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Introduction and Aim: Laparoscopic sleeve gastrectomy (LSG) considered the gold standard for management of morbid obesity, but, it has serious complications. Laparoscopic greater curvature plication (LGCP) is a restrictive procedure to lower the complications of LSG with the advantage of being a reversible procedure. The current work was designed to compare between Laparoscopic sleeve gastrectomy and greater curve plication in management of morbid obese patients with hiatus hernia. Methodology: This study included 40 morbidly obese patients with hiatal hernia, who underwent laparoscopic Nissen Fundoplication with Greater Curvature Plication (Group A) or Laparoscopic Crural Repair with Sleeve Gastrectomy (Group B). Results: Vomiting was the most common postoperative complaint. Two out of 20 patients (10%) In cases of LGCP developed prolonged nausea, vomiting and sialorrhea for 5 and 7 days but subsided subsequently with antiemetics, proton pump inhibitors, and prokinetics. Intraoperative hemorrhage in two cases of LGCP, Two out of 20 patients (10%) In cases of LGCP developed prolonged nausea, vomiting and sialorrhea for 5 and 7 days but subsided subsequently with antiemetics, proton pump inhibitors, and prokinetics. Four patients of 20 patients (20%) In cases of LGCP developed weight regain and sleeve gastrectomy revision was obtained by performing re-laparoscopy. Conclusion: LSG is a better procedure than LGCP as the most important disadvantage of Laparoscopic gastric plication are that it causes a high rate of recurrence and occurrence of early postoperative complaints.

Reaction of 4,6-dimethyl-3-cyanopyridine-2(1H)-thione (IIIa) or 4,5,6-trisubstituted-3-cyanopyridine-2(1H)-thiones (IIIb–d) with 2-chloromethylquinazoline-4(3H)-one (IVa) furnished the corresponding 3-amino-2-(4-oxo-3,4-dihydroquinazolin-2-yl)thieno[2,3-b]pyridines (VIa–d). Reaction of aminothieno-pyridines (VIa, b, d) were reacted with triethyl orthoformate, acetic anhydride or nitrous acid to furnish pyridothienopyrimidoquinazolines (VIIIa, b, d), (IXa, b, d) or pyridothienotriazinoquinazolines (Xa, b, d). The new compound, 3-cyano-5-acetyl-6-methyl-4-styrylpyridine-2(1H)-thione (IIIe) was synthesized and reacted with 2-chloromethyl-1H-benzimadazole to give 5-acetyl-3-amino-2-(1H-benzimidazol-2-yl)-6-methyl-4-styryl-thieno[2,3-b]pyridine (XII) which was used as a key intermediate for synthesizing pyridothienopyrimidobenzimidazoles (XIII, XIV). All newly synthesized compounds were characterized on the basis of their elemental and spectral analyses. Also, most of the synthesized compounds were screened in vitro for their antifungal activity.

The present study examined the effects of maternal perinatal dietary ALA enrichment on the high fat diet (HFD)-induced lipid disarray in the adult offspring of low density lipoprotein receptor knock-out (LDLRKO) mice. Female LDLRKO mice received, during pregnancy and lactation, isocaloric diets with either corn oil, RD, or flax oil, ALA. The weaning offspring was given a regular chow diet for a washout period of eight weeks, which was followed by HFD for eight weeks. Plasma and liver lipids and SCD1 activity were then analyzed. The HFD-fed RD adult offspring had substantially higher plasma cholesterol levels than the HFD-fed ALA offspring (15.7 versus 9.7 mmole/l, p0.00001) and non-alcoholic fatty liver disease (NAFLD) (65.0 versus 23.9 mg/g lipids, p0.00001). Liver lipids oleic acid (OA) content and monounsaturated to saturated fatty acids (MUFA/SAT) ratio, were two times lower in RD compared to ALA (p0.0001). The threefold HFD-induced SCD1 raised activity (p0.00001), and OA produced from SA, observed in RD adult offspring were prevented by perinatal ALA. In conclusion, the resilience of SCD1 to HFD- induced increased activity may account for the beneficial effects of perinatal ALA dietary enrichment in preventing NAFLD and hypercholesterolemia from occurring in adult LDLRKO offspring mice.

