Permeabilised skeletal muscle reveals mitochondrial deficiency in malignant hyperthermia-susceptible individuals

Background: Individuals genetically susceptible to malignant hyperthermia (MH) exhibit hypermetabolic reactions when exposed to volatile anaesthetics. Mitochondrial dysfunction has previously been associated with the MH-susceptible (MHS) phenotype in animal models, but evidence of this in human MH is limited. Methods: We used high resolution respirometry to compare oxygen consumption rates (oxygen flux) between permeabilised human MHS and MH-negative (MHN) skeletal muscle fibres with or without prior exposure to halothane. A substrate-uncoupler-inhibitor titration protocol was used to measure the following components of the electron transport chain under conditions of oxidative phosphorylation (OXPHOS) or after uncoupling the electron transport system (ETS): complex I (CI), complex II (CII), CI+CII and, as a measure of mitochondrial mass, complex IV (CIV). Results: Baseline comparisons without halothane exposure showed significantly increased mitochondrial mass (CIV, P=0.021) but lower flux control ratios in CI+CII(OXPHOS) and CII(ETS) of MHS mitochondria compared with MHN (P=0.033 and 0.005, respectively) showing that human MHS mitochondria have a functional deficiency. Exposure to halothane triggered a hypermetabolic response in MHS mitochondria, significantly increasing mass-specific oxygen flux in CI(OXPHOS), CI+CII(OXPHOS), CI+CII(ETS), and CII(ETS) (P=0.001–0.012), while the rates in MHN samples were unaltered by halothane exposure. Conclusions: We present evidence of mitochondrial dysfunction in human MHS skeletal muscle both at baseline and after halothane exposure

Eosinophil and T Cell Markers Predict Functional Decline in COPD Patients

BACKGROUND. The major marker utilized to monitor COPD patients is forced expiratory volume in one second (FEV1). However, asingle measurement of FEV1 cannot reliably predict subsequent decline. Recent studies indicate that T lymphocytes and eosinophils are important determinants of disease stability in COPD. We therefore measured cytokine levels in the lung lavage fluid and plasma of COPD patients in order to determine if the levels of T cell or eosinophil related cytokines were predictive of the future course of the disease. METHODS. Baseline lung lavage and plasma samples were collected from COPD subjects with moderately severe airway obstruction and emphysematous changes on chest CT. The study participants were former smokers who had not had a disease exacerbation within the past six months or used steroids within the past two months. Those subjects who demonstrated stable disease over the following six months (ΔFEV1 % predicted = 4.7 ± 7.2; N = 34) were retrospectively compared with study participants who experienced a rapid decline in lung function (ΔFEV1 % predicted = -16.0 ± 6.0; N = 16) during the same time period and with normal controls (N = 11). Plasma and lung lavage cytokines were measured from clinical samples using the Luminex multiplex kit which enabled the simultaneous measurement of several T cell and eosinophil related cytokines. RESULTS AND DISCUSSION. Stable COPD participants had significantly higher plasma IL-2 levels compared to participants with rapidly progressive COPD (p = 0.04). In contrast, plasma eotaxin-1 levels were significantly lower in stable COPD subjects compared to normal controls (p < 0.03). In addition, lung lavage eotaxin-1 levels were significantly higher in rapidly progressive COPD participants compared to both normal controls (p < 0.02) and stable COPD participants (p < 0.05). CONCLUSION. These findings indicate that IL-2 and eotaxin-1 levels may be important markers of disease stability in advanced emphysema patients. Prospective studies will need to confirm whether measuring IL-2 or eotaxin-1 can identify patients at risk for rapid disease progression.National Heart, Lung, and Blood Institute (NO1-HR-96140, NO1-HR-96141-001, NO1-HR-96144, NO1-HR-96143; NO1-HR-96145; NO1-HR-96142, R01HL086936-03); The Flight Attendant Medical Research Institute; the Jo-Ann F. LeBuhn Center for Chest Diseas

A note on the boundary contribution with bad deformation in gauge theory

Motivated by recently progresses in the study of BCFW recursion relation with nonzero boundary contributions for theories with scalars and fermions\cite{Bofeng}, in this short note we continue the study of boundary contributions of gauge theory with the bad deformation. Unlike cases with scalars or fermions, it is hard to use Feynman diagrams directly to obtain boundary contributions, thus we propose another method based on the ${\cal N}=4$ SYM theory. Using this method, we are able to write down a useful on-shell recursion relation to calculate boundary contributions from related theories. Our result shows the cut-constructibility of gauge theory even with the bad deformation in some generalized sense.Comment: 16 pages, 7 figure

Impact on genitourinary function and quality of life following focal irreversible electroporation of different prostate segments

