ACT), and to determine the proportions of patients with poorly controlled asthma who had undergone spirometry, used asthma medication, or been examined by a pulmonary physician. In 2014-2015, the study recruited 326 subjects aged 16-50 years who had self-reported physician-diagnosed asthma and presence of respiratory symptoms during the previous 12 months. The clinical outcome measures were body mass index (BMI), forced vital capacity (FVC) and forced expiratory volume in one second (FEV1), fractional exhaled nitric oxide (FeNO), immunoglobulin E (IgE) in serum and serum C-reactive protein (CRP). An ACT score ≤ 19 was defined as poorly controlled asthma. Overall, 113 subjects (35%) reported poor asthma control. The odds ratios (ORs) and 95% confidence intervals (CIs) for factors associated with poorly controlled asthma were: self-reported occupational exposure to vapor, gas, dust, or fumes during the previous 12 months (OR 2.0; 95% CI 1.1-3.6), body mass index ≥ 30 kg/m2 (OR 2.2; 95% CI 1.2-4.1), female sex (OR 2.6; 95% CI 1.5-4.7), current smoking (OR 2.8; 95% CI 1.5-5.3), and past smoking (OR 2.3; 95% CI 1.3-4.0). Poor asthma control was also associated with reduced FEV1 after bronchodilation (β -3.6; 95% CI -7.0 to -0.2). Moreover, 13% of the participants with poor asthma control reported no use of asthma medication, 51% had not been assessed by a pulmonary physician, and 20% had never undergone spirometry. Because these data are cross-sectional, further studies assessing possible risk factors in general and objectively measured occupational exposure in particular are needed. However, our results suggest that there is room for improvement with regards to use of spirometry and pulmonary physician referrals when a patient's asthma is inadequately controlled.

Background and aims Biological therapy for inflammatory bowel disease is efficient in many cases but not all. The underlying molecular mechanisms behind non-response to biological therapy in inflammatory bowel disease are poorly described. Therefore, we aimed to characterize the mucosal cytokine transcript profile in non-immunogenic, non-responder patients with adequate trough level. Material and methods Patients with ulcerative colitis (UC) ( n =  21) and Crohn’s disease (CD) ( n =  12) with non-response to biological therapy (anti-tumor necrosis factor (TNF) or vedolizumab) were included. Reference groups were A: untreated patients with UC or CD at debut of disease who had severe 1-year outcome, B: patients with UC or CD treated to endoscopic remission with biological agents, and C: healthy normal controls. Mucosal transcripts of TNF, interleukin (IL)17 and IL23 were measured by reverse transcription real-time quantitative polymerase chain reaction. Results Of the non-responders, 2 out of 12 CD and 1 out of 21 UC patients needed surgery during follow-up. Of the remaining non-responding patients, 8 out of 10 CD and 12 out of 20 UC patients switched biologic treatment. The remaining 2 CD and 8 UC patients continued treatment with the same biological agent with the addition of steroids, immunomodulators (AZA/MTX) and /or local steroids/5ASA. Twelve (8 UC/4 CD) out of 20 IBD patients were still non-responders after changing biological therapy to either anti-TNF (2), vedolizumab (9) or ustekinumab (1). The transcripts of IL17, IL23 and TNF were significantly upregulated in the non-response group compared to normal controls and patients in remission. In UC, 24% of the non-responders had normal mucosal TNF transcript indicating a non-TNF mediated inflammation. No obvious differences in gene expression were observed between primary and secondary non-responders, nor between anti-TNF and vedolizumab non-responders. Conclusions Mucosal transcripts of IL17 and IL23 are highly associated with non-response to biological therapy, whereas some UC patients may also have a non-TNF mediated inflammatory pathway.

Systematic retrospective processing of previously analysed biological samples has been proven to be a valuable tool in the search for new drugs (e.g. new psychoactive substances (NPS)) and for quality assessment in clinical and forensic toxicology. In a previous study, we developed a strategy for retrospective data-analysis using a personalized library of synthetic cannabinoids, designer benzodiazepines and synthetic opioids obtained from the crowdsourced database HighResNPS (https://highresnps.com). In this study, the same strategy was employed for the compounds within the groups of NPS that were not previously included such as synthetic cathinones, phenethylamines, aminoindanes, arylalkylamines, piperazine derivates, piperidines, pyrrolidines, indolalkylamines and arylcyclohexylamines. Synthetic opioids and designer benzodiazepines, which were not part of the previous study, were also included. To enhance the effectiveness of the retrospective analysis, a predicted retention time was included for all entries. Data files from the analysis of 2186 forensic post mortem samples with an Agilent Technologies 6540 ultra-high pressure liquid chromatography quadrupole time-of-flight mass spectrometry (UHPLC-QTOF-MS) performed in the laboratory from January 2014 to December 2021 were retrospectively processed with the up-to-date library. Tentative findings were classified in two groups: The findings where MS/MS data was acquired for library match (category 1) and the less certain findings where such data lacked (category 2). Five compounds of category 1 (three synthetic cathinones and two indolalkylamines) were identified in 12 samples. Only one of the findings, 4-MEAPP (4-methyl-α-ethylaminopentiophenone), was deemed plausible after reviewing case information. As many as 501 presumably positive category 2 findings were detected. Using the predicted retention time as an additional criterion the number was significantly reduced but still too high for a manual review. This work has demonstrated that the strategy developed in the previous study can be applied to other NPS groups. However, it is important to note the limitations such a method may have in detecting compounds at very low concentrations. •Using an established strategy to detect NPS retrospectively in post mortem samples.•Integrating the crowdsourced database HighResNPS consisting of HR-MS data of NPS.•Predicted retention times was used in the evaluation of presumable identifications.•4-methyl-α-ethylaminopentiophenone was detected in a reprocessed old sample.

ObjectivesDeclining participation in epidemiological studies has been reported in recent decades and may lead to biased prevalence estimates and selection bias. The aim of the study was to identify possible causes and effects of non-response in a population-based study of respiratory health in Norway.DesignThe Telemark study is a longitudinal study that began with a cross-sectional survey in 2013.SettingIn 2013, a random sample of 50 000 inhabitants aged 16–50 years, living in Telemark county, received a validated postal questionnaire. The response rate was 33%. In this study, a random sample of 700 non-responders was contacted first by telephone and then by mail.Outcome measuresResponse rates, prevalence and OR of asthma and respiratory symptoms based on exposure to vapours, gas, dust or fumes (VGDF) and smoking. Causes of non-response.ResultsA total of 260 non-responders (37%) participated. Non-response was associated with younger age, male sex, living in a rural area and past smoking. The prevalence was similar for responders and non-responders for physician-diagnosed asthma and several respiratory symptoms. The prevalence of chronic cough and use of asthma medication was overestimated in the Telemark study, and adjusted prevalence estimates were 17.4% and 5%, respectively. Current smoking was identified as a risk factor for respiratory symptoms among responders and non-responders, while occupational VGDF exposure was a risk factor only among responders. The Breslow-Day test detected heterogeneity between productive cough and occupational VGDF exposure among responders.ConclusionsThe Telemark study provided valid estimates for physician-diagnosed asthma and several respiratory symptoms, while it was necessary to adjust prevalence estimates for chronic cough and use of asthma medication. Reminder letters had little effect on risk factor associations. Selection bias should be considered in future investigations of the relationship between respiratory outcomes and exposures.