IR-792 as near IR (NIR) laser dye was dissolved with different concentrations in two types of ionic liquids (ILs) of different anion and cation, 1-Ethyl-3-methylimidazolium bis(trifluoromethylsulfonyl) imide (EMIM TFSI) & 1-Butyl-3-methylimidazolium tetrafluoroborate (BMIM BF4), as the benign green solvent and in methanol (MeOH) as a standard solvent. The behavior of fluorescence of IR-792 dye was studied. The fluorescence of IR-792 dissolved in the ILs was heavily compared to organic solvent. Some photo-physical parameters of IR-792 were calculated. Mainly, IR-792 had a very low quantum yield of fluorescence with high intersystem crossing rate & fluorescence lifetime in picosecond range. Optical absorption and behavior of fluorescence for the rigorously the purified imidazolium ILs in the neat condition and effect of IR-792 on their fluorescence have been examined. The emission behavior of IR-792 in green solvents was independent upon the wavelength of excitation, while the emission behavior of green solvents dependent upon the wavelength of excitation whether in pure state or with NIR laser dye. At most, the intensity of fluorescence of ILs is dependent upon dye concentration.

Diffuse reflection of laser radiation by a biological tissue always gives rise to the formation of a biospeckle pattern. The biospeckle pattern depends on the surface irregularities and carries significant information about the surface roughness. Biospeckle imaging has been extensively applied to medicine, biology and agriculture for evaluating different types of biological tissues, since it is safe, simple and non-destructive optical method. In consequence of the texture properties of biospeckle pattern, various texture analysis methods have been presented in literature for extracting the information involved in biospeckle patterns. In this work, first, an experimental setup to simultaneously capture multiple biospeckle patterns from many cross-section areas of bovine articular cartilage tissue surface is investigated. Next, a new model based on local contrast measurement is proposed on the captured biospeckle patterns for final and proper estimation of the average roughness of the various cross-section areas of articular cartilage surface. The proposed model computes the local contrast for pairs of pixels at different neighborhood separation distances in order to obtain three contrast features. The obtained results showed that the contrast features can efficiently differentiate between the average roughness of the different cross-section areas of articular cartilage surface with 0.02 μm accuracy.

The kinetics and efficiency of mitochondrial oxidative phosphorylation (OxPhos) can depend on the choice of respiratory substrates. Furthermore, potential differences in this substrate dependency among different tissues are not well-understood. Here, we determined the effects of different substrates on the kinetics and efficiency of OxPhos in isolated mitochondria from the heart and kidney cortex and outer medulla (OM) of Sprague-Dawley rats. The substrates were pyruvate+malate, glutamate+malate, palmitoyl-carnitine+malate, alpha-ketoglutarate+malate, and succinate±rotenone at saturating concentrations. The kinetics of OxPhos were interrogated by measuring mitochondrial bioenergetics under different ADP perturbations. Results show that the kinetics and efficiency of OxPhos are highly dependent on the substrates used, and this dependency is distinctly different between heart and kidney. Heart mitochondria showed higher respiratory rates and OxPhos efficiencies for all substrates in comparison to kidney mitochondria. Cortex mitochondria respiratory rates were higher than OM mitochondria, but OM mitochondria OxPhos efficiencies were higher than cortex mitochondria. State 3 respiration was low in heart mitochondria with succinate but increased significantly in the presence of rotenone, unlike kidney mitochondria. Similar differences were observed in mitochondrial membrane potential. Differences in H(2)O(2) emission in the presence of succinate±rotenone were observed in heart mitochondria and to a lesser extent in OM mitochondria, but not in cortex mitochondria. Bioenergetics and H(2)O(2) emission data with succinate±rotenone indicate that oxaloacetate accumulation and reverse electron transfer may play a more prominent regulatory role in heart mitochondria than kidney mitochondria. These studies provide novel quantitative data demonstrating that the choice of respiratory substrates affects mitochondrial responses in a tissue-specific manner.

Hypertension is a complex disease and a leading cause of morbidity and mortality globally. Although oxidative stress and mitochondrial dysfunction have been found in the kidney in various models of hypertension, progressive alteration of mitochondrial oxidative phosphorylation (OxPhos) in the kidney during the development of salt-sensitive hypertension has not been characterized. The present study determined changes of OxPhos in kidneys of Dahl salt-sensitive (SS) rats before (0.4% NaCl diet; LS) and after switching to a high salt diet (4.0% NaCl; HS) during the development of hypertension. Mitochondria were isolated from the outer medulla (OM) and cortex of the kidney of SS rats fed a LS diet since weaning and studied at days 3, 7, 14 & 21 of a HS diet feeding. Oxygen consumption rates (OCR) were measured in mitochondria energized with pyruvate + malate as substrates for three different respiratory states using an Oroboros Oxygraph-2k Instrument. This includes i) leak state (in the absence of ADP), ii) ADP-stimulated state, and iii) uncoupled state (in the presence of an uncoupler FCCP). A biphasic pattern of ADP-stimulated OCR with progressive uncoupling was observed in both the renal OM and cortex. Mitochondrial efficiency for ATP synthesis was increased in the early phases of hypertension (3 & 7 days) but was severely compromised in the established phases of hypertension (14 & 21 days). This decreased mitochondrial efficiency was associated with uncoupling of OxPhos and high levels of oxidative stress which we hypothesized were due to mitochondrial ROS stimulation of membrane NOXs. To test this, experiments were performed in SS rats with double knock out (DKO) of the cytosolic subunit of NOX2 (p67 phox ) and NOX4 (SS p67phox-/-/Nox4-/- ). DKO SS rats were fed a HS diet and OCR of renal cortical and OM mitochondria was determined at days 7 and 14. In contrast to SS rats, the DKO SS rats fed a HS diet showed no significant differences in mitochondrial OCR in the cortex or OM, nor to a control group maintained on a LS diet. HS diet in SS rats initially increases the efficiency of renal cortical and medullary mitochondrial ATP production (days 1-7) followed by an enhanced ROS production with mitochondrial uncoupling and reduced efficiency of ATP production by the third week.