© Turkish Society of Radiology 2018. PURPOSE We aimed to evaluate the genitourinary function and quality of life (QoL) following the ablation of different prostate segments with irreversible electroporation (IRE) for localized prostate cancer (PCa). METHODS Sixty patients who received primary focal IRE for organ-confined PCa were recruited for this study. Patients were evaluated for genitourinary function and QoL per prostate segment treated (anterior vs. posterior, apex vs. base vs. apex-to-base, unilateral vs. bilateral). IRE system settings and patient characteristics were compared between patients with preserved vs. those with impaired erectile function and urinary continence. Data were prospectively collected at baseline, 3, 6, and 12 months using the expanded prostate cancer index composite, American Urological Association symptom score, SF-12 physical and mental component summary surveys. Difference over time within segments per questionnaire was evaluated using the Wilcoxon’s signed rank test. Outcome differences between segments were assessed using covariance models. Baseline measurements included questionnaire scores, age, and prostate volume. RESULTS There were no statistically significant changes over time for overall urinary (P = 0.07-0.89), bowel (P = 0.06-0.79), physical (P = 0.18-0.71) and mental (P = 0.45-0.94) QoL scores within each segment. Deterioration of sexual function scores was observed at 6 months within each segment (P = 0.001-0.16). There were no statistically significant differences in QoL scores between prostate segments (P = 0.08-0.97). Older patients or those with poor baseline sexual function at time of treatment were associated with a greater risk of developing erectile dysfunction. CONCLUSION IRE is a feasible modality for all prostate segments without any significantly different effect on the QoL outcomes. Older patients and those with poor sexual function need to be counseled regarding the risk of erectile dysfunction

Quantum field theoretic approach to neutrino oscillations in matter

We consider neutrino oscillations in non-uniform matter in a quantum field theoretic (QFT) approach, in which neutrino production, propagation and detection are considered as a single process. We find the conditions under which the oscillation probability can be sensibly defined and demonstrate how the properly normalized oscillation probability can be obtained in the QFT framework. We derive the evolution equation for the oscillation amplitude and discuss the conditions under which it reduces to the standard Schr\"odinger-like evolution equation. It is shown that, contrary to the common usage, the Schr\"odinger-like evolution equation is not applicable in certain cases, such as oscillations of neutrinos produced in decays of free pions provided that sterile neutrinos with $\Delta m^2\gtrsim 1$ eV$^2$ exist.Comment: LaTeX, 24 pages + 16 pages of appendices, 1 figure. V2: typos correcte

Coupling of alpha(1)-Adrenoceptors to ERK1/2 in the Human Prostate

Introduction: alpha(1)-Adrenoceptors are considered critical for the regulation of prostatic smooth muscle tone. However, previous studies suggested further alpha(1)-adrenoceptor functions besides contraction. Here, we investigated whether alpha(1)-adrenoceptors in the human prostate may activate extracellular signal-regulated kinases (ERK1/2). Methods: Prostate tissues from patients undergoing radical prostatectomy were stimulated in vitro. Activation of ERK1/2 was assessed by Western blot analysis. Expression of ERK1/2 was studied by immunohistochemistry. The effect of ERK1/2 inhibition by U0126 on phenylephrine-induced contraction was studied in organ-bath experiments. Results: Stimulation of human prostate tissue with noradrenaline (30 mu M) or phenylephrine (10 mu M) resulted in ERK activation. This was reflected by increased levels of phosphorylated ERK1/2. Expression of ERK1/2 in the prostate was observed in smooth muscle cells. Incubation of prostate tissue with U0126 (30 mu M) resulted in ERK1/2 inhibition. Dose-dependent phenylephrine-induced contraction of prostate tissue was not modulated by U0126. Conclusions: alpha(1)-Adrenoceptors in the human prostate are coupled to ERK1/2. This may partially explain previous observations suggesting a role of alpha(1)-adrenoceptors in the regulation of prostate growth. Copyright (C) 2011 S. Karger AG, Base

The SABRTooth feasibility trial protocol: a study to determine the feasibility and acceptability of conducting a phase III randomised controlled trial comparing stereotactic ablative radiotherapy (SABR) with surgery in patients with peripheral stage I non-small cell lung cancer (NSCLC) considered to be at higher risk of complications from surgical resection.