Novel 7,7'-((anthracene-9,10-diylbis(methylene))bis(oxy))bis(4-methyl-2H-chromen-2-one) (BisCA) was prepared as fluorescent probe. The chemical structure of the novel BisCA was confirmed by spectroscopic data as well as elemental analyses. The solvatochromic characteristics of the new proble and its precursors were investigated in different solvents including, ethanol, DMF and toluene as protic polar, aprotic polar and non-polar solvents, respectively. Photo-physical parameters of probes, such as fluorescence quantum yields, fluorescence lifetime of excited state, radiative and non-radiative decay, were assessed in different media. The intermolecular H-bond effect on absorption and excitation spectra of the novel probe was reported in different solvents. Also, Onsager cavity radius and dipole moment of ground state and excited state of the probe were calculated as described by Bakhshiev and Reichardt methods.

Tomato is also known as the poor man’s apple in Nepal. China is the largest producer of tomato in the world. Tomato is grown throughout the year in recent years in Nepal with the introduction of plastic house for off season production. Secondary information is used to assess the consumption pattern and national demand of tomato in 2015/16 for Nepal. The result showed the import from India is increasing compared to previous years. The reason behind this might be increase in consumption of tomato in recent years in Nepal. The central development region is the highest consumer of tomato compared to other regions of the country. The average national consumption of tomato was found 11.97Kg/person/year in Nepal.

South Asia is world most densely populated region and houses the largest population of undernourished people. It remains the world’s second poorest region with more than 500 million people living on less than US$1.25 per day. Firstly this paper attempts to show the general situation and production trend of paddy, secondly, scrutinizes the role paddy has been playing in the economy and food security so far and that it is still the most potential means to improve the food security situation and tackle severe under-nutrition as other sectors are, until now, far less furnished to address this issue. This paper probes into various economic and historical perspectives of rice economy and culture in this region, and shows that self-sufficiency in paddy production is paramount to its domestic food security, and thereby proposes that emphasis should be given on increased rice production which is decelerating amid expansion of modern economic sectors.

The optical properties of a visible absorption range6-Substituted-1, 2, 4-Triazine mono glucosyl fluorescent derivative dye, such as absorption spectra, emission spectra in different solvents, were experimentally investigated. As well, some important photo physical parameters such as extinction coefficient (e), cross-sections of the absorption (σa) and the emission (σe), quantum yield (фf), fluorescence lifetime, oscillator strength (f), the dipole moment (μ), decay rate radiative constant (kr), energy yield of fluorescence (Ef) and the length of attenuation Λ (λ) were assessed. The ground-state (μg) and excited-state (μe) dipole moments by solvatochromic correlations method were reported. The dye amplified spontaneous emission (ASE) of 2 × 10−4M with different input pumping energies of a continuous wave blue diode laser (λ = 450 nm) was studied. Photostability of dye was observed that was decreased to 53% of its initial energy by pumping with 100 mW of diode laser after exposure to 120 min.

Diet is a daily activity that has a dramatic impact on health. There is much confusion in society, including among medical professionals, about what constitutes a healthy diet. Many reviews focus on one aspect of healthy dietary practices, but few synthesize this data to form more comprehensive recommendations. This article will critically review and holistically synthesize the data on diet with firm morbidity and mortality endpoints derived from three key, high quality studies, which are further supported with several additional articles. Specific recommendations of types and quantities of food to reduce the risk of heart disease and stroke will be provided. The effect of these diets on cancer and mood disorders as covered in the articles reviewed will also be discussed.

A concise one-step procedure was developed for the synthesis of some newer tetrahydro-4H-benzo[1,3-e]oxazines and β-acylamino ketone derivatives via condensation of cyclohexanone derivative with different aromatic aldehydes and nitriles in the presence of tetrachlorosilane/zinc chloride (TCS/ZnCl2) reagent mixture under ambient conditions. Docking studies for the synthesized benzo-oxazine derivatives were designed and a model of highly active derivatives was mapped for the antimicrobial screening.

The objective of the study was to evaluate the prognostic value of regional cerebral blood flow (CBF) measured by arterial spin labeled (ASL) perfusion MRI in patients with semantic variant primary progressive aphasia (svPPA). We acquired pseudo-continuous ASL (pCASL) MRI and whole-brain T1-weighted structural MRI in svPPA patients (N = 13) with cerebrospinal fluid biomarkers consistent with frontotemporal lobar degeneration pathology. Follow-up T1-weighted MRI was available in a subset of patients (N = 8). We performed whole-brain comparisons of partial volume-corrected CBF and cortical thickness between svPPA and controls, and compared baseline and follow-up cortical thickness in regions of significant hypoperfusion and hyperperfusion. Patients with svPPA showed partial volume-corrected hypoperfusion relative to controls in left temporal lobe and insula. svPPA patients also had typical cortical thinning in anterior temporal, insula, and inferior frontal regions at baseline. Volume-corrected hypoperfusion was seen in areas of significant cortical thinning such as the left temporal lobe and insula. Additional regions of hypoperfusion corresponded to areas without cortical thinning. We also observed regions of hyperperfusion, some associated with cortical thinning and others without cortical thinning, including right superior temporal, inferior parietal, and orbitofrontal cortices. Regions of hypoperfusion and hyperperfusion near cortical thinning at baseline had significant longitudinal thinning between baseline and follow-up scans, but perfusion changes in distant areas did not show progressive thinning. Our findings suggest ASL MRI may be sensitive to functional changes not readily apparent in structural MRI, and specific changes in perfusion may be prognostic markers of disease progression in a manner consistent with cell-to-cell spreading pathology.

International audience; Purpose Since 2011, significant progress was observed in metastatic melanoma (MM), with the commercialisation of seven immunotherapies or targeted therapies, which showed significant improvement in survival. In France, in 2004, the cost of MM was estimated at €1634 per patient; this cost has not been re-estimated since. This study provided an update on survival and cost in real-life clinical practice. Methods Clinical and economic data (treatments, hospitalisations, radiotherapy sessions, visits, imaging and biological exams) were extracted from the prospective MelBase cohort, collecting individual data in 955 patients in 26 hospitals, from diagnosis of metastatic disease until death. Survival was estimated by the Kaplan-Meier method. Costs were calculated from the health insurance perspective using French tariffs. For live patients, survival and costs were extrapolated using a multistate model, describing the 5-year course of the disease according to patient prognostic factors and number of treatment lines. Results Since the availability of new drugs, the mean survival time of MM patients has increased to 23.6 months (95%confidence interval [CI] :21.2;26.6), with 58% of patients receiving a second line of treatment. Mean management costs increased to €269,682 (95%CI:244,196;304,916) per patient. Drugs accounted for 80% of the total cost. Conclusion This study is the first that evaluated the impact of immunotherapies and targeted therapies both on survival and cost in real-life conditions. Alongside the introduction of breakthrough therapies in the first and subsequent lines, MM has been associated with a significant increase in survival but also in costs, raising the question of financial sustainability.