Background Stage I non-small cell lung cancer (NSCLC) is potentially curable, and surgery is considered to be the standard of care for patients with good performance status and minimal co-morbidity. However, a significant proportion of patients with stage I NSCLC have a poorer performance status and significant medical co-morbidity that make them at higher risk of morbidity and mortality from surgery. Stereotactic ablative radiotherapy (SABR), which uses modern radiotherapeutic techniques to deliver large doses of radiation, has shown superiority over conventional radiotherapy in terms of local control and toxicity and is a standard of care for patients with stage I NSCLC who are at too high risk for surgery. However, it is not known whether surgery or SABR is the most effective in patients with stage I NSCLC who are suitable for surgery but are less fit and at higher risk surgical complications. Previous randomised studies have failed to recruit in this setting, and therefore, a feasibility study is required to see whether a full randomised control trial would be possible. Methods/design SABRTooth is a UK-based, multi-centre, open-label, two-group individually (1:1) randomised controlled feasibility study in patients with peripheral stage I NSCLC considered to be at higher risk from surgical resection. The study will assess the feasibility of conducting a definitive large-scale phase III trial. The primary objective is to assess recruitment rates to provide evidence that, when scaled up, recruitment to a large phase III trial would be possible; the target recruitment being 54 patients in total, over a 21-month period. There are multiple secondary and exploratory objectives designed to explore the optimum recruitment and data collection strategies to help optimise the design of a future phase III trial. Discussion To know whether SABR is a better, equivalent or inferior alternative to surgery for higher risk patients is a key question in lung cancer. Other studies comparing SABR to surgery have closed early due to poor recruitment, and therefore, the SABRTooth feasibility study has been designed around the UK National Health Service (NHS) cancer pathway incorporating many design features in order to maximise recruitment for a future definitive phase III trial

Melting of a 2D Quantum Electron Solid in High Magnetic Field

The melting temperature ($T_m$) of a solid is generally determined by the pressure applied to it, or indirectly by its density ($n$) through the equation of state. This remains true even for helium solids\cite{wilk:67}, where quantum effects often lead to unusual properties\cite{ekim:04}. In this letter we present experimental evidence to show that for a two dimensional (2D) solid formed by electrons in a semiconductor sample under a strong perpendicular magnetic field\cite{shay:97} ($B$), the $T_m$ is not controlled by $n$, but effectively by the \textit{quantum correlation} between the electrons through the Landau level filling factor $\nu$=$nh/eB$. Such melting behavior, different from that of all other known solids (including a classical 2D electron solid at zero magnetic field\cite{grim:79}), attests to the quantum nature of the magnetic field induced electron solid. Moreover, we found the $T_m$ to increase with the strength of the sample-dependent disorder that pins the electron solid.Comment: Some typos corrected and 2 references added. Final version with minor editoriol revisions published in Nature Physic

Decreased wheel-running activity in hamsters post myocardial infarction

Reduced exercise capacity is a key symptom and an independent determinant of mortality in patients with heart failure. We analyzed the running activity of hamsters with cardiac dysfunction after myocardial infarction. In 39 male Syrian hamsters aged 10 to 12 weeks, a myocardial infarction (MI) was produced by permanent ligation of the left coronary artery. Spontaneous running activity in a wheel was monitored daily. After four weeks, left ventricular (LV) hemodynamics (catheter tip manometry) were measured at baseline and during inotropic stimulation (isoprenaline 0.03, 0.1 and 0.3 μg/kg/min i.v.). LV infarct size was quantified using planimetry. Four weeks post MI, daily running distance was reduced stepwise in animals with small (4–15 % of LV: 9.8 ± 3.4 km/d) and large (> 15 % of LV: 7.5 ± 3.5 km/d) MI, compared to sham-operated hamsters (11.5 ± 1.5 km/d). Similar reductions were observed in maximum speed and distance of longest running period. MI size influenced daily running distance, maximum speed, and longest running period (linear correlations, all p < 0.05). MI size also impaired LV systolic and diastolic function under isoprenaline stimulation. The results suggest that myocardial infarction reduces running capacity and isoprenaline stimulated LV function in hamsters, mimicking impaired exercise performance in patients with heart failure. Analysis of running activity in hamsters with myocardial infarction offers a unique opportunity for non-invasive and serial functional assessment of heart failure in the experimental setting

An early warning method for agricultural products price spike based on artificial neural networks prediction

In general, the agricultural producing sector is affected by the diversity in supply, mostly from small companies, in addition to the rigidity of the demand, the territorial dispersion, the seasonality or the generation of employment related to the rural environment. These characteristics differentiate the agricultural sector from other economic sectors. On the other hand, the volatility of prices payed by producers, the high cost of raw materials, and the instability of both domestic and international markets are factors which have eroded the competitiveness and profitability of the agricultural sector. Because of the advance in technology, applications have been developed based on Artificial Neural Networks (ANN) which have helped the development of sales forecast on consumer products, improving the accuracy of traditional forecasting systems. This research uses the RNA to develop an early warning system for facing the increase in agricultural products, considering macro and micro economic variables and factors related to the seasons of the year