Introduction Depuis 2011, sept nouveaux medicaments ont ete approuves pour le traitement du melanome metastatique (MM), augmentant significativement la survie des patients et le cout de prise en charge en 1re ligne de traitement. Avec 52 % des patients atteignant aujourd’hui une deuxieme ligne de traitement, la sequence optimale de traitement chez les patients atteints de MM BRAF mute n’est pas encore bien definie. Afin d’informer les decideurs publics sur l’efficience de ces sequences, nous avons realise une analyse cout-efficacite comparant les sequences de traitement pour le MM BRAF mute en vie reelle, en France. Materiel et methodes Lors de l’evaluation de l’efficience la totalite des traitements disponibles doivent etre inclus dans l’analyse, ainsi cinq sequences ont ete comparees : anti-PD1- bitherapies ciblees (BI-TC), BI-TC-Anti-PD1, ipilimumab+ nivolumab-BI-TC, monotherapies ciblees (MONO-TC)-BI-TC et MONO-TC-anti-PD1. Les donnees cliniques (efficacite et utilite) et economiques ont ete extraites de la cohorte prospective MelBase, recueillant des donnees individuelles de 1 435 patients atteints de MM issus de 26 hopitaux francais, du diagnostic jusqu’au deces. Afin de rendre les patients, traites par differentes sequences, comparables il est necessaire de s’affranchir du biais de confusion et ainsi de pouvoir estimer l’effet traitement, pour cela il a ete utilise la ponderation inverse sur le score de propension (IPTW). La survie a ete estimee par la methode de Kaplan-Meier. Les couts ont ete calcules du point de vue de l’assurance maladie sur la base des tarifs francais. La survie et les couts ont ete extrapoles en utilisant un modele multi-etats, decrivant l’evolution de la maladie chez les patients sur un horizon temporel de 10 ans. Resultats Parmi les 1 435 patients, l’efficacite a ete evaluee sur les 608 patients BRAF mutes inclus entre 2013 et 2019. Par rapport a la sequence MONO-TC-Anti-PD1 (la moins chere), trois sequences (BI-TC-Anti-PD1, ipilimumab + nivolumab-BI-TC, MONO-TC-BI-TC) ont ete exclues de la frontiere d’efficience car elles etaient plus cheres et moins efficaces. Il reste la sequence Anti-PD1-Bi-TC, qui a ete associee a des couts supplementaires de 66 343€ et 0,7 annee de vie ponderee par la qualite de vie (QALYs), soit un ratio differentiel cout resultat de 94 776€/QALY. Au regard de la courbe d’acceptabilite, a un seuil de 150 000€, la sequence Mono-TC-Anti-PD1 a pres de 100 % de chance d’etre efficiente, a 300,000€ la sequence Anti-PD1-Bi-TC a 60 % de chance d’etre efficiente. Conclusion Pour les patients presentant un MM BRAF mute, les sequences Anti-PD1-BI-TC et MONO-TC-Anti-PD1 semblent etre les plus efficientes, en France, a partir des donnees observationnelles de la cohorte MelBase.

Introduction Reflection is a special type of reentry in which an electrical wave front travels in a forward direction through tissue that is then re-excited by a wave front that propagates backward. This type of reentry has been studied computationally in 1-dimensional fibers and verified experimentally. Different hypotheses explaining reflected reentry have been proposed based on the structure and heterogeneity of the tissue properties, but the mechanism remains uncertain. Methods and results We used the bidomain model to represent cardiac tissue and the Luo-Rudy model to describe the active membrane properties. We consider an ischemic region in a volume of ventricular myocardium. Our results show that a slow depolarization in the ischemic border zone caused by electrotonic coupling to depolarized tissue in the normal region creates a delay between proximal and distal regions that produces enough electrotonic current in the distal region to re-excite the proximal region. Conclusion Our simulation shows that an early afterdepolarization (EAD) is not the source of the reflection. It depends on the pacing interval and stimulus strength necessary to maintain enough time delay between proximal and distal regions.

Psychometric tests predict conversion of mild cognitive impairment (MCI) to probable Alzheimer's disease (AD). Because the definition of clinical AD relies on those same psychometric tests, the ability of these tests to identify underlying AD pathology remains unclear.To determine the degree to which psychometric testing predicts molecular evidence of AD amyloid pathology, as indicated by cerebrospinal fluid (CSF) amyloid-β (Aβ)1 - 42, in patients with MCI, as compared to neuroimaging biomarkers.We identified 408 MCI subjects with CSF Aβ levels, psychometric test data, FDG-PET scans, and acceptable volumetric MR scans from the Alzheimer's Disease Neuroimaging Initiative (ADNI). We used psychometric tests and imaging biomarkers in univariate and multivariate models to predict Aβ status.The 30-min delayed recall score of the Rey Auditory Verbal Learning Test was the best predictor of Aβ status among the psychometric tests, achieving an AUC of 0.67 ± 0.02 and odds ratio of 2.5 ± 0.4. FDG-PET was the best imaging-based biomarker (AUC 0.67 ± 0.03, OR 3.2 ± 1.2), followed by hippocampal volume (AUC 0.64 ± 0.02, OR 2.4 ± 0.3). A multivariate analysis based on the psychometric tests improved on the univariate predictors, achieving an AUC of 0.68 ± 0.03 (OR 3.38 ± 1.2). Adding imaging biomarkers to the multivariate analysis did not improve the AUC.Psychometric tests perform as well as imaging biomarkers to predict presence of molecular markers of AD pathology in MCI patients and should be considered in the determination of the likelihood that MCI is due to AD.

Cytotoxicity, radiosensitivity, and hyperthermia sensitivity of hyaluronan-mediated dextran-coated super paramagnetic iron oxide nanoparticles (HA-DESPIONs) were assessed in CD44-expressing head and neck squamous cell carcinoma (HNSCC) cell lines at clinically relevant radiation dose and temperatures. Low-passage HNSCC cells were exposed to HA-DESPIONs and cytotoxicity was assessed using MTT assay. Radiosensitizing properties of graded doses of HA-DESPIONs were assessed in both unsorted and CD44-sorted cells using clonogenic assay in combination with 2 Gy exposure to X-rays. Hyperthermia-induced toxicity was measured at 40°C, 41°C, and 42°C using clonogenic assay. Cell death was assessed 24 hours after treatment using a flow cytometry-based apoptosis analysis. Results showed that HA-DESPIONs were nontoxic at moderate concentrations and did not directly radiosensitize the cell lines. Further, there was no significant difference in the radiosensitivity ofCD44highandCD44lowcells. However, HA-DESPIONs enhanced the effect of hyperthermia which resulted in reduced cell survival that appeared to be mediated through apoptosis. We demonstrated that HA-DESPIONs are nontoxic and although they do not enhance radiation sensitivity, they did increase the effect of local hyperthermia. These results support further development of drug-attached HA-DESPIONs in combination with radiation for targeting cancer stem cells (CSCs) and the development of an alternating magnetic field approach to activate the HA-DESPIONs attached to CSCs.

Calcium ion concentration modulates the function of pyruvate dehydrogenase, isocitrate dehydrogenase, and α-ketoglutarate dehydrogenase. Previous studies have shown that despite its ability to affect the function of these dehydrogenases, [Ca2+] does not substantially alter mitochondrial ATP synthesis in vitro under physiological sub-strate conditions. We hypothesize that, rather than contributing to respiratory control, [Ca2+] governs fuel selection. Specifically, cardiac mitochondria are able to use different primary carbon substrates to synthesize ATP aerobically. To determine if and how [Ca2+] affects the relative use of carbohydrates versus fatty acids we measured oxygen consumption and tricarboxylic acid cycle intermediate concentrations in suspensions of cardiac mitochondria with different combinations of pyruvate and palmitoyl-L-carnitine in the media at various [Ca2+] and ADP infusion rates. Results reveal that when both fatty acid and carbohydrate substrates are available, fuel selection is sensitive to both calcium and ATP synthesis rate. When no Ca2+is added under low ATP-demand conditions, β-oxidation provides roughly half of acetyl-CoA for the citrate synthase reaction with the rest coming from the pyruvate dehydrogenase reaction. Under low demand conditions with increasing [Ca2+], the fuel utilization ratio shifts to increased fractional consumption of pyruvate, with 83±10% of acetyl-CoA derived from pyruvate at the highest [Ca2+] evaluated. With high ATP demand, the majority of acetyl-CoA is derived from pyruvate, regardless of the Ca2+level. Our results suggest that changes in work rate alone are enough to effect a switch to carbohydrate use while in vivo the rate at which this switch happens may depend on mitochondrial calcium.Key PointsDespite its effects on activity of mitochondrial dehydrogenases, Ca2+does not substantially alter mitochondrial ATP synthesis in vitro under physiological substrate conditions. Nor does is appear to play an important role in respiratory control in vivo in the myocardium.We hypothesize that Ca2+plays a role mediating the switch in fuel selection to increasing carbohydrate oxidation and decreasing fatty acid oxidation with increasing work rate.To determine if and how Ca2+affects the relative use of carbohydrates versus fatty acids in vitro we measured oxygen consumption and TCA cycle intermediate concentrations in suspensions of purified rat ventricular mitochondria with carbohydrate, fatty acid, and mixed substrates at various [Ca2+] and ATP demand rates.Our results suggest that changes in work rate alone are enough to effect a switch to carbohydrate use in vitro while in vivo the rate at which this switch happens may depend on mitochondrial calcium.

The application of He-Ne laser technologies for description of articular cartilage degeneration, one of the most common diseases worldwide, is an innovative usage of these technologies used primarily in material engineering. Plain radiography and magnetic resonance imaging are insufficient to allow the early assessment of the disease. As surface roughness of articular cartilage is an important indicator of articular cartilage degeneration progress, a safe and noncontact technique based on laser speckle image to estimate the surface roughness is provided. This speckle image from the articular cartilage surface, when illuminated by laser beam, gives very important information about the physical properties of the surface. An experimental setup using a low power He-Ne laser and a high-resolution digital camera was implemented to obtain speckle images of ten bovine articular cartilage specimens prepared for different average roughness values. Texture analysis method based on gray-level co-occurrence matrix (GLCM) analyzed on the captured speckle images is used to characterize the surface roughness of the specimens depending on the computation of Haralick's texture features. In conclusion, this promising method can accurately estimate the surface roughness of articular cartilage even for early signs of degeneration. The method is effective for estimation of average surface roughness values ranging from 0.09 µm to 2.51 µm with an accuracy of 0.03 µm.

Segmenting and quantifying gliomas from MRI is an important task for diagnosis, planning intervention, and for tracking tumor changes over time. However, this task is complicated by the lack of prior knowledge concerning tumor location, spatial extent, shape, possible displacement of normal tissue, and intensity signature. To accommodate such complications, we introduce a framework for supervised segmentation based on multiple modality intensity, geometry, and asymmetry feature sets. These features drive a supervised whole-brain and tumor segmentation approach based on random forest-derived probabilities. The asymmetry-related features (based on optimal symmetric multimodal templates) demonstrate excellent discriminative properties within this framework. We also gain performance by generating probability maps from random forest models and using these maps for a refining Markov random field regularized probabilistic segmentation. This strategy allows us to interface the supervised learning capabilities of the random forest model with regularized probabilistic segmentation using the recently developed ANTsR package--a comprehensive statistical and visualization interface between the popular Advanced Normalization Tools (ANTs) and the R statistical project. The reported algorithmic framework was the top-performing entry in the MICCAI 2013 Multimodal Brain Tumor Segmentation challenge. The challenge data were widely varying consisting of both high-grade and low-grade glioma tumor four-modality MRI from five different institutions. Average Dice overlap measures for the final algorithmic assessment were 0.87, 0.78, and 0.74 for "complete", "core", and "enhanced" tumor components, respectively.

In this work, the thermal characterization of continuously pumped passively Q-switched laser is quantitatively represented. The system under investigation is end-pumped Yb:YAG passively Q-switched by Cr4+:YAG as saturable absorber. The rate equations describing the dynamics of laser action are numerically solved simultaneously with the temperature conductivity heat equation to depict the transient temperature distribution. The study has been performed in the cylindrical coordinates to characterize the temperature distribution in the axial and radial directions. The thermal transient time in both directions as well as the thermal focal length are calculated. The temporal behavior of the temperature distribution has been illustrated in a 3-dimensional diagram.

BACKGROUND The strength-interval (SI) curve is an important measure of refractoriness in cardiac tissue. The anodal SI curve contains a "dip" in which the S2 threshold increases with interval. Two explanations exist for this dip: (1) electrotonic interaction between regions of depolarization and hyperpolarization; and (2) the sodium-calcium exchange (NCX) current. The goal of this study is to use mathematical modeling to determine which explanation is correct. METHODS AND RESULTS The bidomain model represents cardiac tissue and the Luo-Rudy model describes the active membrane. The SI curve is determined by applying a threshold stimulus at different time intervals after a previous action potential. During space-clamped and equal-anisotropy-ratios simulations, anodal excitation does not occur. During unequal-anisotropy-ratios simulations, electrotonic currents, not membrane currents, are present during the few milliseconds before excitation. The dip disappears with no NCX current, but is present with 50% or 75% reduction of it. The calcium-induced-calcium-release (CICR) current has little effect on the dip. CONCLUSIONS These results indicate that neither the NCX nor the CICR current is responsible for the dip in the anodal SI curve. It is caused by the electrotonic interaction between regions of depolarization and hyperpolarization following the S2 stimulus.

Introduction La prise en charge du melanome metastatique (MM) a connu d’importantes avancees, marquee par l’arrivee de 7 therapies ciblees et immunotherapies entre 2011 et 2016. Compte tenu de leur benefice clinique, ces medicaments ont des prix eleves, jusqu’a 1000 fois superieurs aux chimiotherapies, ce qui souleve la question de l’impact budgetaire pour la societe. En France, le cout du MM etait estime a 1653 €/patient en 2004 avant l’arrivee des nouveaux medicaments. En raison des innovations therapeutiques, une reevaluation du cout de prise en charge du MM est necessaire. L’objectif de ce travail etait d’estimer la survie et le cout moyen de la prise en charge d’un patient atteint de MM en pratique courante, depuis l’arrivee des immunotherapies et des therapies ciblees, de leur diagnostic au stade metastatique a 5 ans apres le diagnostic. Patients et methodes Les couts ont ete estimes du point de vue de l’assurance maladie et ont ete calcules a partir des donnees de ressources consommees recueillies prospectivement dans la cohorte MelBase, une cohorte de 955 patients atteints de MM, issus de 26 centres francais. Les ressources consommees incluent les traitements (medicaments et administrations), les hospitalisations, la radiotherapie, les consultations, les examens, depuis le diagnostic du stade metastatique jusqu’au deces ou a la date de derniere nouvelle du patient. La valorisation monetaire a ete realisee en utilisant les tarifs nationaux. La survie a ete evaluee selon la methode de Kaplan-Meier. Pour les patients encore vivants a la date de point, la survie et les couts ont ete extrapoles en utilisant un modele multi-etats, decrivant l’evolution de la maladie des patients pendant 5 ans en fonction de leurs facteurs pronostiques ainsi que leurs lignes de traitements. Resultats Les couts ont ete estimes chez 955 patients inclus entre 2013 et 2016, d’âge moyen 65 ans, dont 59 % d’hommes. Le suivi median est de 11,6 mois et 450 (47 %) patients sont decedes a la date de point (31/07/16). Apres extrapolation, l’esperance de vie attendue des patients est estimee a 23,6 mois [IC 95 % : 21,2 ; 26,6] et 15,5 % [IC 95 % : 12,5 ; 19,0] des patients sont encore vivants a 5 ans. Le cout moyen total de la prise en charge s’eleve a 269 682 € [IC 95 % : 244 196 ; 304 916], dont 80 % lies aux traitements. Conclusion La mise sur le marche des nouveaux medicaments dans le MM s’est accompagnee d’une augmentation significative des couts, en lien avec une survie prolongee. Cette etude est la premiere a evaluer l’impact de l’arrivee des immunotherapies et des therapies ciblee sur la survie et le cout en pratique courante. Avec un cout de prise en charge plus de 100 fois superieur a celui de 2004, se pose la question du financement pour l’assurance maladie.

Introduction La prise en charge du melanome metastatique (MM) a connu de grandes avancees therapeutiques, marquee par l’arrivee de sept therapies ciblees et immunotherapies entre 2011 et 2016. Compte tenu de leur benefice clinique, ces medicaments ont obtenu des prix eleves, jusqu’a 1000 fois superieurs aux chimiotherapies, ce qui souleve la question de leur impact budgetaire. En France, en 2004, le cout du MM etait estime a 1653 €/patient avant l’arrivee des nouveaux medicaments, il a ete reevalue en 2012 a 107 000 €/patient en France apres la disponibilite de l’ipilimumab. En raison des innovations therapeutiques, une reevaluation du cout de prise en charge du MM est essentielle aujourd’hui. L’objectif de notre etude est d’estimer le cout moyen de prise en charge d’un patient atteint de MM en France en 2017, de son diagnostic au stade metastatique a cinq ans. Methodes Les couts ont ete estimes du point de vue de l’Assurance maladie et ont ete calcules a partir des donnees de ressources consommees recueillies prospectivement dans la cohorte MelBase, une cohorte de 955 patients atteints de MM issus de 26 centres francais. Les ressources consommees incluent les traitements, les hospitalisations, la radiotherapie, les consultations, les examens, depuis le diagnostic du stade metastatique jusqu’au deces ou a la date de dernieres nouvelles du patient. La valorisation monetaire a ete realisee en utilisant les tarifs nationaux. Un cout dit « observe » correspondant au cout entre la date d’inclusion du patient jusqu’a sa date de dernier suivi a ete calcule. Si le cout observe est egal au cout total des patients decedes, il sous-estime le cout total des patients encore vivants. Aussi, une extrapolation de la survie et des couts a cinq ans a ete realisee en utilisant un modele multi-etats, decrivant l’evolution de la maladie et la prise en charge du patient selon les lignes de traitements. Le temps passe dans les differents etats depend des facteurs pronostiques du patient et du temps passe dans les etats passes et presents. Le modele a ete realise sous le logiciel R a partir d’une adaptation du tutorial de Williams et al. Le cout total de prise en charge a ete calcule en multipliant le temps passe dans chaque etat (calcule par la methode de l’aire sous courbe) par le cout mensuel moyen de prise en charge des patients dans chaque etat. Les intervalles de confiance ont ete obtenus par bootstrap. Resultats Les couts sont estimes sur 955 patients inclus entre 2013 et 2016, d’âge moyen 65 ans et 59 % sont des hommes. Le suivi median est de 11,6 mois et 450 (47 %) patients sont decedes a la date de point (31/07/16). Apres extrapolation, l’esperance de vie attendue des patients est estimee a 23,6 mois [IC95 % : 21,2 ; 26,6] et 15,5 % [IC95 % : 12,5 % ; 19,0 %] des patients sont encore vivants a cinq ans. Le cout moyen total de la prise en charge s’eleve a 269 682 € [IC95 % : 244 196 ; 304 916], dont 80 % lies aux medicaments. Conclusion La mise sur le marche des nouveaux medicaments dans le MM s’est accompagnee d’une augmentation significative des couts, en lien avec une survie prolongee. Cette etude est la premiere a evaluer le cout selon les lignes de traitement en utilisant un modele multi-etat qui conserve l’information individuelle des patients. Avec un cout de prise en charge plus de 100 fois superieur a celui de 2004, se pose la question de la soutenabilite financiere pour l’Assurance maladie.